Abbreviated New Drug Applications and 505(b)(2) Applications, 69580-69658 [2016-22690]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 81, Number 194 (Thursday, October 6, 2016)]
[Rules and Regulations]
[Pages 69580-69658]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-22690]



[[Page 69579]]

Vol. 81

Thursday,

No. 194

October 6, 2016

Part II





Department of Health and Human Services





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 Food and Drug Administration





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21 CFR Parts 314 and 320





 Abbreviated New Drug Applications and 505(b)(2) Applications; Final 
Rule

Federal Register / Vol. 81 , No. 194 / Thursday, October 6, 2016 / 
Rules and Regulations

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 320

[Docket No. FDA-2011-N-0830]
RIN 0910-AF97


Abbreviated New Drug Applications and 505(b)(2) Applications

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
issuing a final rule to implement Title XI of the Medicare Prescription 
Drug, Improvement, and Modernization Act of 2003 (MMA), which amended 
provisions of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) 
that govern the approval of 505(b)(2) applications and abbreviated new 
drug applications (ANDAs). This final rule implements portions of Title 
XI of the MMA that pertain to provision of notice to each patent owner 
and the new drug application (NDA) holder of certain patent 
certifications made by applicants submitting 505(b)(2) applications or 
ANDAs; the availability of 30-month stays of approval on 505(b)(2) 
applications and ANDAs that are otherwise ready to be approved; 
submission of amendments and supplements to 505(b)(2) applications and 
ANDAs; and the types of bioavailability and bioequivalence data that 
can be used to support these applications. This final rule also amends 
certain regulations regarding 505(b)(2) applications and ANDAs to 
facilitate compliance with and efficient enforcement of the FD&C Act.

DATES: This rule is effective December 5, 2016.

ADDRESSES: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number found in brackets in the heading of this final rule into 
the ``Search'' box and follow the prompts, and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: 
    With regard to the final rule: Janice L. Weiner, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6268, Silver Spring, MD 20993-0002, 301-
796-3601.
    With regard to the information collection: FDA PRA Staff, Office of 
Operations, Food and Drug Administration, Three White Flint North 
10A63, 11601 Landsdown St., North Bethesda, MD 20852, 
PRAStaff@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Executive Summary
    A. Purpose of the Final Rule
    B. Summary of the Major Provisions of the Final Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations and Acronyms Commonly Used in This 
Document
III. Background
    A. History of This Rulemaking
    B. General Overview of the Final Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
    A. Definitions (Sec.  314.3(b))
    B. Submission of Patent Information (Sec.  314.53)
    C. Patent Certification (Sec. Sec.  314.50(i) and 314.94(a)(12))
    D. Notice of Paragraph IV Certification (Sec. Sec.  314.52 and 
314.95)
    E. Amended Patent Certifications (Sec. Sec.  314.50(i)(6) and 
314.94(a)(12)(viii))
    F. Patent Certification Requirements for Amendments and 
Supplements to 505(b)(2) Applications and ANDAs (Sec. Sec.  314.60, 
314.70, 314.96, and 314.97)
    G. Amendments or Supplements to a 505(b)(2) Application for a 
Different Drug and Amendments or Supplements to an ANDA That 
Reference a Different Listed Drug (Sec. Sec.  314.60, 314.70, 
314.96, and 314.97)
    H. Procedure for Submission of a 505(b)(2) Application Requiring 
Investigations for Approval of a New Indication for, or Other Change 
From, a Listed Drug (Sec.  314.54)
    I. Petition to Request a Change From a Listed Drug (Sec.  
314.93)
    J. Filing an NDA and Receiving an ANDA (Sec.  314.101)
    K. Approval of an NDA and ANDA (Sec.  314.105)
    L. Refusal To Approve an NDA or ANDA (Sec. Sec.  314.125 and 
314.127 and Related Provisions in Sec. Sec.  314.90 and 314.99)
    M. Date of Approval of a 505(b)(2) Application or ANDA (Sec.  
314.107)
    N. Assessing Bioavailability and Bioequivalence for Drugs Not 
Intended To Be Absorbed Into the Bloodstream (Sec.  320.23)
    O. Miscellaneous
    P. Technical Amendments
VI. Effective Date
VII. Economic Analysis of Impacts
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. References

I. Executive Summary

I.A. Purpose of the Final Rule

    This rule implements portions of Title XI of the MMA and revises 
and clarifies FDA regulations relating to 505(b)(2) applications and 
ANDAs in a manner intended to reduce unnecessary litigation, reduce 
delays in the approval of 505(b)(2) applications and ANDAs that are 
otherwise ready to be approved, and provide business certainty to both 
brand name and generic drug manufacturers.
    Title XI of the MMA addressed two key concerns identified in a 
Federal Trade Commission (FTC) report on anticompetitive strategies 
that may delay access to generic drugs by: (1) Limiting the 
availability of 30-month stays of approval on 505(b)(2) applications 
and ANDAs that are otherwise ready to be approved and (2) establishing 
conditions under which a first applicant would forfeit the 180-day 
exclusivity period such that approval of subsequent ANDAs would no 
longer be blocked. FDA has been implementing the MMA directly from the 
statute since its enactment. Based on this experience, FDA is amending 
its regulations to implement portions of the MMA that pertain to 30-
month stays and other matters not related to forfeiture of 180-day 
exclusivity.
    FDA is amending its regulations regarding 505(b)(2) applications 
and ANDAs to facilitate compliance with and efficient enforcement of 
the FD&C Act, and to clarify and update these regulations based on 
recent court decisions and our practical experience implementing 
provisions related to the approval of 505(b)(2) applications and ANDAs. 
For example, we are clarifying requirements for the NDA holder's 
description of the specific approved method of use claimed by the 
patent (the ``use code'') required for publication in FDA's ``Approved 
Drug Products With Therapeutic Equivalence Evaluations'' (commonly 
known as the Orange Book) to address overbroad or ambiguous use codes 
that may delay approval of generic drugs. This clarification is 
intended to facilitate FDA's implementation of the statutory provisions 
that permit 505(b)(2) and ANDA applicants to omit (``carve out'') 
protected conditions of use from labeling and obtain approval for 
conditions of use that are not covered by unexpired patents or 
exclusivity. We also are revising the regulations to codify the types 
of court decisions and other actions that will terminate a 30-month 
stay of approval on a 505(b)(2) application or ANDA. Finally, we are 
updating the regulations to codify FDA's current practice and policy 
and thereby promote transparency.

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I.B. Summary of the Major Provisions of the Final Rule

I.B.1. Submission of Patent Information
    The rule revises and streamlines requirements related to submission 
of patent information on: (1) Patents that claim the drug substance 
and/or drug product and meet the requirements for patent listing on 
that basis; (2) drug substance patents that claim only a polymorph of 
the active ingredient; and (3) certain NDA supplements.
    We are codifying our longstanding requirement that the NDA holder's 
description of the patented method of use required for publication in 
the Orange Book must contain adequate information to assist FDA and 
505(b)(2) and ANDA applicants in determining whether a listed method-
of-use patent claims a use for which the 505(b)(2) or ANDA applicant is 
not seeking approval. To address overbroad or ambiguous use codes, we 
are expressly requiring that if the method(s) of use claimed by the 
patent does not cover an indication or other approved condition of use 
in its entirety, the NDA holder's use code must describe only the 
specific approved method of use claimed by the patent for which a claim 
of patent infringement could reasonably be asserted if a person not 
licensed by the patent owner engaged in the manufacture, use, or sale 
of the drug product.
I.B.2. Timing of Submission of Patent Information
    We are expressly describing our current practice with respect to 
listing patent information that has not been submitted to FDA within 30 
days after patent issuance. Although we list untimely filed patents 
pursuant to section 505(c)(2) of the FD&C Act (21 U.S.C. 355(c)(2)), we 
generally do not require an applicant with a pending 505(b)(2) 
application or ANDA to provide a patent certification to the untimely 
filed patent. Thus, the untimely filed patent will neither delay 
approval of a pending 505(b)(2) application or ANDA until patent 
expiration nor necessitate a carve-out of information related to a 
patented method of use.
    We are expanding the category of untimely filed patent information 
to include certain amendments to the NDA holder's description of the 
approved method(s) of use claimed by the patent, if such changes are 
not submitted: (1) Within 30 days of patent issuance; (2) within 30 
days of approval of a corresponding change to product labeling; or (3) 
within 30 days of a decision by the U.S. Patent and Trademark Office 
(USPTO) or a Federal court that is specific to the patent and alters 
the construction of a method-of-use claim(s) of the patent. This 
revision to our regulations is intended to reduce delays in approval 
related to overbroad or ambiguous patent use codes.
    In addition, we are establishing that the submission date of patent 
information provided by an NDA holder after approval will be the 
earlier of the date on which Form FDA 3542 is date-stamped by the 
Central Document Room or officially received by FDA in an electronic 
format. These revisions are intended to facilitate prompt listing in 
the Orange Book and to remove any ambiguity about the date of 
submission in light of the implications of untimely filed patent 
information for the patent certification obligations of 505(b)(2) and 
ANDA applicants that rely upon the listed drug.
I.B.3. Correction or Change of Patent Information
    We are clarifying and improving the procedures that govern 
challenges to the accuracy or relevance of the NDA holder's submission 
of patent information to the Agency. These procedures allow a person 
(including a 505(b)(2) or ANDA applicant) to request, for example, that 
an NDA holder confirm that a previously submitted use code complies 
with current requirements. We are establishing a 30-day timeframe in 
which the NDA holder will be required to substantively respond to the 
patent listing dispute and verify the accuracy and completeness of the 
response. We intend to take an incremental approach and evaluate 
whether FDA's revisions to the regulations on submission of method-of-
use patent information and patent listing dispute procedures adequately 
address the problem of overbroad and ambiguous use codes before we 
determine whether a process to review a proposed labeling carve-out 
with deference to the 505(b)(2) and/or ANDA applicant(s)' 
interpretation of the scope of the patent is also needed.
    In addition, we are expressly requiring the correction or change of 
patent information by the NDA holder if: (1) The patent or patent claim 
no longer meets the statutory requirements for listing; (2) the NDA 
holder is required by court order to amend patent information or 
withdraw a patent from the list; or (3) the term of a listed patent is 
extended under patent term restoration provisions. These revisions 
facilitate implementation of the MMA provision related to patent 
withdrawal and efficient enforcement of the FD&C Act.
I.B.4. Notice of Paragraph IV Certification--Timing
    We are revising our regulations to clearly delineate the two 
limitations on the timeframe within which notice of a paragraph IV 
certification can be provided to the NDA holder and each patent owner: 
(1) The date before which notice may not be given (reflecting FDA's 
longstanding practice regarding premature notice) and (2) the date, 
established by MMA, by which notice must be given to be considered 
timely.
    For an original application, a 505(b)(2) applicant must send notice 
of a paragraph IV certification on or after the date on which the 
505(b)(2) application is filed and an ANDA applicant must send notice 
of a paragraph IV certification on or after the date on which it 
receives a ``paragraph IV acknowledgment letter'' from FDA stating that 
the application is sufficiently complete to permit a substantive 
review. Both 505(b)(2) and ANDA applicants must send notice of a 
paragraph IV certification not later than 20 days after the date of the 
``postmark'' (as defined in this final rule) on the paragraph IV 
acknowledgment letter.
    For an amendment or supplement, an applicant must send notice of a 
paragraph IV certification contained in an amendment to a 505(b)(2) 
application (that has been filed) or ANDA (that has been received for 
substantive review) or in a supplement to an approved application at 
the same time that the amendment or supplement is submitted to FDA.
    We are establishing a date (the first working day after the day the 
patent is published in the Orange Book) before which an ANDA applicant 
cannot send valid notice of a paragraph IV certification to a newly 
listed patent. Notice of a paragraph IV certification that has been 
sent prematurely is invalid, and will not be considered to comply with 
the FD&C Act's notice requirement. This approach is intended to promote 
equity among ANDA applicants seeking eligibility for 180-day 
exclusivity and to reduce the burden on industry and FDA associated 
with serial submissions and multiple notices of paragraph IV 
certifications related to a newly issued patent.
I.B.5. Notice of Paragraph IV Certification--Content and Methods
    We are revising the content of notice of a paragraph IV 
certification to incorporate requirements added by the MMA and to 
support the efficient enforcement of our regulations. We are also 
expanding the acceptable methods of sending notice of a paragraph IV

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certification beyond registered or certified mail to include 
``designated delivery services.'' This reduces the burden on 505(b)(2) 
and ANDA applicants who currently must submit requests to the Agency to 
send notice by common alternate delivery methods.
I.B.6. Amended Patent Certifications
    We are clarifying the requirements for a 505(b)(2) or ANDA 
applicant to amend a paragraph IV certification after a judicial 
finding of patent infringement to reflect statutory changes made by the 
MMA. We are also clarifying the circumstances and timeframe in which a 
505(b)(2) or ANDA applicant must submit an amended patent certification 
after an NDA holder has withdrawn a patent and requested removal of the 
patent from the Orange Book. The rule codifies our current practice of 
not removing a withdrawn patent from the list until FDA has determined 
that no first applicant is eligible for 180-day exclusivity or the 180-
day exclusivity period based on that patent has expired or has been 
extinguished, and exempting 505(b)(2) applicants from providing or 
maintaining a certification to withdrawn patents. In addition, the rule 
expressly codifies the current requirement for a 505(b)(2) or ANDA 
applicant to submit a patent certification to a timely filed, newly 
issued patent that claims the listed drug or an approved method of 
using such drug.
I.B.7. Patent Certification Requirements for Amendments
    We are clarifying and augmenting the patent certification 
requirements for amendments to 505(b)(2) applications and ANDAs to 
ensure that certain types of changes to the drug product are 
accompanied by an appropriate patent certification (or recertification) 
or statement. An appropriate patent certification (or recertification) 
or statement is required to accompany an amendment to add a new 
indication or other condition of use, to add a new strength, to make 
other-than-minor changes in product formulation, or to change the 
physical form or crystalline structure of the active ingredient. The 
regulations continue to require that a patent certification be amended 
if, at any time before approval, the applicant learns that the 
previously submitted patent certification or statement is no longer 
accurate.
I.B.8. Limitation on Submission of Certain Amendments and Supplements 
to a 505(b)(2) Application or ANDA
    We are codifying our current interpretation of the MMA's 
prohibition on submitting an amendment or a supplement to seek approval 
of: (1) ``[A] drug that is a different drug'' than the drug identified 
in the original 505(b)(2) application; or (2) ``a drug referring to a 
different listed drug'' than the drug cited as the basis for ANDA 
submission. We are implementing these parallel restrictions on 
submission of certain types of changes in an amendment or a supplement 
to a 505(b)(2) application or ANDA in a manner that is consistent with 
the statutory text and preserves a meaningful opportunity for a single 
30-month stay.
I.B.9. 505(b)(2) Applications
    We are requiring a 505(b)(2) applicant to identify one 
pharmaceutically equivalent drug product approved in an NDA, if one or 
more is approved before the original 505(b)(2) application is 
submitted, as a listed drug relied upon, and comply with applicable 
regulatory requirements. This is intended to help ensure that the 
505(b)(2) pathway is not used to circumvent the statutory patent 
certification obligations that would have applied if the proposed 
product could have been approved in an ANDA.
I.B.10. Date of Approval of a 505(b)(2) Application or ANDA
    The rule describes, in a more comprehensive manner, the timing of 
approval of a 505(b)(2) application or ANDA based on the patent 
certification(s) or statement(s) submitted by the 505(b)(2) or ANDA 
applicant. We are revising the regulations to reflect the MMA's 
limitation on multiple 30-month stays of approval of a 505(b)(2) 
application or an ANDA containing a paragraph IV certification to 
certain patents.
    We are clarifying that the statutory 30-month stay begins on the 
later of the date of receipt of notice of paragraph IV certification by 
any owner of the listed patent or by the NDA holder (or its 
representative(s)). This revision codifies our current practice and 
provides an efficient means of ensuring that each patent owner or NDA 
holder receives the full statutory 30-month stay.
    We are codifying the MMA's amendments that clarify the type of 
Federal district and appellate court decisions in patent litigation 
that will terminate a 30-month stay and lead to approval of a 505(b)(2) 
application or ANDA that is otherwise eligible for approval. We are 
also addressing other scenarios in which a 30-month stay may be 
terminated, including written consent to approval by the patent owner 
or exclusive patent licensee, a court order terminating the stay, or a 
court order of dismissal without a finding of infringement in each 
pending suit for patent infringement brought within 45 days of receipt 
of the notice of paragraph IV certification. These clarifications are 
intended to avoid unnecessary delays in approval of 505(b)(2) 
applications and ANDAs while upholding the statutory purpose of the 
stay (i.e., to allow time for patent infringement claims to be 
litigated prior to approval of the potentially infringing product).
I.B.11. Notification of Commercial Marketing
    We are updating the regulations to reflect the MMA provisions that 
modify the types of events that can trigger the start of the 180-day 
exclusivity period. A first applicant is required to submit 
correspondence to its ANDA notifying FDA within 30 days of the date of 
first commercial marketing of the drug product. If a first applicant 
does not notify FDA within this timeframe, we are deeming the date of 
first commercial marketing to be the date of the drug product's 
approval. This may have the effect of shortening the 180-day 
exclusivity period in a similar manner to the current regulatory 
consequence for failure to provide ``prompt'' notice of first 
commercial marketing.
I.B.12. Notification of Court Actions or Written Consent to Approval
    We are expanding the scope of documentation that an applicant must 
submit to FDA regarding patent-related court actions and written 
consent to approval to ensure that FDA is promptly advised of 
information that may affect the timing of approval of a 505(b)(2) 
application or ANDA.

I.C. Legal Authority

    Title XI of the MMA and sections 505, 505A, 505E, and 527 of the 
FD&C Act (21 U.S.C. 355, 355a, 355f, and 360cc), in conjunction with 
our general rulemaking authority in section 701(a) of the FD&C Act (21 
U.S.C. 371(a)), serve as our principal legal authority for this rule.

I.D. Costs and Benefits

    Many provisions of this final rule codify current practice, but 
some elements will lead to changes that generate additional benefits 
and costs. The table summarizes the benefits and costs of this final 
rule. The estimated annualized monetized benefits of this final rule 
are $215,247 at a 3 percent or 7 percent discount rate, while the 
estimated annualized monetized costs are $266,947 at a 3 percent 
discount rate and $275,925 at a 7 percent discount rate. We have also 
identified, but are

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unable to quantify, additional impacts from changes to submitted patent 
information.

                      Summary of Benefits and Costs
------------------------------------------------------------------------
                                             Benefits          Costs
------------------------------------------------------------------------
One-time (Year 1) Cost for Reading the                NA        $466,450
 Rule...................................
Annually Recurring Compliance Costs or          $215,247         213,858
 Savings (Years 1-10)...................
Present Value at 3 Percent..............       1,836,098       2,277,116
Present Value at 7 Percent..............       1,511,803       1,937,983
Annualized Value at 3 Percent...........         215,247         266,947
Annualized Value at 7 Percent...........         215,247         275,925
------------------------------------------------------------------------
NA = Not Applicable.

II. Table of Abbreviations and Acronyms Commonly Used in This Document

------------------------------------------------------------------------
           Abbreviation                        What it means
------------------------------------------------------------------------
ANDA.............................  Abbreviated New Drug Application.
CDER.............................  Center for Drug Evaluation and
                                    Research.
CFR..............................  Code of Federal Regulations.
CSA..............................  Controlled Substances Act.
ESG..............................  Electronic Submissions Gateway.
FD&C Act.........................  Federal Food, Drug, and Cosmetic Act.
FDA..............................  U.S. Food and Drug Administration.
FDASIA...........................  Food and Drug Administration Safety
                                    and Innovation Act.
FOIA.............................  Freedom of Information Act.
FR...............................  Federal Register.
FTC..............................  U.S. Federal Trade Commission.
GAIN.............................  Generating Antibiotic Incentives Now.
GDUFA............................  Generic Drug User Fee Amendments of
                                    2012.
IRTNMTA..........................  Improving Regulatory Transparency for
                                    New Medical Therapies Act.
MMA..............................  Medicare Prescription Drug,
                                    Improvement, and Modernization Act
                                    of 2003.
NDA..............................  New Drug Application.
OGD..............................  Office of Generic Drugs (in FDA's
                                    Center for Drug Evaluation and
                                    Research).
OMB..............................  U.S. Office of Management and Budget.
OND..............................  Office of New Drugs (in FDA's Center
                                    for Drug Evaluation and Research).
Orange Book......................  FDA's ``Approved Drug Products With
                                    Therapeutic Equivalence
                                    Evaluations''.
OTC..............................  Over-the-counter.
RLD..............................  Reference Listed Drug.
U.S..............................  United States.
U.S.C............................  United States Code.
USPS.............................  United States Postal Service.
USPTO............................  U.S. Patent and Trademark Office.
------------------------------------------------------------------------

III. Background

    The 505(b)(2) application and ANDA approval pathways were enacted 
as part of the Drug Price Competition and Patent Term Restoration Act 
of 1984 (Pub. L. 98-417) (Hatch-Waxman Amendments). The Hatch-Waxman 
Amendments reflect Congress's efforts to balance the need to ``make 
available more low cost generic drugs by establishing a generic drug 
approval procedure for pioneer drugs first approved after 1962'' with 
new incentives for drug development in the form of marketing 
exclusivity and patent term extensions (see H. Rept. 98-857, part 1, at 
14-15 (1984), reprinted in 1984 U.S. Code Congressional and 
Administrative News 2647 at 2647-2648).
    A 505(b)(2) application is an NDA that contains full reports of 
investigations of safety and effectiveness, where at least some of the 
information relied upon by the applicant for approval of the NDA comes 
from investigations that were not conducted by or for the applicant and 
for which the applicant has not obtained a right of reference or use 
(e.g., published literature or the Agency's finding of safety and/or 
effectiveness for one or more listed drugs) (see section 505(b)(2) of 
the FD&C Act; compare section 505(b)(1) of the FD&C Act for ``stand-
alone'' NDAs).
    An ANDA contains information to show that the proposed product is 
the same as a previously approved drug (the reference listed drug or 
RLD) with respect to active ingredient, conditions of use, dosage form, 
route of administration, strength, and (with certain permissible 
differences) labeling, among other characteristics. An ANDA applicant 
also must demonstrate that its proposed drug product is bioequivalent 
to the RLD (see section 505(j) of the FD&C Act; compare section 
505(j)(2)(C) for ``petitioned ANDAs''). An applicant that can meet the 
requirements for approval under section 505(j) of the FD&C Act may rely 
upon the Agency's finding of safety and effectiveness for the RLD and 
need not repeat the extensive nonclinical and clinical investigations 
required for approval of a ``stand-alone'' NDA submitted under section 
505(b)(1) of the FD&C Act.
    The timing of approval for a 505(b)(2) application and an ANDA 
(including a petitioned ANDA) is subject to certain patent and 
marketing exclusivity protections. An NDA applicant is required to 
submit information on any patent that claims the drug that is the 
subject of the NDA or that claims a method of using such drug and with 
respect to which a claim of patent infringement could reasonably be 
asserted if a person not licensed by the owner engaged in the 
manufacture, use, or sale of the drug (section 505(b)(1) and (c)(2) of 
the FD&C Act). Upon approval of an NDA under section 505(c) of the FD&C 
Act, we publish certain patent information provided by the NDA holder 
in the Orange Book, available electronically on FDA's Web site at 
https://www.fda.gov/cder.
    A 505(b)(2) application and ANDA must include an appropriate patent 
certification or statement for each patent that claims the listed 
drug(s) relied upon or RLD, respectively, or a method of using such 
drug and for which information is required to be filed under section 
505(b) or 505(c) of the FD&C Act. The 505(b)(2) or ANDA applicant must 
submit one or more of the following certifications or statements:
     That such patent information has not been filed (a 
paragraph I certification);
     that such patent has expired (a paragraph II 
certification);
     the date on which such patent will expire (a paragraph III 
certification);
     that such patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for 
which the 505(b)(2) application or ANDA is submitted (a paragraph IV 
certification);
     that there are no patents that claim the listed drug(s) or 
that claim a use of such drug (a ``no relevant patents'' statement, 
which is submitted instead of a patent certification); or
     that a method-of-use patent does not claim a use for which 
the 505(b)(2) or ANDA applicant is seeking approval (a 505(b)(2)(B) or 
(j)(2)(A)(viii) statement).
    An applicant that submits a paragraph IV certification is required 
to give notice of the paragraph IV certification to the NDA holder for 
the listed drug(s) relied upon or RLD and each owner of the patent that 
is the subject of the certification. Notice of a paragraph IV

[[Page 69584]]

certification subjects the 505(b)(2) or ANDA applicant to the risk that 
it will be sued for patent infringement. If the NDA holder or patent 
owner initiates a patent infringement action within 45 days after 
receiving notice of the paragraph IV certification, there generally 
will be a statutory 30-month stay of approval of the 505(b)(2) 
application or ANDA while the patent infringement litigation is pending 
(see section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act).
    ANDA applicants have a statutory incentive to challenge listed 
patents that may be invalid, unenforceable, or not infringed by the 
drug product described in the ANDA. The first applicant to submit a 
substantially complete ANDA that contains, and for which the applicant 
lawfully maintains, a paragraph IV certification may be eligible for a 
180-day period of marketing exclusivity (180-day exclusivity) during 
which approval of subsequent ANDAs containing a paragraph IV 
certification to a listed patent for the same drug product will not be 
granted (see section 505(j)(5)(B)(iv) of the FD&C Act).

III.A. History of This Rulemaking

    On December 8, 2003, the MMA (Pub. L. 108-173) was signed into law. 
Title XI of the MMA significantly amended provisions of the FD&C Act 
that govern the approval of 505(b)(2) applications and ANDAs. Title XI 
of the MMA addressed two key concerns identified in an FTC report on 
``Generic Drug Entry Prior to Patent Expiration: An FTC Study'' (July 
2002) (Ref. 1) by limiting the availability of 30-month stays of 
approval on 505(b)(2) applications and ANDAs that are otherwise ready 
to be approved (30-month stays) and by establishing conditions under 
which a first applicant would forfeit the 180-day exclusivity period 
such that approval of subsequent ANDAs would no longer be blocked.
    Section 1101 of the MMA provides that a 30-month stay of approval 
of a 505(b)(2) application or ANDA is available only if patent 
infringement litigation was initiated within the 45-day period after 
receipt of notice of a paragraph IV certification for a patent that had 
been submitted to FDA before the date of submission of the 505(b)(2) 
application or ANDA (excluding an amendment or supplement to the 
505(b)(2) application or ANDA). The resulting incentive for an 
applicant to change the listed drug relied upon through an amendment of 
or a supplement to a 505(b)(2) application or ANDA is addressed by the 
MMA's prohibition of the submission of certain types of changes 
(including those requiring reference to a different listed drug) in an 
amendment of or supplement to a 505(b)(2) application or ANDA. In 
addition, section 1101 of the MMA amended the FD&C Act to specify 
certain types of court actions that will terminate a 30-month stay of 
approval.
    Section 1101 of the MMA also created new requirements for 505(b)(2) 
and ANDA applicants sending notice of a paragraph IV certification, 
including changes to the timing and contents of such notice. In 
addition, the MMA established conditions under which a 505(b)(2) or 
ANDA applicant may bring a declaratory judgment action to obtain 
``patent certainty'' (i.e., obtain a judicial determination of non-
infringement, invalidity, or unenforceability) with respect to a listed 
patent for which it has given notice of a paragraph IV certification 
but has not been sued by the NDA holder or patent owner(s) within the 
statutory timeframe. If a patent infringement action is initiated 
against the 505(b)(2) or ANDA applicant, the MMA provides that the 
applicant may assert a counterclaim seeking an order requiring a 
correction or deletion of the patent information submitted to FDA for 
listing by the NDA holder.
    Section 1102 of the MMA altered the conditions under which a 180-
day period of marketing exclusivity attaches by requiring, among other 
things, that a first applicant lawfully maintain the paragraph IV 
certification contained in its submission of a substantially complete 
ANDA. In addition, section 1102 of the MMA established conditions under 
which a first applicant would forfeit the 180-day exclusivity period.
    Section 1103 of the MMA clarified the types of bioavailability and 
bioequivalence data that can be used to support a 505(b)(2) application 
or ANDA for a drug that is not intended to be absorbed into the 
bloodstream.
    On March 3, 2004, we published a notice in the Federal Register 
entitled ``Generic Drug Issues; Request for Comments'' (69 FR 9982), 
which invited public comment to further identify issues related to the 
MMA provisions regarding 30-month stays, 180-day exclusivity, and 
bioavailability and bioequivalence, along with any suggestions for how 
to resolve those issues.
    On February 6, 2015, we published a proposed rule to implement 
portions of the MMA that pertain to 30-month stays and other matters 
not related to forfeiture of 180-day exclusivity, and make our 
regulations governing 505(b)(2) applications and ANDAs consistent with 
the MMA's amendments to the FD&C Act (80 FR 6802, February 6, 2015; see 
also ``Abbreviated New Drug Applications and 505(b)(2) Applications; 
Correction,'' 80 FR 13289, March 13, 2015). In addition, the proposed 
rule would amend the regulations in parts 314 and 320 (21 CFR parts 314 
and 320) regarding 505(b)(2) applications and ANDAs to facilitate 
compliance with and efficient enforcement of the FD&C Act, and to 
clarify and update these regulations based on our practical experience 
implementing the provisions related to approval of 505(b)(2) 
applications and ANDAs. We will determine whether additional rulemaking 
related to 180-day exclusivity is necessary in the future.
    FDA provided 120 days for public comment on the proposed rule, 
including a 30-day extension of the original comment period (see 
``Abbreviated New Drug Applications and 505(b)(2) Applications; 
Extension of Comment Period,'' 80 FR 22953, April 24, 2015). We 
received 13 comment letters on the proposed rule by the close of the 
comment period, each containing 1 or more comments on 1 or more issues. 
We received comments from pharmaceutical industry associations, brand 
and generic drug manufacturers, law firms, and a law student. Based on 
the comments received, FDA is finalizing the proposed rule with certain 
revisions and technical amendments.

III.B. General Overview of the Final Rule

    This final rule implements portions of Title XI of the MMA and 
revises and clarifies FDA regulations relating to 505(b)(2) 
applications and ANDAs. The final rule reflects our consideration of 
comments on the proposed rule, recent court decisions, and legislative 
enactments, and incorporates several clarifying revisions and technical 
amendments. Table 1 summarizes the substantive changes from the 
proposed rule to the final rule.
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IV. Legal Authority

    The MMA and sections 505, 505A, 505E, 527, and 701 (21 U.S.C. 355, 
355a, 355f, 360cc, and 371) of the FD&C Act provide the principal legal 
authority for this final rule. Section 505(b) of the FD&C Act describes 
the contents of an NDA, including a 505(b)(2) application, and 
describes patent listing and patent certification requirements for 
NDAs. Section 505(j) of the FD&C Act describes the contents of an ANDA, 
including bioequivalence information, patent certification 
requirements, and criteria for a petitioned ANDA. Section 505(b) and 
(j) of the FD&C Act restrict certain amendments and supplements to a 
505(b)(2) application or an ANDA. Section 505(b), (c), and (j) of the 
FD&C Act describe the timing of approval for 505(b)(2) applications and 
ANDAs that are subject to certain patent and marketing exclusivity 
protections. Section 505(j) also describes the availability of 180-day 
exclusivity for a first applicant. Section 505(x) describes the date of 
approval of an NDA for which FDA intends to recommend controls under 
the Controlled Substances Act (CSA). Section 701(a) of the FD&C Act 
provides FDA with the authority to issue regulations for the efficient 
enforcement of the FD&C Act.
    Section 505A of the FD&C Act describes the availability of 
pediatric exclusivity and describes the effect of such exclusivity on 
approval of 505(b)(2) applications and ANDAs. Section 505E of the FD&C 
Act describes the availability of an exclusivity period extension for 
certain designated qualified infectious disease products. Section 527 
of the FD&C Act describes the effect of orphan exclusivity on approval 
of 505(b)(2) applications and ANDAs.
    Thus, sections 505, 505A, 505E, and 527 of the FD&C Act, in 
conjunction with our general rulemaking authority in section 701(a) of 
the FD&C Act, serve as our principal legal authority for this final 
rule.

V. Comments on the Proposed Rule and FDA Response

    We received 13 comment letters on the proposed rule by the close of 
the comment period, each containing 1 or

[[Page 69591]]

more comments on 1 or more issues. We received comments from 
pharmaceutical industry associations, brand and generic drug 
manufacturers, law firms, and a law student. Several comments made 
general remarks supporting the proposed rule without focusing on a 
particular proposed provision.
    We describe and respond to specific comments in sections V.A 
through V.O. We have numbered each comment to help distinguish between 
different comments. We have grouped similar comments together under the 
same number, and, in some cases, we have separated different issues 
discussed in the same comment and designated them as distinct comments 
for purposes of our responses. The number assigned to each comment or 
comment topic is purely for organizational purposes and does not 
signify the comment's value or importance or the order in which 
comments were received. We also received comments on topics related to 
505(b)(2) applications and ANDAs that are outside the scope of the 
proposed rule, including, for example, issues related to forfeiture of 
eligibility for 180-day exclusivity and the Drug Efficacy Study 
Implementation, and we are not addressing these comments at this time. 
We are currently implementing the 180-day exclusivity provisions of the 
MMA directly from the statute and will determine whether additional 
rulemaking is necessary in the future.

V.A. Definitions (Sec.  314.3(b))

    We proposed to amend Sec.  314.3(b) to define terms relevant to 
amendments to the FD&C Act made by the MMA and to add definitions of 
terms that have been used by the Agency in the context of implementing 
section 505(b) and (j) of the FD&C Act. We also proposed amendments to 
Sec.  314.3(b) to conform with other changes in the proposed rule (80 
FR 6802), and to incorporate new definitions. We received a general 
comment expressing support for FDA's efforts to clarify and update 
various definitions that are necessary for the efficient enforcement of 
the Hatch-Waxman Amendments. We received no comments on our proposed 
definitions of ``180-day exclusivity period,'' ``abbreviated new drug 
application or ANDA,'' ``active ingredient,'' ``ANDA holder,'' 
``component,'' ``inactive ingredient,'' ``NDA holder,'' ``new drug 
application or NDA,'' ``original NDA,'' ``paragraph IV certification,'' 
``patent owner,'' ``reference standard,'' ``strength,'' and 
``therapeutic equivalents.'' We also received no comments on our 
proposed revisions to the current definitions of ``abbreviated 
application,'' ``act,'' ``applicant,'' ``application,'' ``listed 
drug,'' and ``the list.'' In addition, we received no comments on our 
proposed relocation of the definition of ``active moiety'' that 
currently is in Sec.  314.108(a) to Sec.  314.3(b). Finally, we 
received no comments on our proposed relocation of the definitions that 
currently are in Sec.  320.1(a) and (c) through (g) to Sec.  314.3(b), 
our proposed deletion of Sec.  320.1(b), and our proposed revisions to 
the definitions of ``bioavailability'' and ``bioequivalence.'' 
Therefore, we are finalizing these definitions without change, except 
for the technical amendment to the definition of ``listed drug'' 
described in section V.A.3 (Response 4) and the technical amendments to 
the definitions of ``original NDA,'' ``resubmission,'' and 
``therapeutic equivalents'' described in section V.P.1. We also 
describe a technical amendment to the definition of ``505(b)(2) 
application'' in section V.P.3 and the addition of the defined term 
``Agency'' in section V.P.1.
V.A.1. Definitions of ``Acknowledgment Letter'' and ``Paragraph IV 
Acknowledgment Letter''
    We proposed to establish a definition of the term ``paragraph IV 
acknowledgment letter'' and the related term ``acknowledgment letter'' 
to facilitate implementation of the MMA's requirement for a 505(b)(2) 
or ANDA applicant to send notice of a paragraph IV certification within 
20 days after the date of the postmark on the notice with which FDA 
informs the applicant that the application has been filed (see section 
505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act and section 
V.A.6). We proposed to define ``paragraph IV acknowledgment letter'' to 
mean a written, postmarked communication from FDA to an applicant 
stating that the Agency has determined that a 505(b)(2) application or 
ANDA containing a paragraph IV certification is sufficiently complete 
to permit a substantive review. For 505(b)(2) applications and ANDAs 
that do not contain a paragraph IV certification, we proposed to define 
``acknowledgment letter'' to mean a written, postmarked communication 
from FDA to an applicant stating that the Agency has determined that a 
505(b)(2) application or ANDA is sufficiently complete to permit a 
substantive review. The proposed ``acknowledgment letter'' or 
``paragraph IV acknowledgment letter'' would indicate that the 
505(b)(2) application is regarded as filed or the ANDA is regarded as 
received (see proposed Sec.  314.3(b)).
    As explained in the proposed rule, the ``paragraph IV 
acknowledgment letter'' for 505(b)(2) applications that rely on the 
Agency's finding of safety and/or effectiveness for a listed drug and 
contain a paragraph IV certification would be the filing communication 
that generally is sent to the 505(b)(2) applicant not later than 14 
calendar days after the 60-day filing date and sometimes is referred to 
as the ``74-day letter'' (see 80 FR 6802 at 6811 and 6814 to 6815). 
Unlike the paragraph IV acknowledgment letter for ANDAs, the filing 
communication is typically sent by the Office of New Drugs (OND) in the 
Center for Drug Evaluation and Research (CDER) in a franked envelope 
that may not bear a postmark made by the U.S. Postal Service (USPS). 
For purposes of Sec.  314.52(b) and (c) only, we proposed that the 
``date of the postmark'' on the ``paragraph IV acknowledgment letter'' 
would be considered to be four calendar days after the date on which 
the filing communication is signed by the signatory authority 
(generally the Division Director or designee in the OND review 
division), which generally reflects the date on which the document is 
received by the USPS (see definition of ``postmark'' in proposed Sec.  
314.3). In the proposed rule, we explained that if OND were to send the 
filing communication via electronic transmission in the future, then 
our proposed definition of a ``postmark'' that documents an electronic 
event would apply (see proposed Sec.  314.3(b) and section V.A.6).
    In the following paragraphs, we discuss a comment on these proposed 
definitions. We also received a comment that agrees with the proposed 
definition of ``paragraph IV acknowledgment letter'' and the inclusion 
of this term in revised Sec.  314.101(b)(2). After considering these 
comments, we are revising the definition of ``acknowledgment letter'' 
to delete the reference to 505(b)(2) applications, thereby limiting the 
applicability of this term to ANDAs. We are finalizing the definition 
of ``paragraph IV acknowledgment letter'' without change.
    (Comment 1) One comment requests that FDA clarify whether the terms 
``acknowledgment letter,'' ``acceptance for filing letter,'' and 
``paragraph IV acknowledgment letter'' can be used interchangeably to 
refer to the letter sent to applicants for ANDAs that contain a 
paragraph IV certification.
    (Response 1) FDA separately defines the terms ``acknowledgment 
letter'' and ``paragraph IV acknowledgment letter'' for ANDAs because 
the ``paragraph IV acknowledgment letter'' contains

[[Page 69592]]

information on certain regulatory requirements associated with a 
paragraph IV certification. For administrative reasons, it had been 
FDA's practice to send an ``acknowledgment letter'' rather than a 
``paragraph IV acknowledgment letter'' to an ANDA applicant if an 
original ANDA contained a patent certification or statement other than 
a paragraph IV certification, and the applicant submitted an amendment 
containing a paragraph IV certification before the ANDA has been 
received for substantive review. Accordingly, we proposed to use both 
terms in the regulations where appropriate (see proposed Sec.  314.95). 
Upon further consideration, we are modifying our administrative 
practices to send a ``paragraph IV acknowledgment letter'' to an ANDA 
applicant if the ANDA contains a paragraph IV certification at any time 
prior to receipt of the ANDA. We are making conforming revisions to 
Sec.  314.95(b)(1) and (2), (c)(3), and (d)(2) to remove the reference 
to an ``acknowledgment letter.'' We are retaining a revised definition 
of the term ``acknowledgment letter'' in Sec.  314.3(b) because FDA's 
Office of Generic Drugs (OGD) will continue to send ``acknowledgment 
letters'' for ANDAs that do not contain a paragraph IV certification at 
the time of receipt (see, e.g., section V.D.1.b). (The defined term 
``acknowledgment letter'' for ANDAs differs from the informal use of 
this term for NDAs, which acknowledges the submission of an NDA before 
the Agency has determined whether the NDA can be filed.) FDA no longer 
uses the term ``acceptance for filing letter,'' which is an informal 
term that previously was used to describe an acknowledgment letter for 
an ANDA.
    FDA has concluded that that it is unnecessary to distinguish 
between an ``acknowledgment letter'' and a ``paragraph IV 
acknowledgment letter'' for a 505(b)(2) application. If the 505(b)(2) 
application contains a paragraph IV certification at any time before 
the 505(b)(2) application is filed, the filing communication that FDA 
sends to NDA applicants also will be the ``paragraph IV acknowledgment 
letter'' for 505(b)(2) applicants for purposes of determining the date 
by which notice of paragraph IV certification must be sent (see Sec.  
314.52). We are making a conforming revision to Sec.  314.52(d) to 
remove the reference to an ``acknowledgment letter'' (see section 
V.D.1.b).
V.A.2. Definition of ``Commercial Marketing''
    We proposed to define ``commercial marketing'' to mean the 
introduction or delivery for introduction into interstate commerce of a 
drug product described in an approved ANDA, outside the control of the 
ANDA holder, except for investigational use under part 312 of this 
chapter (21 CFR part 312), but that does not include transfer of the 
drug product for reasons other than sale to parties identified in the 
approved ANDA (see proposed Sec.  314.3(b)). In the following 
paragraphs, we discuss three comments on this proposed definition. 
After considering these comments, we are making editorial corrections 
to clarify the types of transfers of the drug product for reasons other 
than sale that fall within the exception to commercial marketing. We 
also are making amendments to clarify that the definition of commercial 
marketing includes the introduction or delivery for introduction into 
interstate commerce of the reference listed drug by the ANDA applicant.
    (Comment 2) One comment recommends clarifying that commercial 
marketing does not include transfer of the drug product to a third-
party logistics provider or contractor who is not identified in the 
ANDA, provided that the transfer does not take the drug product outside 
the control of the ANDA holder (e.g., transfer of the drug product for 
storage or further distribution only as the ANDA holder may direct in 
the future). This comment also suggests revising the structure of the 
definition to improve clarity. Another comment maintains that the 
proposed definition would limit business flexibility, given that an 
ANDA applicant's transfer of the drug product to a re-packager (e.g., 
to facilitate packaging validation or preparation for product launch) 
would be considered commercial marketing because re-packagers are not 
identified in ANDAs.
    (Response 2) FDA declines to expand the exception to commercial 
marketing to include transfer of the drug product, outside the control 
of the ANDA applicant, for reasons other than sale to third parties not 
identified in the ANDA. FDA's amended definition of ``commercial 
marketing'' creates a bright-line rule for establishing the date of 
first commercial marketing of the drug by any first applicant for 
purposes of determining the start of the 180-day exclusivity period 
(see section 505(j)(5)(B)(iv)(I) of the FD&C Act and Sec.  
314.107(c)(2)). The amended definition also facilitates implementation 
of the statutory provision by which a first applicant may forfeit 
eligibility for 180-day exclusivity due to failure to market the drug 
by the timeframe described in the statute (see section 
505(j)(5)(D)(i)(I) of the FD&C Act).
    Under the amended definition in Sec.  314.3(b), ``commercial 
marketing'' of the drug product refers to a transfer of the drug 
product outside the control of the ANDA applicant, subject to specified 
exceptions, and thus does not include a transfer of the drug product 
within the control of the ANDA applicant. As we explained in the 
proposed rule, the amended definition is intended to clarify that the 
ANDA applicant's shipment of a drug product described in an ANDA to any 
party named in the ANDA for purposes described in the ANDA (e.g., 
contract packaging) is not ``commercial marketing'' of the drug product 
even though such transfer arguably places the drug products outside of 
the control of the manufacturer for some period of time (80 FR 6802 at 
6812). Among other things, an ANDA holder would be required to identify 
a packager or re-packager in a supplement to the ANDA if different 
equipment or facilities are used that have a moderate potential to have 
an adverse effect on factors that may relate to the safety and 
effectiveness of the drug product (see 21 U.S.C. 356a and Sec.  
314.70(c); compare Sec.  314.70(d)). We also note that storage and 
distribution facilities often are identified in ANDAs (see, e.g., draft 
guidance for industry entitled ``Pre-Launch Activities Importation 
Requests (PLAIR)'' (July 2013) at 3, available at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm). 
Accordingly, we do not expect the amended definition to have a 
significant impact on ANDA applicants' business arrangements with third 
parties.
    FDA agrees that the definition of ``commercial marketing'' should 
be revised further for clarity. We also are making amendments to remove 
the reference to an ``approved'' ANDA and to further clarify that the 
definition of commercial marketing includes an ANDA applicant's 
commercial marketing of the reference listed drug, including an 
authorized generic drug (see section 505(j)(5)(B)(iv)(I) of the FD&C 
Act). As revised, commercial marketing is the introduction or delivery 
for introduction into interstate commerce of a drug product described 
in an ANDA, outside the control of the ANDA applicant, except that the 
term does not include transfer of the drug product for investigational 
use under part 312 of this chapter or transfer of the

[[Page 69593]]

drug product to parties identified in the ANDA for reasons other than 
sale. Commercial marketing includes the introduction or delivery for 
introduction into interstate commerce of the reference listed drug by 
the ANDA applicant.
    (Comment 3) One comment agrees with the proposed definition of 
``commercial marketing'' but recommends specifically excluding 
charitable donations of drug product.
    (Response 3) FDA disagrees with the recommendation to exclude 
charitable donations of drug product from the definition of 
``commercial marketing.'' A drug product is introduced or delivered for 
introduction into interstate commerce, outside the control of the ANDA 
applicant, when an ANDA applicant donates the drug product to a 
charitable institution or organization (e.g., a nonprofit hospital or 
health care entity). This introduction or delivery for introduction 
into interstate commerce subjects the donated drug product to 
applicable statutory and regulatory requirements, including, but not 
limited to, requirements intended to ensure that the drug product is 
not adulterated or misbranded (see, e.g., 21 U.S.C. 331, 351, and 352). 
Moreover, even if the charitable institution or organization is 
identified in the ANDA, a charitable donation of drug product is not 
necessarily a transfer of the drug product for reasons other than sale, 
given that there are circumstances in which a donated drug product may 
be sold (see 21 U.S.C. 353(c)(3)(B) and 21 CFR 203.22). FDA does not 
believe the definition of ``commercial marketing'' will impact 
charitable donation of drug product, given that charitable donation of 
drug product met the criteria for commercial marketing under the 
previous definition in Sec.  314.107(c)(4). The comment does not 
provide any explanation for the proposed change, and we do not believe 
that the proposed change is necessary.
V.A.3. Definition of ``Date of Approval''
    We proposed to move the definition of ``date of approval'' from 
Sec.  314.108(a) to Sec.  314.3(b) with several revisions. We proposed 
that the date of approval would mean the date on the approval letter 
from FDA stating that the NDA or ANDA is approved (see proposed Sec.  
314.3(b)). Our proposed revisions broadened the definition to include 
the date of approval for an ANDA, and incorporated the defined term 
``approval letter.'' We also proposed to remove the caveat that the 
date of approval is the date on the approval letter whether or not 
final printed labeling or other materials must still be submitted as 
long as approval of such labeling or materials is not expressly 
required.
    In the following paragraphs, we discuss two comments that disagree 
with these proposed changes. After these comments were submitted, 
Congress enacted the Improving Regulatory Transparency for New Medical 
Therapies Act (IRTNMTA) (Pub. L. 114-89), which addresses the primary 
concern expressed by comments regarding the proposed revision to the 
definition. We are finalizing the definition with technical amendments 
to incorporate IRTNMTA.
    (Comment 4) Two comments recommend that FDA retain the former 
definition of ``date of approval'' in Sec.  314.108 because the 
definition addresses circumstances in which the date on the approval 
letter for an NDA is not the same as the date on which an applicable 
exclusivity period begins to run. The comments contend that the 
qualifying phrase ``as long as approval of such [final printed] 
labeling or materials is not expressly required'' in the former 
definition of ``date of approval'' is not reflected elsewhere in the 
Agency's regulations. Moreover, the comments assert that the proposed 
revision to the definition would effectively reduce the exclusivity 
period for certain approved drug products that cannot be commercially 
marketed until the Drug Enforcement Administration (DEA) has scheduled 
the drug as a controlled substance or until FDA has approved a 
proprietary name (where the name is necessary for the safe use of the 
drug). The comments maintain that FDA did not clearly describe and 
invite comment on these effects of the proposed revision to the 
definition.
    (Response 4) We disagree with comments recommending that we retain 
the former definition of ``date of approval'' in Sec.  314.108. As we 
explained in the proposed rule, FDA's regulations in Sec.  314.105(b) 
specifically address the circumstances in which FDA will approve an NDA 
and issue the applicant an approval letter on the basis of draft 
labeling. Since publication of the proposed rule, FDA has determined 
that an ANDA also may be approved on the basis of draft labeling, 
provided that the only deficiencies in the draft labeling are editorial 
or similarly minor in nature (see guidance for industry entitled 
``Acceptability of Draft Labeling to Support ANDA Approval'' (October 
2015), available at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm) 
(superseding FDA's former policy that final printed labeling is 
required for approval of an ANDA). If draft labeling deficiencies have 
not yet been resolved and are more than ``editorial or similar minor 
deficiencies,'' then the appropriate action is a complete response 
letter (see Sec. Sec.  314.125(b) and 314.110). In the exceptional 
circumstances in which FDA has not yet approved a proprietary name for 
a proposed drug product and determines that the product cannot be 
marketed without a proprietary name, the applicant should receive a 
complete response letter (compare Letter from Janet Woodcock, M.D., 
Director, CDER, to Anil Hiteshi, Spectrum Pharmaceuticals, Inc., dated 
February 24, 2015, regarding Docket No. FDA-2014-P-1615, available at 
https://www.regulations.gov) (denying request for revision of the 
approval date because the approval letter expressly stated that 
Spectrum could market the product with labeling bearing only the 
established name until a proprietary name could be agreed upon). 
Accordingly, it is unnecessary to address any requirements for approval 
of final printed labeling in the definition of ``date of approval.''
    On November 25, 2015, Congress enacted IRTNMTA, which addresses 
concerns that delays in scheduling a newly approved drug may reduce an 
applicable exclusivity period that commences on the ``date of 
approval.'' IRTNMTA provides that the date of approval for an NDA for 
which FDA intends to recommend controls under the CSA is the later of 
the date an NDA is approved under section 505(c) of the FD&C Act or the 
date of issuance of the interim final rule controlling the drug (see 
section 505(x)(1) and (2) of the FD&C Act). To incorporate IRTNMTA, we 
are revising the definition of ``date of approval'' to mean the date on 
the approval letter from FDA stating that the NDA or ANDA is approved, 
except that the date of approval for an NDA described in section 
505(x)(1) of the FD&C Act is determined as described in section 
505(x)(2) of the FD&C Act (see Sec.  314.3(b)).
    As reflected in the revised definition, we are currently 
implementing IRTNMTA directly from the statute and will determine 
whether additional rulemaking is necessary in the future. However, 
given the broader relevance of the term ``date of approval'' to matters 
covered in part 314, we are making other technical amendments to align 
with the revised definition and enhance clarity. These technical 
amendments are described in the following paragraphs.
    We are further revising the proposed definition of ``listed drug'' 
to establish that a drug product is deemed to be a listed drug on the 
``date of approval'' for the NDA or ANDA for that drug

[[Page 69594]]

product, rather than on the ``date of the approval letter'' (see Sec.  
314.3(b)). This technical amendment clarifies the listed drug status of 
a drug product described in section 505(x)(1) of the FD&C Act, and the 
corresponding date on which the drug product will be identified in the 
Orange Book (the list) as a listed drug. We are revising Sec.  
314.105(a) to remove the proposed statement that an NDA is approved on 
the date of the issuance of the approval letter. This statement may be 
inaccurate with respect to drug products described in section 505(x)(1) 
of the FD&C Act, and the text is unnecessary in light of the revised 
definition of ``date of approval'' (see Sec.  314.3(b)). We also are 
revising Sec.  314.105(a) to state that a new drug product may not be 
marketed until the date of approval, rather than the date of the 
approval letter, for consistency with IRTNMTA. Although section 
505(x)(1) of the FD&C Act does not apply to ANDAs, we are making the 
same revisions to Sec.  314.105(d) for consistency. In addition, we are 
revising Sec.  314.107(b) to clarify that this provision describes how 
to determine the first possible date on which a 505(b)(2) application 
or ANDA can be approved, rather than the ``date of approval.'' We also 
are replacing the phrase ``the date the patented drug was approved'' 
with ``the date of approval'' in Sec.  314.107(b)(3)(i)(B) to 
incorporate the revised definition. Finally, in the paragraph heading 
for Sec.  314.108(b), we are replacing the phrase ``date of approval'' 
with ``timing of approval'' to more accurately characterize the content 
of this paragraph.
    In the sections of parts 314 and 320 that are the subject of this 
rulemaking, the references to the ``date of approval'' are intended to 
refer to the revised definition in Sec.  314.3(b). For example, we are 
maintaining the reference to ``date of approval'' in Sec.  
314.53(c)(2)(ii) to ensure that there is no ambiguity post-IRTNMTA 
about the required timeframe for submission of patent information after 
approval, given the implications of untimely filing of patent 
information on the patent certification obligations of 505(b)(2) 
applicants and ANDA applicants that rely upon the listed drug (see 
Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi)). Accordingly, for an NDA 
subject to IRTNMTA, the NDA holder must submit Form FDA 3542 within 30 
days of the later of the date on which the NDA is approved under 
section 505(c) of the FD&C Act or the date of issuance of the interim 
final rule controlling the drug for the patent information to be 
considered timely filed.
V.A.4. Definition of ``Dosage Form''
    We proposed to define ``dosage form'' to mean the physical 
manifestation containing the active and inactive ingredients that 
delivers a dose of the drug product. The physical manifestation 
includes such factors as: (1) The physical appearance of the drug 
product, (2) the physical form of the drug product prior to dispensing 
to the patient, (3) the way the product is administered, and (4) design 
features that affect frequency of dosing (see proposed Sec.  314.3(b)). 
In the following paragraphs, we discuss a comment on this proposed 
definition. After considering this comment, we are finalizing the 
definition without change.
    (Comment 5) One comment recommends that FDA broaden the definition 
of ``dosage form'' by including an additional factor to describe the 
physical manifestation of a drug product. The comment requests that FDA 
establish that a drug product with features that impart properties 
designed to deter tampering, abuse, or misuse of the drug product does 
not have the same dosage form as a similar version of the drug product 
that does not have such properties. The comment suggests that this 
would clarify that abuse-deterrent formulations and non-abuse-deterrent 
formulations of a drug product cannot be considered pharmaceutical 
equivalents or therapeutic equivalents.
    (Response 5) FDA declines to adopt the comment's suggestion at this 
time. FDA may address issues related to the pharmaceutical equivalence 
and therapeutic equivalence of abuse-deterrent formulations of a drug 
product through rulemaking or other regulatory mechanisms.
V.A.5. Definitions of ``First Applicant'' and ``Substantially Complete 
Application''
    We proposed to define the terms ``first applicant'' and 
``substantially complete application'' to incorporate into our 
regulations the definitions established by the MMA, with minor 
editorial changes and additional clarifying text (see section 
505(j)(5)(B)(iv)(II)(bb) and (cc) of the FD&C Act). We proposed to 
define ``first applicant'' to mean an applicant that, on the first day 
on which a substantially complete ANDA containing a paragraph IV 
certification is submitted for approval of a drug, submits a 
substantially complete ANDA that contains, and for which the applicant 
lawfully maintains, a paragraph IV certification for the drug (see 
proposed Sec.  314.3(b)). We proposed to delete the definition of 
``applicant submitting the first application'' in former Sec.  
314.107(c)(2) because that definition was superseded by the statutory 
definition.
    We also proposed to define ``substantially complete application'' 
to mean an ANDA that on its face is sufficiently complete to permit a 
substantive review and contains all the information required under 
section 505(j)(2)(A) of the FD&C Act and Sec.  314.94 (see proposed 
Sec.  314.3(b)). We clarified that any information referenced in the 
ANDA must have been provided to FDA for the ANDA to be substantially 
complete, and we provided examples of other bases for finding that an 
ANDA is not substantially complete (see 80 FR 6802 at 6816 to 6817).
    In the following paragraphs, we discuss a comment on these proposed 
definitions. After considering this comment, we are revising the 
definition of ``substantially complete application'' for consistency 
with Sec.  314.101 and making an editorial correction for clarity. We 
are finalizing the definition of ``first applicant'' with editorial 
changes to more clearly incorporate the defined term ``substantially 
complete application.''
    (Comment 6) One comment recommends that FDA revise the definitions 
of ``first applicant'' and ``substantially complete application'' to 
clarify the content required to support a decision that an ANDA is 
substantially complete ``on its face'' in order to distinguish 
deficiencies that may preclude receipt of an ANDA from review issues.
    (Response 6) FDA is revising the definition of ``substantially 
complete application'' for consistency with other regulations outlining 
the required content of an ANDA and to enhance clarity. Under existing 
Sec.  314.101(b), FDA will receive an ANDA if FDA finds that none of 
the reasons in Sec.  314.101(d) and (e) applies for considering the 
ANDA not to have been received. The deficiencies described in Sec.  
314.101(d) that may result in refusal to receive an ANDA include, but 
are not limited to, an ANDA that is incomplete ``because it does not on 
its face contain information required'' under section 505(j) of the 
FD&C Act and Sec.  314.94 (see Sec.  314.101(d)(3)).
    We are revising the definition of ``substantially complete 
application'' to include an express definition of ``sufficiently 
complete'' to permit a substantive review that aligns with our standard 
for receiving an ANDA. As revised, a ``substantially complete 
application'' is an ANDA that on its face is sufficiently complete to 
permit a substantive review. ``Sufficiently

[[Page 69595]]

complete'' to permit a substantive review means that the ANDA contains 
all the information required under section 505(j)(2)(A)(i) through 
(viii) of the FD&C Act and does not contain a deficiency described in 
Sec.  314.101(d) and (e) (see Sec.  314.3(b)). The phrase ``on its 
face'' describes FDA's threshold determination that the ANDA includes 
the information required to make it sufficiently complete to permit a 
substantive review (i.e., information corresponding to the statutory 
and regulatory requirements for an ANDA). This evaluation does not 
involve a substantive review of the data in the ANDA (see Sec.  
314.101(b)(1)). As discussed in section V.J.2, we are supplementing 
Sec.  314.101(d)(3) to more precisely describe the factors that FDA 
considers in determining whether an ANDA is incomplete on its face.
    FDA is revising the definition of ``first applicant'' to more 
clearly incorporate the defined term ``substantially complete 
application.'' As revised, a first applicant is an ANDA applicant that, 
on the first day on which a substantially complete application 
containing a paragraph IV certification is submitted for approval of a 
drug, submits a substantially complete application that contains, and 
for which the applicant lawfully maintains, a paragraph IV 
certification for the drug.
V.A.6. Definition of ``Postmark''
    We proposed to define the term ``postmark'' to address the MMA's 
requirement that a 505(b)(2) or ANDA applicant send notice of its 
paragraph IV certification within 20 days after the date of the 
postmark on the notice (i.e., the paragraph IV acknowledgment letter) 
with which FDA informs the applicant that the application has been 
filed (see proposed Sec.  314.3(b) and section 505(b)(3)(B)(i) and 
505(j)(2)(B)(ii)(I) of the FD&C Act). The purpose of the postmark is to 
establish a verifiable date from which the 20-day notice period runs. 
In light of the transition by FDA and regulated industry to electronic 
communications, FDA proposed to define a ``postmark'' to mean an 
independently verifiable evidentiary record of the date on which a 
document is transmitted, in an unmodifiable format, to another party. 
For postmarks made by the USPS or a designated delivery service, the 
date of transmission is the date on which the document is received by 
the domestic mail service of the USPS or by a designated delivery 
service. For postmarks documenting an electronic event, the date of 
transmission is the date (in a particular time zone) that FDA sends the 
electronic transmission on its host system as evidenced by a verifiable 
record. If the sender and the intended recipient are located in 
different time zones, it is the sender's time zone that provides the 
controlling date of electronic transmission. In the following 
paragraphs, we discuss two comments on this proposed definition. After 
considering these comments, we are finalizing the definition without 
change.
    (Comment 7) One comment recommends that FDA provide ANDA applicants 
with the option to receive a paragraph IV acknowledgment letter by 
electronic transmission rather than first class mail to help ensure 
prompt receipt by the ANDA applicant irrespective of location. The 
comment suggests that this option may reduce the likelihood that an 
ANDA applicant would fail to send notice of paragraph IV certification 
within 20 days after the date of the postmark on the paragraph IV 
acknowledgment letter, and thereby avoid the administrative consequence 
described in proposed Sec.  314.101(b)(4). Another comment notes that 
the proposed definition of postmark clarifies the date by which notice 
of paragraph IV certification must be sent when ANDA applicants receive 
a paragraph IV acknowledgment letter from FDA both by electronic mail 
and the USPS.
    (Response 7) We agree that electronic transmission of a paragraph 
IV acknowledgment letter to an ANDA applicant may facilitate timely 
sending notice of paragraph IV certification. Our definition of 
``postmark'' is intended to accommodate the electronic transmission of 
paragraph IV acknowledgment letters from FDA to 505(b)(2) and ANDA 
applicants in the future.
    OGD currently sends an ANDA applicant or its authorized 
representative a paragraph IV acknowledgment letter (or an 
acknowledgment letter, if appropriate) in an envelope bearing a 
postmark made by the USPS. If the ANDA applicant or its authorized 
representative has provided an electronic mail address on Form FDA 
356h, which accompanies each submission to the ANDA, OGD also sends a 
courtesy copy of the paragraph IV acknowledgment letter (or an 
acknowledgment letter, if appropriate) by electronic mail and 
subsequently archives the electronic communication. Upon the effective 
date of this final rule (see section VI), the date of FDA's electronic 
transmission of a paragraph IV acknowledgment letter to an ANDA 
applicant also will be the postmark described in section 
505(j)(2)(B)(ii)(I) of the FD&C Act. We no longer intend to send a 
paragraph IV acknowledgment letter to an ANDA applicant by the USPS. 
Accordingly, we expect few circumstances in which there will be a 
question about which postmark controls for purposes of determining the 
date by which notice of paragraph IV certification must be sent. 
However, if an ANDA applicant (or, in the future, a 505(b)(2) 
applicant) receives a paragraph IV acknowledgment letter from FDA both 
by electronic mail and the USPS, the earlier postmark provides the 
controlling postmark.
    Although the comment did not discuss 505(b)(2) applications, we 
note that FDA is committed to adapting its business practices to 
evolving technology and anticipates electronically transmitting 
paragraph IV acknowledgment letters to 505(b)(2) applicants in a manner 
that meets the requirements of the definition of postmark in the 
future.
V.A.7. Definition of ``Tentative Approval''
    We proposed to define ``tentative approval'' to mean the 
notification that an NDA (including a 505(b)(2) application) or ANDA 
otherwise meets the requirements for approval under the FD&C Act, but 
cannot be approved because a listed drug has unexpired orphan drug 
exclusivity, or that a 505(b)(2) application or ANDA otherwise meets 
the requirements for approval under the FD&C Act, but cannot be 
approved until the conditions in Sec.  314.107(b)(1)(iii), (b)(3), or 
(c) are met, because the listed drug has a period of exclusivity under 
Sec.  314.108 or section 505A of the FD&C Act, or because a court order 
under 35 U.S.C. 271(e)(4)(A) orders that the application may be 
approved no earlier than the date specified (see proposed Sec.  
314.3(b) and section 505(j)(5)(B)(iv)(II)(dd)(AA) of the FD&C Act). The 
proposed definition clarified that a drug product that is granted 
tentative approval is not an approved drug and will not be approved 
until FDA issues an approval letter after any necessary additional 
review of the NDA or ANDA. In the following paragraphs, we discuss a 
comment on this proposed definition. After considering this comment, we 
are revising the definition to describe an additional basis for 
tentative approval and making conforming revisions to Sec. Sec.  
314.101(e)(2), 314.105(a) and (d), and 314.107(b)(4) and (d).
    (Comment 8) A comment requests that FDA update proposed Sec.  
314.107(d) to reflect that Generating Antibiotic Incentives Now (GAIN) 
exclusivity may delay approval of a 505(b)(2) application or ANDA, and 
that FDA make any other

[[Page 69596]]

necessary conforming revisions to the regulations.
    (Response 8) We agree with the comment. Title VIII of the Food and 
Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-
144), entitled GAIN, provides an exclusivity period extension for 
certain designated qualified infectious disease products in section 
505E of the FD&C Act. We are revising the definition of ``tentative 
approval'' to indicate that approval of a 505(b)(2) application or ANDA 
also may be delayed by a period of exclusivity for the listed drug 
under section 505E of the FD&C Act. We are making similar revisions to 
our regulations on approval of an NDA or ANDA (Sec.  314.105(a) and 
(d)) and delay due to exclusivity (Sec.  314.107(d)). We are also 
revising our regulations on tentative approval to explain that FDA will 
issue a tentative approval letter when tentative approval is 
appropriate in accordance with Sec.  314.107 (see Sec.  314.107(b)(4)).
    GAIN also extends by 5 years the 4-year period described in section 
505(c)(3)(E)(ii) and (j)(5)(F)(ii) of the FD&C Act after which certain 
505(b)(2) applications or ANDAs containing a paragraph IV certification 
may be submitted. Accordingly, we are revising Sec.  314.101(e)(2) to 
remove the cross-reference to Sec.  314.108(b)(2) and expressly state 
that FDA will refuse to file an NDA or will consider an ANDA not to 
have been received if submission of a 505(b)(2) application or an ANDA 
is not permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), or 
505E(a) of the FD&C Act. For completeness, we are making a technical 
amendment to Sec.  314.101(e)(2) to reference pediatric exclusivity 
under section 505A(b)(1)(A)(i)(I) and (c)(1)(A)(i)(I) of the FD&C Act, 
which extends by 6 months the 4-year period described in section 
505(c)(3)(E)(ii) and (j)(5)(F)(ii) of the FD&C Act.

V.B. Submission of Patent Information (Sec.  314.53)

V.B.1. General Requirements for Submission of Patent Information (Sec.  
314.53(b) and (c))
    Section 314.53(b) of our regulations requires that an applicant 
submitting an NDA, an amendment to an NDA, or, except as provided in 
Sec.  314.53(d)(2), a supplement to an approved application, submit the 
patent information described in Sec.  314.53(c) to its NDA on Forms FDA 
3542a and 3542 with the filing or upon and after approval, 
respectively. The information requested in Form FDA 3542 must be 
provided for any patent that claims the approved drug substance, 
approved drug product, or any approved method of using the drug and 
with respect to which a claim of patent infringement could reasonably 
be asserted if a person not licensed by the owner engaged in the 
manufacture, use, or sale of the drug. FDA publishes certain 
information from Form FDA 3542 in the Orange Book after approval of the 
NDA or the supplement. The following sections describe our proposed 
revisions to these regulations and our responses to the comments that 
we received on the proposed rule.
    V.B.1.a. Drug substance (active ingredient) and drug product 
(formulation or composition) patents. We proposed to revise Sec.  
314.53(c)(1) to omit the reference to ``complete'' patent information 
and clarify that FDA will accept a submission of patent information on 
Forms FDA 3542a or 3542, as appropriate, that omits requested patent 
information if the omission is permitted under an exception in Sec.  
314.53(c)(2). We proposed that an applicant need only satisfy the 
requirements for patent listing set forth in section 505(b)(1) and 
(c)(2) of the FD&C Act and, subject to the requirements for submission 
of method-of-use patent information, need not identify each basis on 
which the patent claims the drug (see proposed Sec.  314.53(c)(2)(i)(S) 
and (c)(2)(ii)(T)). Accordingly, if a patent is eligible for listing as 
claiming both the drug substance and the drug product, an applicant 
only would be required to identify one of these two bases for listing. 
We proposed to clarify that these proposed exceptions to the required 
submission of patent information do not alter the requirements for 
submission of method-of-use patent information (see proposed Sec.  
314.53(c)(2)(i)(O)(3) and (c)(2)(ii)(P)(4)).
    One comment supports these streamlined requirements for listing 
patents that claim the drug substance and/or drug product in the Orange 
Book. In the following paragraphs, we discuss two other comments on 
these proposed revisions. After considering these comments, we are 
finalizing these requirements without change. We are making conforming 
revisions to Sec.  314.53(c)(2)(ii) to replace the phrase ``the patent 
declaration is incomplete'' with ``the patent declaration does not 
contain the required information.''
    (Comment 9) One comment requests that FDA revise Sec.  314.53(c)(1) 
to state that FDA will not accept patent information ``unless and 
until'' it is submitted on the appropriate form and contains the 
required information. The comment maintains that this revision would 
clarify that submission of patent information is considered complete 
only as of the date on which all required information has been 
submitted to FDA.
    (Response 9) We decline to revise Sec.  314.53(c)(1) as requested. 
FDA's existing regulations already require that if an NDA holder timely 
submits the required patent information, but FDA notifies the NDA 
holder that its Form FDA 3542 is incomplete or shows that the patent is 
not eligible for listing, the NDA holder must submit an acceptable Form 
FDA 3542 within 15 days of FDA's notification to be considered timely 
filed as of the date of the original submission of patent information 
(see Sec.  314.53(c)(2)(ii)). FDA believes the current procedure is 
adequate to ensure timely and complete submission of patent 
information.
    (Comment 10) One comment requests that FDA require additional 
detail regarding drug substance claims, where the drug product's active 
ingredient may not be self-evident. The comment also suggests that FDA 
require more detail regarding drug product claims to enable FDA to 
determine whether a new patent certification is required for a 
505(b)(2) or ANDA applicant's change in product formulation and avoid 
an unwarranted opportunity for a 30-month stay.
    (Response 10) The comment does not clearly describe the additional 
information requested or provide adequate support for any proposed 
change. FDA previously has explained that ``identification of the 
relevant patent(s), as opposed to the individual patent claims (other 
than for method-of-use patents), satisfies the [FD&C Act's] explicit 
requirements [and] provides sufficient information to potential 
applicants to determine if a more thorough patent search or analysis is 
warranted'' (``Applications for FDA Approval to Market a New Drug: 
Patent Submission and Listing Requirements and Application of 30-Month 
Stays on Approval of [ANDAs] Certifying That a Patent Claiming a Drug 
Is Invalid or Will Not Be Infringed; Final Rule'' 68 FR 36676 at 36685, 
June 18, 2003). (The MMA superseded certain provisions of the 2003 
Final Rule related to 30-month stays of approval; the superseded 
regulations were subsequently revoked by technical amendment (see 
``Application of 30-Month Stays on Approval of [ANDAs] and Certain 
[NDAs] Containing a Certification That a Patent Claiming the Drug Is 
Invalid or Will Not Be Infringed; Technical Amendment'' (69 FR 11309, 
March 10, 2004)).) Moreover, it is unnecessary for an NDA holder to 
submit more detailed patent information regarding drug product claims 
for purposes of determining whether a 505(b)(2) or

[[Page 69597]]

ANDA applicant must amend a previously submitted patent certification 
due to a change in the formulation of its proposed product because the 
505(b)(2) or ANDA applicant has an independent duty to evaluate whether 
a previously submitted patent certification continues to be accurate 
after any change in the formulation of its proposed drug product. We 
also are adding Sec. Sec.  314.60(f)(3) and 314.96(d)(3) to expressly 
describe when a change in product formulation requires an appropriate 
patent certification or a recertification (see section V.F.1).
    V.B.1.b. Drug substance patents that claim only a polymorph of the 
active ingredient. We proposed to revise Sec.  314.53(c)(2)(i)(M)(2) 
and (c)(2)(ii)(N)(2) to only require an applicant to provide 
information on whether the patent claims a polymorph (generally, a 
different crystalline or amorphous form of the same drug substance) 
that is the same active ingredient described in the NDA, amendment, or 
supplement if the only basis on which the patent is eligible for 
listing is that it claims the polymorph. We proposed conforming 
revisions to Sec.  314.53(b)(1) and (2), (c)(2)(i)(M)(3), and 
(c)(2)(ii)(N)(3) to provide that the applicant's certification 
regarding test data required by Sec.  314.53(b) applies only to patents 
that claim only a polymorph.
    We received two comments that agreed with the proposed provision. 
In the following paragraphs, we discuss another comment on this 
proposed revision. After considering the comment, we are finalizing 
these revisions without change.
    (Comment 11) One comment suggests that FDA require more specific 
information about the polymorph claimed in the patent that is the same 
active ingredient in the approved drug product to guide development of 
proposed products intended for submission in a 505(b)(2) application or 
ANDA.
    (Response 11) The comment does not clearly describe the additional 
information requested; however, we disagree with the premise of the 
comment. FDA requires the NDA holder to submit information on Form FDA 
3542 to enable the Agency to determine whether the patent or patent 
information is eligible for listing in the Orange Book based on the 
criteria in our regulations, to enable the Agency to implement section 
505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act, and to assist the 
Agency with its administrative listing responsibilities. The drug 
substance and drug product designation for listing of a patent in the 
Orange Book is not intended to define the scope of patent claims that 
an NDA holder or patent owner may assert in patent infringement 
litigation against a 505(b)(2) or ANDA applicant (see Sec.  
314.53(c)(2)(ii)(T)). Each 505(b)(2) or ANDA applicant is responsible 
for conducting its own analysis of the scope of relevant patents.
    V.B.1.c. Method-of-use patents. We proposed to revise Sec.  
314.53(b)(1) to further clarify that an NDA applicant or holder may 
submit a single Form FDA 3542a or Form FDA 3542, as appropriate, for a 
patent claiming more than one method of use, provided that each method 
of use is listed separately along with the patent claim number(s) of 
the patent claim(s) that corresponds to the pending or approved method 
of use.
    We also proposed to revise our regulations to enhance compliance by 
NDA applicants and holders with the requirements for identifying the 
specific section(s) of product labeling that corresponds to the method 
of use claimed by the patent and, upon approval, describing the 
approved method of use claimed by the patent (the ``use code'') 
required for publication in the Orange Book (see proposed Sec.  
314.53(b)(1), (c)(2)(i)(O)(2), (c)(2)(ii)(P)(2) and (3)). To address 
situations in which the scope of the method of use claimed by the 
patent is narrower than an indication or other condition of use 
described in product labeling, we proposed to expressly require that if 
the scope of the method-of-use claim(s) of a patent does not cover 
every use of the drug, the applicant must identify only the specific 
sections of product labeling that correspond to the specific portion(s) 
of the indication or other condition of use claimed by the patent (see 
proposed Sec.  314.53(b)(1)). We also proposed that if the scope of the 
method-of-use claim(s) of the patent does not cover every approved use 
of the drug, the NDA holder's use code must describe only the specific 
portion(s) of the indication or other method of use claimed by the 
patent (see proposed Sec.  314.53(c)(2)(ii)(P)(3)). Finally, we 
proposed to codify the Agency's longstanding requirement that the NDA 
holder's use code must contain adequate information to assist 505(b)(2) 
and ANDA applicants in determining whether a listed method-of-use 
patent claims a use for which the 505(b)(2) or ANDA applicant is not 
seeking approval (see proposed Sec.  314.53(c)(2)(ii)(P)(3)).
    Several comments support FDA's proposed revisions to the 
regulations regarding the submission of information on method-of-use 
patents. In the following paragraphs, we discuss other comments on the 
submission of information on method-of-use patents. After considering 
all of these comments, we are making clarifying revisions to Sec.  
314.53(b)(1), (c)(2)(i)(O)(1) and (2), (c)(2)(ii)(P)(1) through (3), 
and (e), and conforming revisions to Forms FDA 3542a and 3542.
    (Comment 12) One comment suggests that the Agency's proposal 
regarding the required content of the use code appears to shift to the 
NDA holder the Agency's burden of determining whether a 505(b)(2) or 
ANDA applicant is not seeking approval for a protected use. Another 
comment objects to FDA's requirement that the NDA holder's use code 
contain adequate information to assist 505(b)(2) and ANDA applicants in 
determining whether a listed method-of-use patent claims a use for 
which the 505(b)(2) or ANDA applicant is not seeking approval. The 
comment contends that this approach would require NDA holders to 
speculate about the protected uses that a prospective 505(b)(2) or ANDA 
applicant may seek to omit from labeling. Moreover, the comment asserts 
that this proposal is unworkable given that a 240-character use code 
may not adequately describe a series of patent claims of varying scope. 
The comment further notes that the use code does not obviate the need 
for the 505(b)(2) or ANDA applicant to evaluate the scope of the 
patent.
    (Response 12) FDA disagrees with these comments regarding the 
content requirements for the use code. Given the Agency's ministerial 
role in patent listing, we require an NDA holder to provide adequate 
information about the scope of a listed method-of-use patent to assist 
505(b)(2) and ANDA applicants in assessing whether the listed patent 
claims a use for which the 505(b)(2) or ANDA applicant is not seeking 
approval and to enable FDA to evaluate whether a proposed labeling 
carve-out is appropriate (see section 505(b)(2)(B) and (j)(2)(A)(viii) 
of the FD&C Act, respectively; see also Caraco Pharm. Labs. v. Novo 
Nordisk A/S, 132 S. Ct. 1670, 1684 (2012) (``Use codes are pivotal to 
the FDA's implementation of the Hatch-Waxman Amendments'')).
    We are finalizing the requirement in Sec.  314.53(c)(2)(ii)(P)(3) 
that the NDA holder's description of the patented method of use 
required for publication must contain adequate information to assist 
505(b)(2) and ANDA applicants in determining whether a listed method-
of-use patent claims a use for which the 505(b)(2) or ANDA applicant is 
not seeking approval, with punctuation changes and clarifying revisions 
to the parenthetical example. We also are

[[Page 69598]]

expressly requiring that the NDA holder's description of the patented 
method of use meets the statutory standard for an NDA holder's 
submission of patent information (see section 505(b)(1) and (c)(2) of 
the FD&C Act). As revised, the parenthetical text explains that if the 
method(s) of use claimed by the patent does not cover an indication or 
other approved condition of use in its entirety, then the NDA holder 
must describe only the specific approved method of use claimed by the 
patent for which a claim of patent infringement could reasonably be 
asserted if a person not licensed by the owner of the patent engaged in 
the manufacture, use, or sale of the drug product (see Sec.  
314.53(c)(2)(ii)(P)(3)). We are making conforming revisions to Sec.  
314.53(b)(1). The use code must only describe a patented method of use 
that is described in FDA-approved product labeling because the scope of 
the approved conditions of use of a drug product is described in the 
FDA-approved product labeling. We generally describe this content 
requirement for the use code as the ``specific approved method of use 
claimed by the patent.'' The development of the use code does not 
require speculation about the protected uses that a prospective 
505(b)(2) or ANDA applicant may seek to omit from labeling; rather, it 
simply requires the NDA holder to describe only the specific approved 
method(s) of use claimed by the patent. This requirement also does not 
shift to the NDA holder the Agency's burden of determining whether a 
505(b)(2) or ANDA applicant is not seeking approval for a protected 
use. Based on the use code provided by the NDA holder, FDA determines 
the specific labeling that describes the protected use and decides 
whether a 505(b)(2) application can be approved with that information 
omitted from the labeling or, in the case of an ANDA, whether an ANDA 
that omits the protected information from the labeling will be rendered 
less safe or effective for its remaining non-protected conditions of 
use (see Sec.  314.127(a)(7)).
    Given that the majority of use codes listed in the Orange Book do 
not approach 240 characters, this limitation is not expected to affect 
the accuracy of the NDA holder's description of the specific approved 
method(s) of use claimed by the patent. Nevertheless, FDA is expanding 
the use code character limit to 250 characters because FDA's database 
system can accommodate this additional text. We agree that the use code 
is not intended to substitute for the 505(b)(2) or ANDA applicant's 
review of the patent and the approved labeling in making decisions 
about whether to challenge a listed patent, request a delay in approval 
until expiry of the listed patent, or not request approval for a use 
claimed by the listed patent.
    (Comment 13) One comment recommends that FDA clarify the directions 
on Form FDA 3542 for submitting the use code to avoid potential 
confusion about whether the NDA holder's use code should be based on 
language from the approved labeling or from the patent claim(s).
    (Response 13) FDA agrees with the recommendation to clarify the 
instructions on Form FDA 3542 and the related regulations regarding the 
use code. We are revising Sec.  314.53(b)(1) to clarify the general 
requirement that the NDA holder's description of the patented method of 
use required by Sec.  314.53(c)(2)(ii)(P)(3) must describe only the 
approved method(s) of use claimed by the patent (see Response 12 for a 
discussion of the ``specific approved method of use claimed by the 
patent''). We also are revising Sec.  314.53(c)(2)(i)(O)(1) and 
(c)(2)(ii)(P)(1) to remove the phrases ``or related indication'' and 
``or indication,'' respectively, and supplementing Sec.  
314.53(c)(2)(ii)(P)(3) to clarify that the use code must describe only 
the specific approved method of use claimed by the patent. In other 
words, the scope of the use code must not extend beyond the scope of 
the patent claim(s) and, within the boundary established by the patent 
claim(s), the use code must only describe a patented method of use that 
has been approved by FDA as reflected in approved product labeling (see 
Caraco Pharm. Labs., 132 S. Ct. 1670 at 1683, n.7 (rejecting an 
argument that the use code may sweep more broadly than the patent based 
on the requirement to provide a description of each approved method of 
use or indication) (emphasis added)). Consistent with our clarifying 
revisions to Sec.  314.53(c)(2)(ii)(P)(3), we are revising section 4.2b 
of Form FDA 3542 to state that the NDA holder must submit the 
description of the specific approved method of use claimed by the 
patent that is proposed for inclusion as the ``use code'' in the Orange 
Book. We also are making conforming revisions to Sec.  314.53(e) to 
replace the phrase ``approved indications or other conditions of use 
covered by a patent'' with the ``description of the method of use 
claimed by the patent as required by Sec.  314.53(c)(2)(ii)(P)(3).''
    (Comment 14) One comment proposes that FDA standardize use codes 
rather than relying on the NDA holder's description of the approved 
method of use claimed by the patent. Another comment recommends that 
FDA further describe its expectations for the content of use codes by 
providing hypothetical examples in which the patented method-of-use 
claim is broader, narrower, or co-extensive with an approved indication 
or other condition of use or that uses different terminology. The 
comment also suggests that FDA provide advice on the content of the use 
code where the method of use claimed by the patent is described in a 
section of labeling other than Indications and Usage.
    (Response 14) We decline to adopt standardized use codes because we 
do not believe that standardized use codes would accurately capture the 
nuances of the method-of-use patent claims that NDA holders may submit 
to FDA for listing. FDA's role in listing patents remains ministerial 
(see ``Abbreviated New Drug Application Regulations; Patent and 
Exclusivity Provisions; Final Rule,'' 59 FR 50338 at 50349, October 3, 
1994; see also 68 FR 36676 at 36687), and we continue to believe that 
there is a need for accurate and detailed information related to the 
approved methods of use claimed in the patent being submitted for 
listing (see 68 FR 36676 at 36682). Since 2003, when we began requiring 
NDA holders to submit the use code for publication in the Orange Book 
(see 68 FR 36676 at 36683), the Agency has gained significant 
experience in implementing section 505(b)(2)(B) and (j)(2)(A)(viii) of 
the FD&C Act based on the NDA holder's use code. Based on our 
experience, we are clarifying the use code requirements through this 
rulemaking. We expect that these clarifying revisions to our 
regulations will improve the accuracy of use codes. As the U.S. Supreme 
Court noted in Caraco Pharm. Labs.: ``An overbroad use code . . . 
throws a wrench into the FDA's ability to approve generic drugs as the 
statute contemplates'' (132 S. Ct. 1670 at 1684). Although we decline 
to provide hypothetical examples, the following general principles 
illustrate the clarifying revisions to the regulations regarding the 
content of use codes.
     Patented method of use is broader than an indication or 
other approved condition of use: The use code must only describe a 
patented method of use that is described in FDA-approved product 
labeling. If the method of use claimed by the patent uses different 
terminology than the approved labeling and/or is broader than an 
indication or other approved condition of use, then the use code would 
need to be phrased more narrowly than the patent claim to

[[Page 69599]]

only describe the specific patented method of use that is described in 
FDA-approved product labeling.
     Patented method of use is co-extensive with an indication 
or other approved condition of use: The use code must describe only the 
specific approved method of use claimed by the patent.
     Patented method of use is narrower than an indication or 
other approved condition of use: If the method of use claimed by the 
patent does not cover an indication or other approved condition of use 
in its entirety, then the NDA holder must describe only the specific 
approved method of use claimed by the patent--not the broader 
indication or other approved condition of use that may include, but is 
broader than, the use claimed by the patent.
    For example, Prandin (repaglinide) tablets currently are indicated 
as an adjunct to diet and exercise to improve glycemic control in 
adults with type 2 diabetes mellitus, and U.S. Patent No. 6,677,358 
(358 patent) was listed in the Orange Book as claiming a method of 
using Prandin. In Novo Nordisk A/S v. Caraco Pharm. Labs., the Federal 
Circuit explained that claim 4 of the 358 patent ``claims `[a] method 
for treating non-insulin dependent diabetes mellitus (NIDDM) comprising 
administering to a patient in need of such treatment repaglinide in 
combination with metformin.' . . . An appropriate use code therefore 
must be limited to use of `repaglinide in combination with metformin' 
to treat NIDDM'' (688 F.3d 766 at 768 (Fed. Cir. 2012)) (internal 
citation omitted). A similar approach would apply if the patented 
method of use is described in a section of labeling other than 
Indications and Usage. For example, if the patent claims a novel dosing 
regimen for a particular indication, the use code must specifically 
describe the protected dosing regimen for that indication and not only 
the indication to which the dosing regimen relates. Thus, if the 
method(s) of use claimed by the patent does not cover an indication or 
other approved condition of use in its entirety, an NDA holder's 
submission of a use code that describes an entire indication or other 
approved condition of use would violate FDA's regulations.
    FDA requires the NDA holder to submit an accurate description, 
subject to the verification under penalty of perjury required by Sec.  
314.53(c)(2)(ii)(R), of the specific approved method of use claimed by 
the patent to implement section 505(b)(2)(B) and (j)(2)(A)(viii) of the 
FD&C Act. An inaccurate description of the approved method of use 
claimed by the patent (e.g., one that incorrectly describes the entire 
indication or condition of use to which the patented method of use 
relates rather than the specific approved method of use claimed by the 
patent) would impede FDA's ability to make a scientific determination 
about whether a 505(b)(2) application or ANDA may be approved with 
labeling that omits the protected information corresponding to the use 
code.
    As described in Sec.  314.53(b)(1), each approved method of use 
claimed by the patent must be separately identified and thus will 
require separate listing(s) of method-of-use information in section 4 
of Form FDA 3542. We are revising Forms FDA 3542 and 3542a to 
facilitate separate listings of method-of-use information. We also are 
revising Sec.  314.53(c)(2)(ii) to clarify the Agency will not list or 
publish patent information if it is not provided on Form FDA 3542.
    (Comment 15) One comment requests that FDA clarify the level of 
detail with which an NDA applicant must identify the specific sections 
of product labeling that correspond to the specific portion(s) of the 
indication or other condition of use claimed by the patent. Another 
comment recommends that FDA replace the term ``specific sections'' with 
``specific language'' and eliminate the parenthetical text in proposed 
Sec.  314.53(c)(2)(i)(O)(2) and (c)(2)(ii)(P)(2) to clarify that the 
protected use may encompass less than the entirety of one of the 
``sections'' of the product labeling. This comment also recommends that 
FDA replace the phrase ``corresponds to the method of use claimed by 
the patent'' with ``is claimed by the method of use claimed by the 
patent'' in proposed Sec.  314.53(b)(1), (c)(2)(i)(O)(2), and 
(c)(2)(ii)(P)(2) to result in a more accurate identification of the 
specific labeling that describes a protected method of use.
    (Response 15) FDA agrees that the regulations should clearly define 
the requirement to identify the specific labeling that describes the 
method of use claimed by the patent. FDA is revising its regulations to 
clarify that, for approved NDAs, the NDA holder submitting information 
on the method-of-use patent must identify with specificity the 
section(s) and subsection(s) of the approved labeling that describe the 
method(s) of use claimed by the patent submitted (see Sec.  
314.53(b)(1)). FDA is making conforming revisions to Sec.  
314.53(c)(2)(ii)(P)(2) and section 4.2a of Form FDA 3542 with respect 
to approved labeling, and to Sec.  314.53(c)(2)(i)(O)(2) and section 
4.2a of Form FDA 3542a with respect to proposed labeling.
    Identifying the section(s) and subsection(s) of the approved 
labeling with specificity means listing on Form FDA 3542 (or, with 
respect to proposed labeling, Form FDA 3542a) each section and 
subsection of labeling that contains information describing the 
patented method of use.
     For prescription drug products with labeling in the 
``physician labeling rule'' (PLR) format (see ``Requirements on Content 
and Format of Labeling for Human Prescription Drug and Biological 
Products,'' 71 FR 3922, January 24, 2006), the section(s) and 
subsection(s) of the approved labeling should be identified by the 
section and subsection number (see 21 CFR 201.56(d) and 201.57). For 
example, ``section 1, subsection 1'' refers to the first indication 
listed in approved product labeling (see Sec.  201.57(c)(2)).
     For prescription drug products with labeling not in PLR 
format, the section(s) and subsection(s) of the approved labeling 
should be identified by the section and subsection title (see 
Sec. Sec.  201.56(b) and (e) and 201.80).
     For nonprescription drug products, the section(s) and 
subsection(s) of the approved labeling should be identified by the 
section and subsection title (see 21 CFR 201.66).
    An NDA holder should evaluate whether FDA-approved revisions to 
product labeling (e.g., conversion to PLR format) warrant submission of 
a revised Form FDA 3542 for the purpose of updating section 4.2a.
    FDA agrees that the protected use may comprise less than the 
entirety of a section or subsection of the approved product labeling. 
However, it is unnecessary to require an NDA holder to identify the 
specific language in approved product labeling that describes the 
patented method of use because the use code and identification of the 
specific section(s) and subsection(s) of labeling that describe the 
patented method of use are sufficient for FDA to evaluate a 505(b)(2) 
or ANDA applicant's proposed labeling. Accordingly, FDA declines to 
replace the term ``specific sections'' with ``specific language'' in 
Sec.  314.53(c)(2)(i)(O)(2) and (c)(2)(ii)(P)(2). FDA is removing the 
parenthetical text in proposed Sec.  314.53(c)(2)(i)(O)(2) and 
(c)(2)(ii)(P)(2) because it is unnecessary in light of other clarifying 
revisions to the regulations regarding the use code.
    If a 505(b)(2) or ANDA applicant submits a statement under section 
505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act, FDA evaluates the 
505(b)(2) or ANDA applicant's proposed labeling

[[Page 69600]]

to determine whether the applicant is not seeking approval for the 
protected use based on the use code submitted by the NDA holder and 
with reference to the labeling section(s) and subsection(s) identified 
by the NDA holder. FDA determines the specific labeling that describes 
the patented method of use, and decides whether the 505(b)(2) 
application can be approved with that information omitted from the 
labeling or, in the case of an ANDA, whether an ANDA that carves out 
the protected information from the labeling would be rendered less safe 
or effective than the listed drug for the remaining non-protected 
conditions of use and preclude approval (see Sec.  314.127(a)(7)). For 
example, FDA has determined that it can approve ANDAs for broad, 
general indications that may partially overlap with a protected method 
of use, as long as any express references to the protected use are 
omitted from the labeling (see Hospira, Inc. v. Burwell, 2014 WL 
4406901 at *17 (D. Md., Sept. 5, 2014) (upholding FDA's interpretation 
of section 505(j)(2)(A)(viii) of the FD&C Act)). Although 
identification of the section(s) and subsection(s) of labeling 
identified by the NDA holder may assist FDA in exercising its 
scientific judgment to implement section 505(b)(2)(B) and 
(j)(2)(A)(viii) of the FD&C Act, FDA is not bound by the section(s) and 
subsection(s) identified by the NDA holder in section 4.2a of Form FDA 
3542 in making its determination. FDA will use its independent 
scientific judgment to determine which section(s) and/or subsection(s) 
of labeling contain language that must be carved out based on the use 
code provided.
    FDA agrees that the identified section(s) and subsection(s) of 
labeling should not merely ``correspond'' to the method of use claimed 
by the patent because the term ``correspond'' could be interpreted in 
an inappropriately broad manner. To enhance accuracy, FDA is revising 
Sec.  314.53(b)(1), (c)(2)(i)(O)(2), and (c)(2)(ii)(P)(2) to require 
that the identified section(s) and subsection(s) of labeling 
``describe'' the method of use claimed by the patent.
    (Comment 16) One comment recommends that FDA require NDA holders to 
resubmit patent information on the updated Form FDA 3542 for all 
currently listed patents to maintain or revise the Orange Book listing. 
This comment also suggests that FDA request public comment on revisions 
to Forms FDA 3542a and 3542 to conform with the changes described in 
the proposed rule.
    (Response 16) We disagree with the recommendation to require NDA 
holders to resubmit Form FDA 3542 for all currently listed patents to 
maintain their current Orange Book listings. Given that over 10,000 
patent listings appear in the Orange Book, this recommendation would 
impose a significant burden on NDA holders and the Agency without a 
commensurate benefit. If a person seeks to confirm the accuracy or 
relevance of patent information currently listed in the Orange Book in 
light of the patent listing requirements set forth in Sec.  
314.53(b)(1) and (c), the person may submit a patent listing dispute 
under Sec.  314.53(f)(1) (see section V.B.4.a). NDA applicants and 
holders will be required to submit patent information on the updated 
Forms FDA 3542a and 3542 on a prospective basis.
    FDA requested public comment on its proposed revisions to the 
regulations and has made certain changes to the regulations in response 
to those comments. FDA is revising Forms FDA 3542a and 3542 to conform 
to the requirements established by this final rule.
    V.B.1.d. Patents previously submitted for listing. We proposed to 
revise Sec.  314.53(c)(2)(i)(J) and (c)(2)(ii)(K) to remove the 
requirement that an applicant provide information on whether the patent 
has been submitted previously for the NDA or supplement. We received no 
comments regarding this proposed revision; however, we have decided not 
to finalize this proposed change. Instead, we have decided to retain 
the existing requirement to assist the Orange Book staff with updating 
listed patent information where appropriate (see 68 FR 36676 at 36686 
and ``Agency Information Collection Activities; Submission for [OMB] 
Review; Comment Request; Applications for [FDA] Approval to Market a 
New Drug . . . ,'' 72 FR 21266 at 21269, April 30, 2007).
    V.B.1.e. Reissued patents. We proposed to require an NDA holder to 
submit additional information on patents that have been reissued by the 
USPTO under 35 U.S.C. 251. We proposed that an NDA applicant or holder 
must include information on whether a patent submitted for listing is a 
reissuance of a patent previously submitted for listing for the NDA or 
supplement (see proposed Sec.  314.53(c)(2)(i)(J) and (c)(2)(ii)(K)). 
Our proposal reflected our consideration of the original patent and the 
reissued patent as a ``single bundle of patent rights,'' albeit patent 
rights that may have changed with reissuance, for purposes of 
administering the patent certification requirements of the FD&C Act and 
any 30-month stay of approval or 180-day exclusivity that relates to a 
paragraph IV certification to the original patent. In the following 
paragraphs, we discuss three comments on this proposal (see section 
V.E.3 for a discussion of comments on patent certification requirements 
for reissued patents). After considering these comments, we are not 
finalizing this proposal.
    (Comment 17) The first comment recommends that FDA reevaluate its 
proposed regulations on reissued patents in light of a recent court 
decision rejecting FDA's ``single bundle of patent rights'' approach in 
a case involving the pre-MMA version of the FD&C Act. The second 
comment suggests that FDA further consider its ``single bundle of 
patent rights'' approach given the possibility for issuance of multiple 
patents based on continuing applications referring to the original 
patent application. The third comment supports the business certainty 
provided by FDA's ``single bundle of patent rights'' approach because 
the requirement for a 505(b)(2) or ANDA applicant to provide an 
appropriate patent certification or statement for a reissued patent 
would be governed by the provisions regarding untimely filed patents if 
either the original patent or the reissued patent was late-listed as to 
a pending 505(b)(2) application or ANDA.
    (Response 17) FDA agrees that the ``single bundle of patent 
rights'' approach reflected in its proposed regulations on reissued 
patents should not be finalized in light of the recent decision in 
Mylan Pharms., Inc. v. FDA, 594 Fed. Appx. 791 (4th Cir. Dec. 16, 
2014). In Mylan, the Court determined that a reissued patent ``is a 
separate grant of rights, even if elements of the reissued patent 
overlap with those of the original patent'' (see 594 Fed. Appx. 791 at 
797). The Court held that the statutory reference to ``the patent which 
is the subject of the certification'' in the pre-MMA version of section 
505(j)(5)(B)(iv) of the FD&C Act means that each patent (original and/
or reissued) that is the subject of a paragraph IV certification may be 
a basis for eligibility for 180-day exclusivity.
    Although the Mylan decision involved the pre-MMA version of the 
FD&C Act (in which eligibility for 180-day exclusivity was evaluated on 
a patent-by-patent basis), the Court's interpretation of ``the patent 
which is the subject of the certification'' is relevant to the current 
version of the FD&C Act when determining eligibility for first 
applicant status under the MMA's 180-day exclusivity scheme (see

[[Page 69601]]

section 505(j)(5)(B)(iii) of the FD&C Act). Accordingly, the Agency now 
considers reissued patents as separate and distinct from the original 
patent for purposes of administering the patent certification 
requirements of the FD&C Act and any 30-month stay of approval or 180-
day exclusivity. Given that a reissued patent will be treated no 
differently than an original patent, it is unnecessary for FDA to 
require that an NDA holder's submission of patent information include 
information on whether the patent is a reissued patent of a patent 
previously submitted for listing, and we are not finalizing proposed 
Sec.  314.53(c)(2)(i)(J) and (c)(2)(ii)(K).
    Upon patent reissuance, the original patent is surrendered and 
ceases to have legal effect (see 37 CFR 1.178(a)). Thus, an NDA holder 
is required to withdraw the original patent and request that the 
original patent be removed from listing in the Orange Book after patent 
reissuance (see Sec.  314.53(f)(2)). Consistent with our policy for any 
request to remove a patent from listing in the Orange Book, an original 
patent that has been reissued would remain listed in the Orange Book 
until FDA determined that no first applicant is eligible for 180-day 
exclusivity based on a paragraph IV certification to that patent or 
after the 180-day exclusivity period of a first applicant based on that 
patent has expired or has been extinguished.
V.B.2. When and Where To Submit Patent Information (Sec.  314.53(d))
    V.B.2.a. Submission of patent information for NDA supplements 
(Sec.  314.53(d)(2)). We proposed to revise Sec.  314.53(d)(2) to 
create two broad categories of supplements for purposes of required 
submission of patent information. For supplements that seek approval 
for a change that would result in a new entry in the Orange Book (e.g., 
a change to the dosage form, route of administration, strength, or 
prescription drug status), we proposed that an applicant would continue 
to submit the complete patent information required under Sec.  
314.53(c) with submission of the supplement and following approval, 
respectively. For supplements that seek approval for another type of 
change (e.g., to change the formulation, to add a new indication or 
other condition of use, or to make any other patented change regarding 
the drug substance, drug product, or any method of use that would not 
result in a new entry in the Orange Book), we proposed that the patent 
information submission requirements would depend on whether the 
existing patent information submitted to FDA for the product approved 
in the original NDA continued to claim the changed product.
    If the patents listed for the approved NDA also claim the drug or 
method of using the drug for which approval is sought in the NDA 
supplement, we proposed that we would permit an applicant to submit a 
statement declaring that the patent(s) currently listed for a specific 
NDA (identified by NDA number and product number as listed in the 
Orange Book) continue to claim the drug or method of using the drug for 
which approval is sought in the NDA supplement, if this statement is 
accompanied by the signed patent declaration verification required by 
Sec.  314.53(c)(2)(i)(Q) and (c)(2)(ii)(R) and if patent information 
required by Sec.  314.53(c)(2)(ii) previously was submitted. If, 
however, a listed patent no longer claims the product as changed by the 
supplement, then we proposed that the applicant must submit a request 
to correct or remove the patent information from the list at the time 
of approval of the supplement (see proposed Sec.  314.53(f)(2)). 
Correspondingly, if one or more existing patents claim the product as 
changed by the supplement and this patent information has not been 
submitted to FDA, we proposed that the applicant must submit the patent 
information with the supplement and following approval of the 
supplement. We proposed a conforming revision to Sec.  314.70(f) to 
clarify that an applicant that submits a supplement to an NDA also must 
comply with the patent information requirements under Sec.  314.53.
    One comment supports the proposal because it would reduce 
duplicative submissions of patent information for supplements. We are 
finalizing proposed Sec.  314.53(d)(2)(i) with an editorial change to 
clarify that Sec.  314.53(d)(2)(i)(A) and (B) also apply to a 
supplement that seeks to add (rather than change) a dosage form, route 
of administration, or strength. To facilitate implementation of this 
provision, we are revising Sec.  314.53(c)(2)(i)(F) and (c)(2)(ii)(F) 
to require that the NDA applicant or holder, respectively, identify the 
dosage form(s), route(s) of administration and whether the drug is 
proposed or approved for prescription use or over-the-counter (OTC) use 
in its submission of patent information. We are making conforming 
revisions to Forms FDA 3542a and 3542.
    We are making several clarifying revisions to proposed Sec.  
314.53(d)(2)(ii). The proposed rule explained that we would permit an 
NDA holder to submit a statement declaring that the patent(s) currently 
listed for a specific NDA continue to claim the drug or method of using 
the drug for which approval is sought in the NDA supplement (instead of 
resubmitting the patent information with the NDA supplement), if this 
statement is accompanied by a signed patent declaration verification 
(see 80 FR 6802 at 6823). Consistent with the intent of the proposed 
rule to reduce duplicative submissions of patent information and 
enhance efficiency, we are not requiring an NDA holder to submit a 
statement with an NDA supplement if the NDA holder is not required to 
resubmit patent information pursuant to Sec.  314.53(d)(2)(ii)(A). 
Accordingly, if an NDA supplement is approved for a change other than 
one of the changes listed in Sec.  314.53(d)(2)(i) and the NDA holder 
does not submit Form FDA 3542 or submit a request to withdraw the 
patent or patent information from the list under Sec.  314.53(f)(2)(iv) 
(see Sec.  314.53(d)(2)(ii)(B) and (C)), FDA will consider the NDA 
holder to have affirmed that any currently listed patent(s) continues 
to claim the drug product as changed by the supplement. We are revising 
Sec.  314.53(d)(2)(ii)(A) to clarify that patent information already 
submitted to FDA refers to information required by Sec.  314.53(c). We 
also are revising Sec.  314.53(d)(2)(ii)(A) to clarify that the 
requirement to resubmit patent information with a supplement if the 
description of the patented method of use would change upon approval of 
the supplement refers to the published description of the patented 
method of use (i.e., the use code).
    We are making a conforming revision to Sec.  314.53(c) to clarify 
that if the applicant submits a supplement for a change other than one 
of the changes listed under Sec.  314.53(d)(2)(i), then the patent 
information submission requirements of Sec.  314.53(d)(2)(ii) apply 
(see Sec.  314.53(c)(2)(i)(S)(3) and (c)(2)(ii)(T)(3)).
    V.B.2.b. Untimely filing of patent information (Sec. Sec.  
314.53(d)(3), 314.50(i)(4), and 314.94(a)(12)(vi)). We proposed to 
revise our regulations regarding the submission of information on 
patents issued after the approval of an NDA or supplement to expressly 
describe our longstanding practice with respect to listing patent 
information that is not timely filed (see proposed Sec.  314.53(d)(3)). 
Proposed Sec.  314.53(d)(3) stated that if a patent is issued after 
approval and the required patent information is not submitted within 30 
days of the issuance of the patent, FDA will list the patent, but 
patent certifications will be governed by the provisions regarding 
untimely filed

[[Page 69602]]

patents in Sec. Sec.  314.50(i)(4) and (6) and 314.94(a)(12)(vi) and 
(viii). We also proposed to revise Sec. Sec.  314.50(i)(4) and 
314.94(a)(12)(vi) to state that, except as provided in Sec.  
314.53(f)(1), an NDA holder's amendment to the description of the 
approved method(s) of use claimed by the patent (``use code'') will be 
considered untimely filing of patent information if:
     The amendment is submitted more than 30 days after patent 
issuance and it is not related to a corresponding change in approved 
product labeling; or
     The amendment is submitted more than 30 days after a 
corresponding change in approved product labeling.
    Two comments agreed with this proposal. In the following 
paragraphs, we discuss two other comments on the proposal for certain 
amendments to the description of the approved method of use claimed by 
the patent to be considered untimely filing of patent information. 
After considering these comments, we are making clarifying revisions to 
the regulations and describing an additional set of circumstances in 
which an NDA holder's amendment to the description of the approved 
method(s) of use claimed by the patent will not be considered untimely 
filing of patent information.
    (Comment 18) One comment recommends that FDA withdraw its proposal, 
given that changes in patent law or interpretation, developments in 
patent-specific litigation, and/or proceedings before the USPTO may 
affect the scope of a patent claim's coverage and necessitate revisions 
to the use code. The comment notes that these events typically occur 
more than 30 days after patent issuance and do not involve a 
corresponding change in product labeling. Another comment recommends 
that FDA reevaluate its proposal to consider certain changes to the use 
code as untimely filed patent information in light of the lack of 
clarity on setting use codes.
    (Response 18) We decline to withdraw our proposal given the 
important role of use codes in enabling a 505(b)(2) or an ANDA 
applicant to state that it is not seeking approval for the method of 
use claimed by the patent (see section 505(b)(2)(B) and (j)(2)(D)(viii) 
of the FD&C Act). However, we agree that revisions to the use code may 
be appropriate in other limited circumstances, as reflected in our 
revisions to Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi). Our 
approach is intended to enhance the accuracy of use codes and ensure 
that 505(b)(2) and ANDA applicants have timely notice of changes to the 
asserted patent coverage for a listed drug, while reducing 
opportunities for manipulation of patent use codes.
    As a preliminary matter, we are revising the regulations to more 
clearly describe the circumstances in which an NDA holder's amendment 
to the description of the approved method(s) of use claimed by the 
patent will not be considered untimely filing of patent information 
(see Sec. Sec.  314.50(i)(4)(i)(A) and (B) and 314.94(a)(12)(vi)(A)(1) 
and (2)). As revised, an NDA holder's amendment to the description of 
the approved method(s) of use claimed by the patent will be considered 
timely filed if it is submitted within 30 days of patent issuance or 
within 30 days of approval of a corresponding change to product 
labeling. We also are revising the regulations to provide that an NDA 
holder's amendment to the description of the approved method(s) of use 
claimed by the patent will be considered timely filed patent 
information if it is submitted within 30 days of a decision by the 
USPTO or a Federal court that is specific to the patent and alters the 
construction of a method-of-use claim(s) of the patent (see Sec. Sec.  
314.50(i)(4)(i)(C) and 314.94(a)(12)(vi)(A)(3)). The amendment must 
contain a copy of the USPTO or court decision, and the accompanying 
Form FDA 3542 must identify the decision as a change related to the 
patent in section 1.h of the form (see the following discussion 
regarding revisions to Sec.  314.53(c)(2)(i)(K) and (c)(2)(ii)(L)).
    Our addition of Sec. Sec.  314.50(i)(4)(i)(C) and 
314.94(a)(12)(vi)(A)(3) permits NDA holders to make timely revisions to 
the use code based on a patent-specific decision by the USPTO (e.g., 
inter partes review, post-grant review, and reexamination) or by a 
Federal court (e.g., Markman hearing) that construes the terms of the 
patent claim(s). An NDA holder may submit a revised use code based on a 
patent-specific decision by either a Federal district court, the Court 
of Appeals for the Federal Circuit, or the U.S. Supreme Court. We 
decline to broaden the scope of this provision to allow for use code 
changes to be considered timely filed based solely on changes in patent 
law or interpretation that are not specific to the patent for which the 
use code was submitted because we are not experts in patent law and 
would be unable to evaluate arguments that could effectively remove the 
limitation for untimely filing of method-of-use patent information.
    Our clarifying revisions to the regulations are expected to address 
concerns about how to set use codes, and there is no need to reevaluate 
our proposal on this basis.
    To facilitate implementation of this provision, FDA is revising 
Sec.  314.53(c)(2)(i)(K) and (c)(2)(ii)(L) to require that if the 
patent has been submitted previously for listing, the NDA holder must 
identify all change(s) from the previously submitted patent information 
and specify whether the change is related to the patent (e.g., patent 
term extension or patent-specific decision by the USPTO or a Federal 
court) or related to an FDA action or procedure (e.g., FDA approval of 
a supplement that changes the approved conditions of use of the drug). 
This information will assist the Orange Book staff in updating listed 
patent information where appropriate and replaces the current 
requirement that an applicant only identify whether the expiration date 
is a new expiration date.
    We also are making technical amendments in Sec. Sec.  314.50(i)(4) 
and 314.94(a)(12)(vi) to explain that a 505(b)(2) or ANDA applicant 
generally is not required to submit a patent certification or statement 
to address the patent or patent information that is late-listed with 
respect to the pending 505(b)(2) application or ANDA. Although a patent 
certification or statement generally would not be required in this 
circumstance, we would permit an applicant to submit and maintain a 
patent certification (including a paragraph IV certification) or a 
statement pursuant to section 505(b)(2)(B) or 505(j)(2)(B)(viii) of the 
FD&C Act, if desired. For example, an ANDA applicant may wish to submit 
a paragraph IV certification to challenge the method-of-use patent with 
the revised use code if the applicant may be eligible for 180-day 
exclusivity based on that certification.
    V.B.2.c. Where to send submissions of Forms FDA 3542a and 3542 
(Sec.  314.53(d)(4)). We proposed to clarify that patent information 
submitted on Form FDA 3542a with the filing of an NDA, amendment, or 
supplement must be submitted to the CDER Central Document Room, and 
should not be submitted to the Orange Book staff (see proposed Sec.  
314.53(d)(4)(i); see also Sec. Sec.  314.50(h) and 314.70(f)). We also 
proposed to require that patent information submitted on Form FDA 3542 
upon and after approval of an NDA or supplement be submitted directly 
to the Orange Book staff through the OGD Document Room. Our proposal to 
designate the OGD Document Room as the official repository for 
submission of Form FDA 3542 was intended to facilitate prompt listing 
of patent information in the Orange Book after Form FDA 3542 has been 
officially

[[Page 69603]]

received by the Agency (see proposed Sec.  314.53(d)(4)(ii) and 
(d)(5)).
    In the following paragraphs, we discuss a comment on these proposed 
revisions. After considering this comment, we are finalizing Sec.  
314.53(d)(4)(ii) with revisions to maintain the CDER Central Document 
Room as the official repository for submission of Form FDA 3542 and we 
are finalizing Sec.  314.53(d)(4)(i) and (ii) to clarify that Forms FDA 
3542a and 3542 can be submitted electronically. We also are finalizing 
Sec.  314.53(d)(4)(i) and (ii) with an editorial correction to the 
title of Forms FDA 3542a and 3542, and we are making the same 
correction in Sec.  314.53(f)(2)(ii) through (iv).
    (Comment 19) One comment requests confirmation that NDA holders may 
submit Form FDA 3542 to the OGD Document Room through the Electronic 
Submissions Gateway (ESG). The comment also recommends that FDA clarify 
that Form FDA 3542a must be submitted to the NDA via CDER's Central 
Document Room.
    (Response 19) FDA is revising Sec.  314.53(d) to expressly provide 
that Form FDA 3542 can be submitted in an electronic format submission 
that complies with Sec.  314.50(l)(5), which permits submission through 
the ESG. This revision and the corresponding revision to Sec.  
314.53(d)(5) are intended to clarify how submission dates are 
determined for Form FDA 3542, given the implications of untimely filing 
of patent information on the patent certification obligations of 
505(b)(2) and ANDA applicants that rely upon the listed drug (see 
Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi)). Beginning in May 2017, 
Form FDA 3542 and other submissions under section 505(b), (i), and (j) 
of the FD&C Act must be submitted in the electronic format specified by 
FDA (see section 745A(a) of the FD&C Act (21 U.S.C. 379k-1(a)) and 
guidance for industry entitled ``Providing Regulatory Submissions in 
Electronic Form--Certain Human Pharmaceutical Product Applications and 
Related Submissions Using the eCTD Specifications'' (May 2015), 
available at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm). 
Accordingly, we only have specified the method of submission where it 
is important to describe how receipt dates or submission dates are 
determined for a particular type of submission.
    Based on the transition to electronic submission of Form FDA 3542 
and related changes in FDA's administrative processes, we are not 
finalizing our proposal to change the official repository for 
submission of Form FDA 3542. Thus, Form FDA 3542 must continue to be 
submitted to the NDA via the CDER Central Document Room or the ESG. The 
CDER Central Document Room and the ESG promptly direct submissions of 
Form FDA 3542 to the Orange Book staff for listing in the Orange Book. 
To ensure that patents and patent information are listed in the Orange 
Book only after Form FDA 3542 has been officially received by FDA, the 
Orange Book staff intends to rely only on submissions of Form FDA 3542 
that are received from the Central Document Room and disregard any 
duplicate copies or courtesy copies of Form FDA 3542 that are submitted 
through other channels. We are revising Sec.  314.53(d)(4)(ii) to 
emphasize that Form FDA 3542 should not be submitted to the Orange Book 
staff.
    V.B.2.d. Submission date of patent information (Sec.  
314.53(d)(5)). We proposed to revise Sec.  314.53(d)(5) to establish 
that the submission date of patent information provided by an NDA 
holder after approval of an application is the earlier of the date on 
which Form FDA 3542 is date-stamped by the OGD Document Room or 
officially received electronically by FDA through the ESG (i.e., at the 
completion of electronic transmission). We proposed that patent 
information sent to another location at FDA would not be considered 
received by FDA for purposes of Sec.  314.53(d)(3) on timely filing and 
a 505(b)(2) or ANDA applicant's patent certification obligations 
pursuant to Sec.  314.50(i)(4) and (6) or Sec.  314.94(a)(12)(vi) and 
(viii), respectively, unless it is sent to the official repository 
identified in the regulation. In the following paragraphs, we discuss 
two comments on this provision. After considering these comments, we 
are finalizing Sec.  314.53(d)(5) with revisions unrelated to the 
comments to conform to the changes made to Sec.  314.53(d)(4)(ii).
    (Comment 20) One comment suggests that FDA provide a list of 
untimely filed patent information to facilitate evaluation of patent 
certification obligations by 505(b)(2) and ANDA applicants. Another 
comment recommends that FDA include in the Orange Book the date on 
which the patent information was submitted to FDA.
    (Response 20) FDA agrees that modifying the Orange Book to list the 
date on which patent information was submitted to FDA as described in 
Sec.  314.53(d)(5) would enable applicants to determine whether a 
patent is late-listed as to a pending 505(b)(2) application or ANDA and 
avoid the need for applicants to contact the Orange Book staff for this 
information. FDA intends to list the date of submission of patents and 
patent information in the Orange Book on a prospective basis beginning 
as soon as practicable after the effective date of this rule. This 
addition to the Orange Book does not require any modification to the 
regulations. FDA does not intend to separately publish a list of 
untimely filed patent information.
V.B.3. Public Disclosure of Patent Information (Sec.  314.53(e))
    We proposed technical corrections to Sec.  314.53(e) to delete the 
reference to monthly supplements to the Orange Book and clarify that 
copies of the ``submitted patent information'' (rather than copies of 
the ``file'') may be requested from FDA's Freedom of Information Staff. 
We also proposed to expressly state that the submitted patent 
information, and requests for delisting patents, will be subject to 
public disclosure (see proposed Sec.  314.53(e)). In the preamble to 
the proposed rule, we explained that FDA may elect to proactively post 
on FDA's Web site a copy of the submitted patent information (Form FDA 
3542) for listed patents in advance of a request under the Freedom of 
Information Act (FOIA) based on our anticipation of requests for this 
information. In the following paragraphs, we discuss a comment on the 
potential for proactive posting of Form FDA 3542 on FDA's Web site. 
After considering this comment, we are making an editorial correction 
to clarify the information that may be subject to public disclosure.
    (Comment 21) One comment urges FDA not to proactively post Form FDA 
3542 on the FDA Web site based on concerns that the patent information 
could be misused or lead to misinterpretation of the scope of relevant 
patent rights in litigation or commercial contexts.
    (Response 21) FDA is not persuaded by the comment, given that Form 
FDA 3542 must contain the verification required by Sec.  
314.53(c)(2)(ii)(R) and may be subject to disclosure under FOIA and 
applicable disclosure regulations. Moreover, FDA has advised 
prospective 505(b)(2) and ANDA applicants that the use code and other 
information provided on Form FDA 3542 is not meant to substitute for 
the applicant's review of the patent. However, at this time, FDA does 
not intend to proactively post Form FDA 3542 for patent information 
submitted for listing in the Orange Book because there is an adequate 
mechanism to obtain a Form FDA 3542 on an individual basis through a 
FOIA request. We are revising Sec.  314.53(e) to clarify that the 
submitted

[[Page 69604]]

patent information and requests to remove a patent or patent 
information from the list may be subject to public disclosure.
V.B.4. Correction or Change of Patent Information (Sec.  314.53(f))
    V.B.4.a. Requests by persons other than the NDA holder (Sec.  
314.53(f)(1)). We proposed to revise Sec.  314.53(f) to clarify and 
improve the mechanism for challenging the accuracy or relevance of 
patent information submitted to the Agency under Sec.  314.53 and 
listed in the Orange Book (see proposed Sec.  314.53(f)(1)). First, we 
proposed to establish a 30-day timeframe in which the NDA holder would 
be required to respond to FDA's request to confirm the correctness or 
omission of patent information to facilitate timely resolution of the 
patent listing dispute. Second, we proposed enhanced procedures to 
govern challenges to the accuracy or relevance of an NDA holder's 
submission of method-of-use patent information so that the Agency has 
additional information to implement section 505(b)(2)(B) and 
(j)(2)(A)(viii) of the FD&C Act in cases where the accuracy or 
relevance of the use code is disputed (see proposed Sec.  
314.53(f)(1)).
    For a patent listing dispute regarding method-of-use patent 
information, we proposed to ask the NDA holder to confirm the 
correctness of its description of the approved indication or method of 
use that has been included as the ``use code'' in the Orange Book, and 
provide information on the specific approved use claimed by the patent 
that would enable the Agency to make a determination in accordance with 
section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act (see proposed 
Sec.  314.53(f)(1)). We proposed that if the NDA holder confirms the 
accuracy of its submitted patent information in response to FDA's 
request, fails to timely respond to the request, or submits a revision 
to the use code that does not provide adequate clarity for FDA to 
determine whether the scope of a proposed labeling carve-out would be 
appropriate based on the NDA holder's use code and approved labeling, 
FDA would review a proposed labeling carve-out(s) for the 505(b)(2) 
application or ANDA with deference to the 505(b)(2) or ANDA applicant's 
interpretation of the scope of the patent. In such a case, we explained 
that FDA would consider the use code and labeling information submitted 
by the NDA holder on Form FDA 3542, the history of labeling changes 
related to approval of an indication(s) for the drug product, the 
505(b)(2) or ANDA applicant's interpretation of the scope of the 
patent, the need for consistent labeling among products approved under 
section 505(j) of the FD&C Act, and the requirements of Sec. Sec.  
314.94(a)(8)(iv) and 314.127(a)(7), as appropriate.
    Two comments support FDA's proposed revisions to the patent listing 
dispute procedure. In the following paragraphs, we discuss several 
other comments on this proposal. After considering these comments, we 
are revising Sec.  314.53(f)(1) to describe the rules that will apply 
to patent listing disputes involving drug substance, drug product, and 
method-of-use claims. We also are revising Sec.  314.53(c)(2)(ii)(R) to 
expressly state that the requirement to verify the accuracy and 
completeness of the submission of patent information applies to a 
response to a patent listing dispute under Sec.  314.53(f)(1). We 
intend to take a stepwise approach and evaluate whether FDA's revisions 
to the regulations on submission of method-of-use patent information 
(see Sec.  314.53(b)(1) and (c)(2)) and patent listing dispute 
procedures adequately address the problem of overbroad and ambiguous 
use codes before we establish a process to review a proposed labeling 
carve-out with deference to the 505(b)(2) and/or ANDA applicant(s)' 
interpretation of the scope of the patent. Therefore, at this time, we 
are not finalizing our proposal to review a proposed labeling carve-out 
with deference to the applicant(s)' interpretation of the scope of the 
patent in certain circumstances. We will continue to consider whether 
there is a need to finalize this proposal in the future.
    (Comment 22) Three comments indicate that there are inconsistencies 
between the text of proposed Sec.  314.53(f) and the process described 
in the corresponding preamble, and request that FDA clarify the 
circumstances in which the Agency proposes to review a proposed 
labeling carve-out for a 505(b)(2) application or ANDA with deference 
to the 505(b)(2) or ANDA applicant's interpretation of the scope of the 
patent. Several comments contend that it is inappropriate to defer to 
the 505(b)(2) or ANDA applicant's interpretation of the scope of the 
patent where the NDA holder has confirmed the accuracy of the use code. 
One comment asserts that this approach will encourage 505(b)(2) and 
ANDA applicants to routinely dispute method-of-use patent information 
in an attempt to receive deference on a narrow interpretation of the 
method-of-use patent and submit a statement under section 505(b)(2)(B) 
or (j)(2)(A)(viii) of the FD&C Act instead of a patent certification. 
One comment also contends that the Agency's standard for determining 
that an NDA holder's revision to the use code ``does not provide 
adequate clarity'' or determining that there is ``insufficient 
information'' to evaluate a proposed labeling carve-out is 
impermissibly vague.
    (Response 22) FDA has made multiple changes to address the issue of 
overbroad and ambiguous use codes, including revisions to the 
regulations on submission of patent information and revisions to the 
patent listing dispute procedures (see sections V.B.1.c and V.B.2.b). 
We initially intend to evaluate whether these revisions to the 
regulations adequately address the problem of overbroad and ambiguous 
use codes. If these revisions to our regulations do not adequately 
address the problem, we will further consider whether to finalize the 
proposal to review a proposed labeling carve-out for a 505(b)(2) 
application or ANDA with deference to the 505(b)(2) and/or ANDA 
applicant(s)' interpretation of the scope of the patent. If FDA decides 
to finalize the proposal, FDA would clarify the process and the 
circumstances in which such deference may be given.
    We are revising the regulation to provide a more detailed 
description of the procedure for patent listing disputes directed to 
the accuracy or relevance of submitted patent information regarding an 
approved method of using the drug product (see Sec.  314.53(f)(1) and 
(f)(1)(i)(B); see also Sec.  314.53(f)(1)(i)(A) (describing patent 
listing dispute procedures directed to drug substance or drug product 
claims)). We also are revising Sec.  314.53(c)(2)(ii)(R) to expressly 
state that the requirement that an NDA holder verify the accuracy and 
completeness of the submission of patent information applies to a 
response to a request under Sec.  314.53(f)(1). This regulatory 
approach is intended to provide the Agency with additional information 
to facilitate implementation of section 505(b)(2)(B) and 
(j)(2)(A)(viii) of the FD&C Act (see section 701(a) of the FD&C Act).
    For all patent listing disputes, we are requiring that the patent 
listing dispute communication contain a statement of dispute that 
describes the specific grounds for disagreement regarding the accuracy 
or relevance of patent information for FDA to send to the applicable 
NDA holder. If a person disputes the accuracy or relevance of submitted 
patent information regarding an approved method of using the drug 
product, this statement of dispute must be only a narrative description 
(no more than 250 words) of the person's

[[Page 69605]]

interpretation of the scope of the patent with respect to the method of 
use.
    FDA intends to forward the statement of dispute (without review or 
redaction) to the applicable NDA holder using the electronic mail 
(email) address or facsimile (fax) number provided by the NDA holder on 
the most recent Form FDA 356h submitted to the NDA. Therefore, the 
person submitting the patent listing dispute communication should 
clearly identify the statement of dispute that he or she intends for 
FDA to send to the applicable NDA holder, and only include information 
for which the person consents to disclosure.
     For patent listing disputes directed to drug substance or 
drug product claims, the NDA holder must confirm the correctness of the 
patent information and include the signed verification required by 
Sec.  314.53(c)(2)(ii)(R) or withdraw or amend the patent information 
in accordance with Sec.  314.53(f)(2) within 30 days of the date on 
which the Agency sends the statement of dispute. Although proposed 
Sec.  314.53(f)(1) would have permitted disputes over the omission of 
patent information, it is unnecessary for FDA to request the NDA holder 
to confirm the omission of patent information for a listed patent 
because we no longer require an NDA holder to identify whether a patent 
claims both the drug substance and the drug product (see Sec.  
314.53(c)(2)(ii)(T)). Accordingly, we are making a conforming amendment 
to remove the phrase ``or omission of patent information'' from Sec.  
314.53(f)(1)(i)(A). Unless the NDA holder withdraws or amends its 
patent information in response to the patent listing dispute, the 
Agency will not change the patent information in the Orange Book (see 
Sec.  314.53(f)(1)(i)(A)).
     For patent listing disputes directed to method-of-use 
claims, the NDA holder must confirm the correctness of the NDA holder's 
description of the approved method of use claimed by the patent that 
has been included as the ``use code'' in the Orange Book or withdraw or 
amend the patent information in accordance with Sec.  314.53(f)(2). In 
either case, the NDA holder must provide a narrative description (no 
more than 250 words) of the NDA holder's interpretation of the scope of 
the patent that explains why the existing or amended ``use code'' 
describes only the specific approved method of use claimed by the 
patent for which a claim of patent infringement could reasonably be 
asserted if a person not licensed by the owner of the patent engaged in 
the manufacture, use, or sale of the drug product. The NDA holder must 
also include the signed verification required by Sec.  
314.53(c)(2)(ii)(R) and submit its response within 30 days of the date 
on which the Agency sends the statement of dispute (see Sec.  
314.53(f)(1)(i)(B)). Any response from the NDA holder that is submitted 
after 30 days will be considered untimely. The narrative description 
must only contain information for which the NDA holder consents to 
disclosure because FDA will send the text of the statement to the 
person who submitted the patent listing dispute without review or 
redaction to further assist the person (generally a 505(b)(2) or ANDA 
applicant, a prospective applicant, or its representative) in 
determining whether a use for which an applicant may seek approval is a 
protected use.
    We are revising the regulation to clarify that if the NDA holder 
timely responds to the patent listing dispute with a confirmation of 
the correctness of the patent information, the narrative description 
required by Sec.  314.53(f)(1)(i)(B), and the signed verification 
required by Sec.  314.53(c)(2)(ii)(R), the Agency will not change the 
patent information in the Orange Book (see Sec.  
314.53(f)(1)(i)(B)(1)). We are also revising the regulation to more 
clearly state that if the NDA holder timely responds to FDA's request 
with revised patent information, the narrative description required by 
Sec.  314.53(f)(1)(i)(B), and the signed verification required by Sec.  
314.53(c)(2)(ii)(R), FDA will update the Orange Book to reflect the 
revised patent information (see Sec.  314.53(f)(1)(i)(B)(2) and 
Response 26). This approach provides additional clarity, and 
establishes a mechanism for a person (including a 505(b)(2) or ANDA 
applicant) to request that an NDA holder confirm compliance with the 
updated requirements for submission of patent information described in 
Sec.  314.53(b) and (c).
    A 505(b)(2) application or ANDA must contain an appropriate 
certification or statement for each listed patent, including the 
disputed patent, during and after the patent listing dispute (see Sec.  
314.53(f)(1)(ii)). A disputed method-of-use patent may continue to be 
the subject of a paragraph IV certification. We do not believe that an 
ongoing patent listing dispute process will have an impact on the 
timing of approval of a 505(b)(2) application or ANDA that is otherwise 
eligible for approval and relies on the listed drug for which the 
disputed patent is listed in the Orange Book. FDA may consider the 
narrative description from the NDA holder required by Sec.  
314.53(f)(1)(i)(B), as appropriate, to assist FDA in exercising its 
scientific judgment to implement section 505(b)(2)(B) and 
(j)(2)(A)(viii) of the FD&C Act.
    To advise prospective and pending 505(b)(2) or ANDA applicants of a 
patent listing dispute involving a method-of-use patent, FDA will 
promptly post information about the patent listing dispute on a Web 
page linked to the Orange Book. FDA intends to provide information such 
as the relevant drug product, NDA number, NDA holder, U.S. Patent 
Number, relevant use code(s), and whether the NDA holder has timely 
responded to the patent listing dispute (see Sec.  314.53(f)(1)(iii)).
    (Comment 23) Three comments recommend that FDA withdraw or revise 
the proposal to review, in certain circumstances, a proposed labeling 
carve-out for a 505(b)(2) application or ANDA with deference to the 
505(b)(2) or ANDA applicant's interpretation of the scope of the 
patent. One comment contends that there is no basis for FDA's proposed 
approach because the statutory scheme contemplates that disputes over 
the scope of a method-of-use patent will be resolved by Federal courts 
in patent infringement litigation, especially given that the MMA 
established a counterclaim procedure in which a 505(b)(2) or ANDA 
applicant may seek an order requiring the NDA holder to correct or 
delete the submitted patent information. Another comment maintains that 
it would be legally inappropriate for FDA to defer to the 505(b)(2) or 
ANDA applicant's view of the scope of a patent that the applicant does 
not own, especially if the NDA holder has confirmed the accuracy of the 
use code. Two comments suggest that when patent listing disputes arise, 
FDA should seek clarification or correction of patent information 
through other means.
    (Response 23) We believe that FDA has the authority to establish a 
regulation describing the limited circumstances in which the Agency 
would defer to the 505(b)(2) or ANDA applicant's interpretation of the 
scope of a patent that it does not own. However, in light of the 
incremental approach that we are taking to this issue, we are not 
finalizing this aspect of our proposal at this time. We will continue 
to consider whether there is a need to finalize this proposal in the 
future.
    The statutory provisions that permit a 505(b)(2) or ANDA applicant 
to submit a statement that a listed patent does not claim a use for 
which the applicant is seeking approval complement the patent 
certification requirements (see section 505(b)(2)(A) and (B) and 
(j)(2)(A)(vii)

[[Page 69606]]

and (viii) of the FD&C Act). FDA's revised regulations are intended to 
preserve FDA's ministerial role in listing patents (see 59 FR 50338 at 
50349 and 68 FR 36676 at 36683 and 36687) and to also address ambiguous 
or overbroad use codes that could be a barrier to approval of a 
505(b)(2) application or ANDA for uses that are not claimed by the 
listed patent (see Sec.  314.53(b)(1), (c)(2)(ii)(P)(3), and (f)(1)). 
If an NDA holder provides a timely response to a patent listing dispute 
and a 505(b)(2) or ANDA applicant disagrees with the NDA holder's 
response to the patent listing dispute (or disagrees with the use 
code), the 505(b)(2) or ANDA applicant may submit a paragraph IV 
certification to challenge the method-of-use patent and assert a 
counterclaim in the context of an infringement action or pursue a 
declaratory judgment action, as appropriate, to obtain patent certainty 
(see section 505(c)(3)(D)(i) and (ii) and (j)(5)(C)(i) and (ii) of the 
FD&C Act).
    We disagree, however, that the counterclaim procedure in section 
505(c)(3)(D)(ii) and (j)(5)(C)(ii) of the FD&C Act obviates the need 
for an enhanced patent listing dispute procedure. Nothing in the FD&C 
Act precludes FDA from developing a procedure for patent listing 
disputes in light of our broad authority to issue regulations for the 
efficient enforcement of the FD&C Act. As the U.S. Supreme Court 
observed in Caraco Pharm. Labs., ``the counterclaim cannot restore the 
smooth working of a statutory scheme thrown off kilter by an overly 
broad use code. At best, it permits the generic manufacturer to do what 
the scheme contemplates it should do--file an ANDA with a section viii 
statement--but only after expensive and time-consuming litigation. A 
fix is in order, but it must come from Congress or FDA'' (132 S.Ct. 
1670 at 1689).
    Finally, we note that comments recommending that FDA seek 
clarification or correction of patent information through other means 
do not describe an alternative to the approach we proposed. We believe 
that the modifications that we have made to the patent listing dispute 
procedure, discussed in Response 22, and our stepwise approach to 
evaluating whether FDA's revisions to this procedure and the 
regulations on submission of method-of-use patent information address 
the problem of overbroad and ambiguous use codes, adequately address 
the comments received on our proposal.
    (Comment 24) Three comments assert that FDA's proposed deference to 
the 505(b)(2) or ANDA applicant's interpretation of the scope of the 
patent would be inconsistent with the Agency's longstanding ministerial 
role in patent-related matters. These comments suggest that FDA lacks 
the expertise to assess the adequacy of use codes and determine whether 
deference to the 505(b)(2) or ANDA applicant's interpretation of the 
scope of the patent is justified. A fourth comment suggests that FDA 
provide an administrative appeals process and Administrative Law Judge 
review where FDA reviews a proposed labeling carve-out for a 505(b)(2) 
application or ANDA with deference to the 505(b)(2) or ANDA applicant's 
interpretation of the scope of the patent. This comment also suggests 
that FDA avoid a ``mere ministerial approach.''
    (Response 24) As noted in Response 23, we are not finalizing this 
proposal at this time. Accordingly, we do not need to address comments 
regarding specific aspects of implementation of this proposal in this 
final rule.
    (Comment 25) One comment recommends that FDA require an NDA holder 
to respond to a request to confirm the accuracy or relevance of patent 
information in 15 days, rather than 30 days. The comment maintains that 
a 15-day timeframe is consistent with the regulatory timeframe to make 
corrections to an incomplete or otherwise inadequate submission of 
patent information (see Sec.  314.53(c)(2)(ii)).
    (Response 25) We decline to modify the regulation as requested. We 
believe that a period of 30 days from the date on which FDA sends the 
statement of dispute to the NDA holder provides an appropriate 
opportunity for the NDA holder to consider the statement of dispute and 
submit a response that addresses the requirements of Sec.  
314.53(f)(1)(i).
    (Comment 26) Two comments recommend that FDA clarify that an NDA 
holder's amendment to the use code in response to a patent listing 
dispute will not be considered untimely filed patent information under 
Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi). One comment expresses 
concern that whether and how an NDA holder responds to a method-of-use 
patent listing dispute may affect the availability of a 30-month stay 
should the NDA holder subsequently file a patent infringement action in 
response to notice of a paragraph IV certification to the patent.
    (Response 26) We agree that an NDA holder's amendment to its use 
code or related information on Form FDA 3542 in response to a patent 
listing dispute should not be considered untimely filed patent 
information if it is submitted within 30 days of FDA's request under 
Sec.  314.53(f)(1)(i)(B) and contains the information required under 
Sec.  314.53(f)(1)(i)(B)(1) or (2) (see Sec. Sec.  314.50(i)(4)(i) and 
314.94(a)(12)(vi)(A) (describing untimely filing of patent information 
``except as provided in Sec.  314.53(f)(1)'')). We note, however, that 
if an NDA holder responds to the patent listing dispute with an 
amendment to its use code more than 30 days after the date on which FDA 
sends the statement of dispute to the NDA holder, FDA will consider the 
amendment to be untimely filing of patent information because the 
submission does not comply with the requirements of Sec.  314.53(f)(1).
    The patent listing dispute procedure would not have an impact on 
the availability of a 30-month stay if other statutory and regulatory 
criteria are met (see section 505(c)(3)(C) and (j)(5)(B)(iii) of the 
FD&C Act and Sec.  314.107).
    V.B.4.b. Requests by NDA holder (Sec.  314.53(f)(2)). We proposed 
to expressly require that if an NDA holder determines that a patent or 
patent claim (e.g., a method-of-use claim) no longer meets the 
statutory requirements for listing, the NDA holder must promptly notify 
FDA to withdraw the patent or patent information and request that the 
patent or patent information be removed from the list (see proposed 
Sec.  314.53(f)(2)(i) and section 505(b)(1) and (c)(2) of the FD&C 
Act). If an NDA holder is required by court order to amend patent 
information or withdraw a patent from the list, we proposed to require 
the NDA holder to submit a copy of the court order to the Orange Book 
Staff within 14 calendar days of the date on which the order was 
entered. We also proposed to codify our current practice of removing a 
patent or patent information from the Orange Book when the NDA holder 
has informed us that the patent no longer meets the statutory 
requirements for listing if there is no first applicant eligible for 
180-day exclusivity or upon the expiration of the 180-day exclusivity 
period (see proposed Sec.  314.53(f)(2)(i)). In addition, we proposed 
that if the term of the patent is extended under the patent term 
restoration provisions of 35 U.S.C. 156, the NDA holder must submit a 
correction to the patent expiration date on Form FDA 3542 within 30 
calendar days of receipt of a certificate of extension or documentation 
of an extension of the term of the patent (see proposed Sec.  
314.53(f)(2)(ii) and 35 U.S.C. 156(e)(1) and (2)).
    We proposed to require that corrections or changes to previously 
submitted patent information must be submitted on Form FDA 3542a or 
3542,

[[Page 69607]]

as appropriate (see proposed Sec.  314.53(f)(2)(iii)). However, we 
proposed to clarify that an NDA holder's withdrawal of a patent and 
request to remove a patent from the list is not required to be 
submitted on Form FDA 3542, but the request must specify the patent 
number, the application number, and each product(s) approved in the 
application to which the request applies (see proposed Sec.  
314.53(f)(2)(iv)).
    In the following paragraphs, we discuss two comments on these 
proposed provisions. After considering these comments, we are making 
clarifying revisions to the description of the required amendment or 
supplement and the address to which the amendment or supplement must be 
submitted, and technical amendments described in sections V.B.2.c and 
V.P.3 We are also revising proposed Sec.  314.53(f)(2)(i) to more 
precisely describe our practice of removing a patent or patent 
information from the list in response to an NDA holder's request if 
there is no first applicant eligible for 180-day exclusivity based on a 
paragraph IV certification to that patent or after the 180-day 
exclusivity period of a first applicant based on that patent has 
expired or has been extinguished.
    (Comment 27) Two comments request that FDA clarify the implications 
of failing to timely amend patent information or withdraw a patent. One 
of the comments requests that FDA clarify the meaning of ``promptly 
notify FDA'' in proposed Sec.  314.53(f)(2)(i), and explain whether the 
timeframe may differ based on the circumstances (e.g., delay withdrawal 
of an original patent held invalid until the reissued patent has 
issued). The other comment suggests that if the NDA holder fails to 
timely notify FDA of a patent term extension or of a court order to 
amend patent information or withdraw a patent from the list, the patent 
should be considered untimely filed.
    (Response 27) FDA is establishing regulatory timeframes for 
withdrawal or amendment of patent information and withdrawal of a 
patent to promote the NDA holder's timely compliance with obligations 
under the FD&C Act and applicable regulations. If the NDA holder 
determines that a patent or patent claim no longer meets the statutory 
requirements for listing, the NDA holder must ``promptly notify FDA'' 
to withdraw the patent or patent information or amend the patent 
information to ensure that pending 505(b)(2) applications or ANDAs that 
contain a patent certification to the amended or withdrawn patent or 
patent information are not inappropriately delayed if they are 
otherwise eligible for approval. An NDA holder's withdrawal or 
amendment of patent information or withdrawal of the patent within 14 
days of the date on which the NDA holder determines that the patent or 
patent claim no longer meets the requirements for listing under section 
505(b)(1) or (c)(2) of the FD&C Act would be considered ``prompt.'' If 
a court enters a final decision from which no appeal has been or can be 
taken that a patent is invalid, the NDA holder must promptly notify FDA 
to withdraw the patent and request that the patent be removed from the 
list irrespective of whether the NDA holder or patent owner is 
separately requesting a reissue of the patent.
    We decline to modify the regulation to consider a patent untimely 
filed if the NDA holder fails to notify FDA of a court order to amend 
or withdraw patent information within 14 days because a court can 
enforce a failure to comply with its order. We also decline to modify 
the regulation to consider a patent untimely filed if the NDA holder 
fails to notify FDA of a patent term extension within 30 days because 
NDA holders have adequate incentive to inform FDA of any patent term 
extension. We require NDA holders to submit on Form FDA 3542 a 
correction to the expiration date of the listed patent if the term is 
extended under 35 U.S.C. 156(e) to ensure that prospective 505(b)(2) 
and ANDA applicants have timely notice of changes to the asserted 
patent coverage for a listed drug.
    (Comment 28) One comment recommends that FDA clarify where an NDA 
holder should send a voluntary request to remove patent information 
from the list.
    (Response 28) We agree. We are revising Sec.  314.53(f)(2)(iv) to 
clarify that the NDA holder must submit an amendment to its NDA to the 
same addresses described in Sec.  314.53(d)(4)(ii) to promptly notify 
FDA to withdraw a patent and request that FDA remove a patent from the 
list. We are also revising Sec.  314.53(f)(2)(i) and (iii) to clarify 
that an NDA holder must submit a copy of a court order to amend patent 
information or withdraw a patent from the list in an amendment to its 
NDA that bears the identification described in Sec.  314.53(d)(6) 
(``Time Sensitive Patent Information''). In addition, we are changing 
the address for submission of the amendment from the Orange Book Staff 
to the CDER Central Document Room, consistent with Sec.  
314.53(d)(4)(ii).

V.C. Patent Certification (Sec. Sec.  314.50(i) and 314.94(a)(12))

V.C.1. Method-of-Use Patents (Sec. Sec.  314.50(i)(1)(iii) and 
314.94(a)(12)(iii))
    We proposed to revise Sec. Sec.  314.50(i)(1)(iii) and 
314.94(a)(12)(iii) to clarify that a 505(b)(2) or ANDA applicant that 
is not seeking approval for a condition of use other than an indication 
(e.g., a dosing regimen) that is covered by a method-of-use patent for 
the listed drug(s) relied upon or RLD, respectively, may submit a 
statement under section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C 
Act, instead of a patent certification with respect to any such method-
of-use claims.
    We received no comments regarding this proposed revision. We are 
finalizing proposed Sec. Sec.  314.50(i)(1)(iii) and 314.94(a)(12)(iii) 
with technical amendments to reflect the claim-based approach to patent 
certification requirements for patents that include a method-of-use 
claim (i.e., a 505(b)(2) or ANDA applicant may submit a statement with 
respect to one or more method-of-use claims and a paragraph IV 
certification with respect to the remaining patent claims). As revised, 
a statement under section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the 
FD&C Act may be submitted if the applicant is not seeking approval for 
``an'' indication or other condition of use claimed by a method-of-use 
patent rather than ``any'' indications or other conditions of use 
claimed by the method-of-use patent (see Sec. Sec.  314.50(i)(1)(iii) 
and 314.94(a)(12)(iii)).
    We also are making technical amendments throughout part 314 to 
clarify that a 505(b)(2) or ANDA applicant may submit an appropriate 
patent certification or statement (see, e.g., Sec. Sec.  
314.50(i)(1)(i)(A) through (C), (i)(5), (i)(6), (i)(6)(ii), 
(i)(6)(iii)(A)(1) and (2); 314.53(d)(3); and 314.94(a)(12)(i)(A) and 
(B), (a)(12)(vii) and (viii), (a)(12)(viii)(B), and 
(a)(12)(viii)(C)(1)(i) and (ii)).
V.C.2. Method-of-Manufacturing Patents (Deletion of Sec. Sec.  
314.50(i)(2) and 314.94(a)(12)(iv))
    We proposed to remove Sec. Sec.  314.50(i)(2) and 
314.94(a)(12)(iv), which provide that an applicant is not required to 
make a certification with respect to any patent that claims only a 
method of manufacturing the drug product (method-of-manufacturing 
patent or process patent) for which the applicant is seeking approval. 
We proposed this deletion for clarity and consistency with the 
regulation that

[[Page 69608]]

prohibits an NDA holder from submitting information on a patent that 
only claims a method of manufacturing the drug product (see Sec.  
314.53(b)).
    In the following paragraphs, we discuss a comment on this proposed 
deletion. After considering this comment, we are removing (and 
reserving) Sec. Sec.  314.50(i)(2) and 314.94(a)(12)(iv).
    (Comment 29) One comment recommends that FDA permit the listing of 
process patents that claim production of the active pharmaceutical 
ingredient in the approved drug product (e.g., synthesis process or 
impurity reduction process).
    (Response 29) We decline to adopt the suggestion provided in the 
comment. The FD&C Act requires an NDA applicant or holder to submit 
information on any patent that claims the drug or that claims a method 
of using such drug and with respect to which a claim of patent 
infringement could reasonably be asserted if a person not licensed by 
the owner engaged in the manufacture, use, or sale of the drug (see 
section 505(b)(1) and (c)(2) of the FD&C Act). A method-of-
manufacturing patent or process patent does not meet the statutory 
requirement for listing because it does not claim an approved drug or 
an approved method of using the drug. We note, however, that a product-
by-process patent is eligible for listing in the Orange Book because 
the invention claimed by the patent is, for example, the novel drug 
product and not the process used to make the product (see 68 FR 36676 
at 36679 to 36680).
V.C.3. Licensing Agreement (Sec. Sec.  314.50(i)(3) and 
314.94(a)(12)(v))
    We proposed to revise Sec.  314.50(i)(3) regarding licensing 
agreements to remove the references to an ``immediate effective date'' 
and clarify that the patent owner with whom the applicant has a 
licensing agreement may consent to approval of the 505(b)(2) 
application (if otherwise justified) as of a specific date. We 
explained that this proposed revision did not alter the current 
requirements for a 505(b)(2) (or ANDA) applicant to submit a paragraph 
IV certification to a patent that claims the listed drug relied upon 
even though the applicant has a licensing agreement with the patent 
owner (see proposed Sec. Sec.  314.50(i)(3) and 314.94(a)(12)(v)). We 
further explained that an applicant that has a licensing agreement with 
the patent owner would still be required to send notice of the 
paragraph IV certification to the NDA holder and each patent owner.
    In the following paragraphs, we discuss a comment on this proposed 
revision. After considering this comment, we are making a clarifying 
revision and editorial corrections to Sec.  314.50(i)(3) and conforming 
revisions to Sec.  314.94(a)(12)(v).
    (Comment 30) One comment requests that FDA revise Sec.  
314.50(i)(3) to apply to an ``agreement'' between a 505(b)(2) applicant 
and the patent owner(s), rather than restrict the provision to a 
``licensing agreement.'' The comment maintains that other forms of 
agreement (e.g., a covenant not to sue) should not be treated 
differently for purposes of determining the earliest date agreed upon 
by the applicant and relevant patent owner(s) for approving an 
application. The comment also recommends that FDA amend Sec.  
314.94(a)(12)(v) to expressly describe consent to approval as of a 
specific date because the provision also should apply to ANDAs.
    (Response 30) We decline to modify Sec.  314.50(i)(3) to broadly 
refer to an agreement between a 505(b)(2) applicant and the patent 
owner. Licensing agreements are described in section 505(b)(1) and 
(c)(2) of the FD&C Act, which refer to a patent with respect to which a 
claim of patent infringement could reasonably be asserted if a person 
not licensed by the owner engaged in the manufacture, use, or sale of 
the drug. It accords with the statute for a 505(b)(2) applicant to 
submit a paragraph IV certification based on a licensing agreement with 
the patent owner, and for the patent owner to consent to approval of 
the 505(b)(2) application as of a specific date (if the 505(b)(2) 
application is otherwise eligible for approval). However, it is unclear 
whether other types of agreements (e.g., a covenant not to sue) would 
necessarily be consistent with a paragraph IV certification that the 
patent is invalid, unenforceable, or will not be infringed by the 
manufacture, use, or sale of the proposed product for which the 
505(b)(2) application (or ANDA) is submitted. The FD&C Act does not 
contemplate FDA enforcement of private agreements between a 505(b)(2) 
(or ANDA) applicant and a patent owner that are unrelated to the 
statutory and regulatory requirements for approval.
    As a practical matter, it is unnecessary to broaden this provision 
to describe other circumstances in which a patent owner may consent to 
approval as of a specific date. If a 505(b)(2) applicant submits a 
paragraph IV certification and the patent owner provides a covenant not 
to sue, then the patent owner would not initiate patent infringement 
litigation within the 45-day period and there would be no 30-month stay 
of approval. If a 505(b)(2) applicant changes a previously submitted 
certification or statement to a paragraph IV certification, the patent 
owner and NDA holder for the listed drug relied upon may waive their 
opportunity to file a patent infringement action within the 45-day 
period (see Sec.  314.107(f)(3)).
    We agree that the regulations should expressly provide that if an 
ANDA applicant has a licensing agreement with a patent owner, the 
patent owner may consent to approval of the ANDA as of a specific date 
(if the ANDA is otherwise eligible for approval). We are revising Sec.  
314.94(a)(12)(v) to describe the requirements for a written statement 
from the patent owner that has a licensing agreement with the applicant 
and consents to approval of the ANDA as of a specific date. Agreements 
between an ANDA applicant and a brand name drug company that must be 
filed with the Assistant Attorney General and the FTC are described in 
section 1112 of the MMA.
    We also are revising Sec. Sec.  314.50(i)(3) and 314.94(a)(12)(v) 
to clarify that the 505(b)(2) application or ANDA will be approved 
based on consent to approval as of a specific date only if the 
505(b)(2) application or ANDA is ``otherwise eligible for approval'' 
rather than ``otherwise justified.''

V.D. Notice of Paragraph IV Certification (Sec. Sec.  314.52 and 
314.95)

V.D.1. Timing of Notice
    V.D.1.a. Date before which notice may not be given. We proposed to 
revise our regulations to clearly delineate the two limitations on the 
timeframe within which notice of a paragraph IV certification to a 
listed patent must be provided to the NDA holder and each patent owner: 
The date before which notice must not be given and, as discussed in 
section V.D.1.b, the date by which notice must be given.
    We proposed to codify our longstanding policy that notice of a 
paragraph IV certification may not be sent by a 505(b)(2) or ANDA 
applicant unless and until we have notified the applicant that its 
application has been filed or received, as appropriate (see proposed 
Sec. Sec.  314.52(b)(1) and 314.95(b)(1)). We proposed that any notice 
sent by a 505(b)(2) or ANDA applicant before the receipt of an 
acknowledgment letter or paragraph IV acknowledgment letter is invalid, 
and thus does not trigger either the 45-day period in which the NDA 
holder and each patent owner may initiate a patent

[[Page 69609]]

infringement action and obtain a 30-month stay or the beginning of any 
related 30-month period. We proposed that an applicant that prematurely 
sends notice of a paragraph IV certification would be required to 
resend notice within the required timeframe after the 505(b)(2) 
application or ANDA has been filed or received, respectively, to 
satisfy the notice requirement of the FD&C Act and, in the case of a 
first applicant, to qualify for 180-day exclusivity (see proposed 
Sec. Sec.  314.52(b)(2) and 314.95(b)(2)).
    We proposed to clarify that if a 505(b)(2) or ANDA applicant 
submits an amendment containing a paragraph IV certification before the 
filing or receipt of the 505(b)(2) application or ANDA, respectively, 
the applicant would be required to wait until it has received an 
acknowledgment letter or a paragraph IV acknowledgment letter before 
sending notice of its paragraph IV certification to the NDA holder and 
each patent owner (see proposed Sec. Sec.  314.52(b) and (d)(2) and 
314.95(b) and (d)(2)).
    With respect to patents that are listed in the Orange Book after 
submission of an ANDA, we proposed that any notice of paragraph IV 
certification would be invalid and would not be considered to comply 
with the notice requirement of the FD&C Act if it is sent before the 
first working day after the day the patent is listed in the Orange Book 
(see proposed Sec. Sec.  314.94(a)(12)(viii)(C)(1)(ii) and 
314.95(b)(2)). We proposed that the term ``working day'' would have the 
meaning provided in 21 CFR 1.377 (``any day from Monday through Friday, 
excluding Federal holidays''). We explained that this proposal is 
intended to discourage ANDA applicants from submitting a paragraph IV 
certification and sending notice to the NDA holder and each patent 
owner every day during the 30-day period after issuance of a patent 
that could be listed for the RLD in an effort to qualify as a first 
applicant eligible for 180-day exclusivity if such patent ultimately is 
listed for the RLD in the Orange Book. We also noted that this proposed 
requirement would ensure that all ANDA applicants (irrespective of time 
zone) have a reasonable opportunity to be first to certify to a newly 
listed patent.
    In the following paragraphs, we discuss several comments on our 
proposed regulations regarding the date before which notice of 
paragraph IV certification must not be given. After considering these 
comments, we are revising Sec.  314.52(b)(2) to provide that a 
505(b)(2) applicant must send notice of a paragraph IV certification on 
or after the date of filing of the 505(b)(2) application described in 
Sec.  314.101(a)(2) or (3), as applicable, rather than on or after the 
date it receives a paragraph IV acknowledgment letter. We are revising 
proposed Sec.  314.95(b)(2) to delete the reference to an 
``acknowledgment letter'' because an ANDA applicant will now receive a 
``paragraph IV acknowledgment letter'' if it amends its ANDA to add a 
paragraph IV certification before the ANDA is received (see section 
V.A.1).
    (Comment 31) One comment asserts that the statutory terms 
``submits'' and ``files'' in section 505(j)(2)(B)(ii)(I) and (II) of 
the FD&C Act, respectively, indicate that an ANDA applicant may send 
notice of a paragraph IV certification at the time of submission of an 
amendment to an ANDA containing a paragraph IV certification, even if 
the ANDA has not yet been ``filed'' (i.e., ``received'' under Sec.  
314.101(b)). The comment suggests that ANDA applicants that submit an 
amendment containing the first paragraph IV certification to a patent 
listed for the RLD are concerned that they may risk eligibility for 
180-day exclusivity if they do not send notice at the time of 
submission of the amendment, even though the ANDA has not been received 
under Sec.  314.101(b). The comment proposes that FDA allow ANDA 
applicants to ``change'' rather than ``amend'' their patent 
certification in an amendment prior to filing, and consider the date of 
the ``change'' for purposes of determining eligibility for 180-day 
exclusivity.
    (Response 31) We disagree with the comment's interpretation of 
section 505(j)(2)(B)(ii)(II) of the FD&C Act, and decline to adopt the 
comment's proposed revision to the regulations governing submission of 
a paragraph IV certification prior to receipt of the ANDA.
    As a preliminary matter, we note that the requirement that an ANDA 
applicant must wait until its ANDA has been received before sending 
notice of a paragraph IV certification ensures that the NDA holder and 
patent owner do not needlessly expend resources to initiate litigation 
with respect to an ANDA that is incomplete and therefore may not be 
reviewed by the Agency (see ``Abbreviated New Drug Application 
Regulations,'' 54 FR 28872 at 28887, July 10, 1989; see also 59 FR 
50338 at 50349 to 50350). This reflects the Agency's view that Congress 
did not intend for incomplete ANDA submissions to have the potential to 
trigger legal action by an NDA holder or patent owner (see 54 FR 28872 
at 28887; see also Allergan, Inc. v. Actavis, Inc., 2014 WL 7336692 at 
*12 (E.D. Tex. 2014) (finding that the act of infringement created by 
35 U.S.C. 271(e)(2) requires that the ANDA has been received by FDA, 
not merely transmitted to FDA). Accordingly, our existing regulations 
require that an ANDA applicant's notice of a paragraph IV certification 
must include a statement that FDA has received the ANDA (see Sec.  
314.95(c)(1)).
    The requirement that notice of a paragraph IV certification only be 
sent after FDA has received the ANDA was ratified by the MMA, which 
established a 20-day period for sending notice of a paragraph IV 
certification that runs from the date of the postmark on the notice 
with which FDA informs the applicant that the ANDA has been filed 
(i.e., received under Sec.  314.101(b)) (see section 
505(j)(2)(B)(ii)(I) of the FD&C Act and section V.D.1.b). The MMA also 
requires that an ANDA applicant send notice of a paragraph IV 
certification submitted in an amendment or supplement to the ANDA at 
the time of submission of the amendment or supplement, regardless of 
whether the applicant already has given notice with respect to another 
paragraph IV certification contained in the ANDA or in an amendment or 
supplement to the ANDA (see section 505(j)(2)(B)(ii)(II) of the FD&C 
Act). Consistent with the framework established by section 
505(j)(2)(B)(ii) of the FD&C Act, FDA interprets section 
505(j)(2)(B)(ii)(II) of the FD&C Act to apply only to an amendment to 
the ANDA that is submitted after the Agency has received the ANDA (see 
SB Pharmco Puerto Rico, Inc. v. Mutual Pharmaceutical Co., 552 F. Supp. 
2d 500, 510 (E.D. Pa.), appeal dismissed, 2008 U.S. App. LEXIS 27672 
(Fed. Cir. 2008) (upholding FDA's interpretation of section 
505(j)(2)(B)(ii)(II) of the FD&C Act and finding that notice of a 
paragraph IV certification sent at the time of submission of an 
amendment to an ANDA that had not yet been received ``was not valid or 
timely''). Thus, we disagree with the comment's suggestion that an ANDA 
applicant can submit an amendment containing a paragraph IV 
certification before the ANDA is received and immediately send notice 
of the paragraph IV certification. If an ANDA applicant submits an 
amendment containing a paragraph IV certification before it has 
received a paragraph IV acknowledgment letter advising that the ANDA 
has been received for substantive review, the applicant is required to 
send notice of its paragraph IV certification within 20 days after the 
date of the postmark on the paragraph IV acknowledgment letter.
    Based on the Agency's interpretation of the statute, it is 
unnecessary to use the terminology suggested in the

[[Page 69610]]

comment to describe an amendment that contains a paragraph IV 
certification to a newly listed patent or that changes a previously 
submitted patent certification or statement to a paragraph IV 
certification and is submitted before receipt of the ANDA.
    The relevant date for determining eligibility for 180-day 
exclusivity based upon submission of a paragraph IV certification 
contained in an amendment is the date of submission of the amendment. 
We are revising Sec.  314.95(d)(2) to clarify that if an ANDA 
applicant's notice of paragraph IV certification is timely provided in 
accordance with Sec.  314.95(b)(2) and the applicant has not submitted 
a previous paragraph IV certification, FDA will base its determination 
of whether the applicant is a first applicant on the date of submission 
of the amendment containing the paragraph IV certification.
    (Comment 32) One comment accepts FDA's ``settled administrative 
practice'' that a 505(b)(2) or ANDA applicant may not send notice of 
paragraph IV certification until the application is accepted for 
review, but contends that FDA may not condition a 505(b)(2) applicant's 
ability to send notice on its prior receipt of a paragraph IV 
acknowledgment letter that would be sent up to 14 days after the 
505(b)(2) application is accepted for review (filed). The comment 
maintains that the benefits of this approach have not been shown to 
outweigh the costs of a potential 2-week delay in approval of a 
505(b)(2) application, and that the proposal is inconsistent with the 
statute. Another comment recommends that FDA send a paragraph IV 
acknowledgment letter to a 505(b)(2) applicant via email on the date on 
which the 505(b)(2) application is filed to eliminate the disparity 
between the dates on which paragraph IV acknowledgment letters are sent 
to 505(b)(2) and ANDA applicants. A third comment requests that FDA 
clarify when an ANDA applicant can send notice if the paragraph IV 
acknowledgment letter is not received on day 60.
    (Response 32) We agree that there should not be a delay of 
approximately 2 weeks between the date on which a 505(b)(2) application 
is filed and the date on or after which a 505(b)(2) applicant must send 
notice of a paragraph IV certification to the NDA holder and each 
patent owner. We are revising proposed Sec.  314.52(b)(1) and (2) to 
provide that a 505(b)(2) applicant must send notice of a paragraph IV 
certification on or after the date of filing of the 505(b)(2) 
application described in Sec.  314.101(a)(2) or (3), as applicable, 
rather than on or after the date it receives a paragraph IV 
acknowledgment letter, and we are making conforming revisions to Sec.  
314.52(d)(1) and (2). This revised approach ensures that notice of a 
paragraph IV certification will not be sent before the Agency has filed 
the relevant 505(b)(2) application, and avoids a delay of up to 2 weeks 
in the potential initiation of patent infringement litigation by an NDA 
holder or patent owner and any corresponding 30-month stay of approval 
of the 505(b)(2) application.
    FDA determines whether a 505(b)(2) application may be filed within 
60 days after FDA is in receipt of the 505(b)(2) application (see Sec.  
314.101(a)(1)). If the 505(b)(2) applicant does not receive a refusal 
to file letter on or before day 60, the 505(b)(2) application is deemed 
filed. If FDA refuses to file the 505(b)(2) application and the 
505(b)(2) application is filed over protest or resubmitted, then the 
date of filing described in Sec.  314.101(a)(3) applies. We are 
requiring that a 505(b)(2) applicant send notice of a paragraph IV 
certification on or after the date of filing of the 505(b)(2) 
application, but not later than 20 days after the date of the postmark 
on the paragraph IV acknowledgment letter (see Sec.  314.52(b)(1)). The 
``paragraph IV acknowledgment letter'' for a 505(b)(2) application is 
the filing communication that generally is sent to the 505(b)(2) 
applicant not later than 14 calendar days after the 60-day filing date 
(sometimes referred to as the ``74 day letter'') (see section V.A.1). 
The ``date of the postmark'' for a paragraph IV acknowledgment letter 
for a 505(b)(2) application is considered to be four calendar days 
after the date on which the letter is signed by the signatory authority 
(generally the Division Director or designee in the OND review 
division). Accordingly, this revision to our regulations implements the 
statutory requirement that notice be sent within 20 days of the 
postmark on the filing communication while preserving the principle 
that notice must not be sent before a 505(b)(2) application is filed.
    We are maintaining the requirement that an ANDA applicant must send 
notice of a paragraph IV certification on or after the date it receives 
a paragraph IV acknowledgment letter because FDA intends to 
electronically transmit the letter to the ANDA applicant on the date on 
which the ANDA is received under Sec.  314.101(b). Accordingly, in 
contrast to the interval of up to 14 days for 505(b)(2) applications, 
there is no interval between the date on which the ANDA is received 
under Sec.  314.101(b) and the date on which an ANDA applicant receives 
a paragraph IV acknowledgment letter (see section V.A.6). An ANDA 
applicant can send notice of a paragraph IV certification submitted in 
an original ANDA or submitted in an amendment to an ANDA that has not 
yet been received on or after the date the ANDA applicant receives a 
paragraph IV acknowledgment letter.
    (Comment 33) One comment asserts that the proposed requirement that 
a paragraph IV certification must not be submitted earlier than the 
first working day after the day the patent or patent claim is listed in 
the Orange Book would conflict with the statute and prevent ANDA 
applicants from submitting a paragraph IV certification to a newly 
listed patent at the first lawful opportunity. Another comment 
maintains that the proposed requirement for submission of a paragraph 
IV certification to a newly listed patent may result in multiple ANDA 
applicants becoming eligible for 180-day exclusivity and thus would 
dilute the value of 180-day exclusivity.
    (Response 33) We believe that our approach to patent certification 
requirements for newly listed patents is consistent with the statute 
and provides a reasonable opportunity for ANDA applicants to compete to 
have the first substantially complete ANDA that contains a paragraph IV 
certification to a listed patent for the RLD.
    The requirement that an ANDA applicant must not submit a paragraph 
IV certification earlier than the first working day after the day the 
patent or patent claim is listed in the Orange Book reflects FDA's 
determination that selecting the first working day after the day on 
which the patent information is published creates a level playing field 
for all ANDA applicants (see Sec. Sec.  314.94(a)(12)(viii)(C)(1)(ii) 
and 314.95(b)(2)). One court has determined, in the absence of a 
regulation to the contrary, that ``reality matters'' if a patent has 
been submitted to FDA, and an ANDA applicant can submit a paragraph IV 
certification even if the patent is not yet listed in the Orange Book 
(see Teva Pharms., USA, Inc. v. Leavitt, 548 F.3d 103, 105 (D.C. Cir. 
2008)). However, FDA has determined that permitting serial submissions 
of amendments and multiple notices of paragraph IV certifications is 
overly burdensome to FDA and NDA holders. Such a practice makes it 
difficult to determine which paragraph IV certification and notice of 
paragraph IV certification is valid. Our decision to

[[Page 69611]]

level the playing field for paragraph IV certifications in this manner 
is consistent with our authority to establish rules for the efficient 
enforcement of the FD&C Act (see section 701(a) of the FD&C Act).
    We are not persuaded by the comment's assertion that leveling the 
playing field for ANDA applicants will dilute the value of 180-day 
exclusivity. For example, FDA continues to receive multiple ANDAs on 
the day that 4 years of a 5-year exclusivity period under section 
505(j)(5)(F)(ii) of the FD&C Act has expired (the first day that ANDAs 
containing a paragraph IV certification are permitted to be submitted) 
even though many of these ANDAs will likely share eligibility for 180-
day exclusivity.
    (Comment 34) One comment supports the proposed requirement that a 
paragraph IV certification must not be submitted earlier than the first 
working day after the day the patent or patent claim is listed in the 
Orange Book, but recommends that FDA establish a time after which 
patent information listed in the Orange Book will be deemed to have 
been published the next day. Another comment suggests that FDA 
instantaneously notify ANDA applicants when a patent is listed for the 
RLD after ANDA submission to provide an equal opportunity for timely 
submission of an appropriate patent certification or statement to the 
pending ANDA and, if applicable, notice of paragraph IV certification.
    (Response 34) We decline to adopt the suggestions provided in the 
comments. FDA generally posts daily electronic updates to the Orange 
Book in the afternoon (Eastern Standard Time); however, we are not 
establishing a specific time by which FDA will update the Orange Book 
to preserve flexibility in the event of technical difficulties. 
Applicants will have an equal opportunity for timely submission of an 
appropriate patent certification or statement for a newly listed patent 
or patent claim because FDA will make this information publicly 
available through the Orange Book. Although we decline to undertake the 
burden of notifying individual ANDA applicants when a patent or patent 
claim for the RLD is newly listed in the Orange Book, we are committed 
to facilitating public access to the Orange Book through efficient 
means (see, e.g., the ``Orange Book Express'' mobile application 
launched on November 9, 2015).
    V.D.1.b. Date by which notice must be given. We proposed to 
establish a regulation that would implement section 505(b)(3)(B) and 
(j)(2)(B)(ii) of the FD&C Act by providing that an applicant must send 
notice of a paragraph IV certification contained in a 505(b)(2) 
application or ANDA not later than 20 days after the date of the 
``postmark'' on the acknowledgment letter or paragraph IV 
acknowledgment letter (see proposed Sec. Sec.  314.52(b)(1) and 
314.95(b)(1) and section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the 
FD&C Act). We proposed a definition of the term ``postmark'' and, as 
applied to paragraph IV acknowledgment letters for 505(b)(2) 
applications, an alternate proposed interpretation of the term 
``postmark'' to reflect current practice regarding the mailing of 
filing communications (see section V.A.1). We also proposed to specify 
the method of calculating the 20-day period for providing notice of a 
paragraph IV certification (see proposed Sec. Sec.  314.52(b)(1) and 
314.95(b)(1)).
    We proposed that an applicant must send notice of a paragraph IV 
certification contained in an amendment to a 505(b)(2) application or 
ANDA that has been filed or received for substantive review, 
respectively, or in a supplement to an approved 505(b)(2) application 
or ANDA at the same time that the amendment or supplement is submitted 
to FDA (see proposed Sec. Sec.  314.52(d)(1) and 314.95(d)(1) and 
section 505(b)(3)(B)(ii) and (j)(2)(B)(ii)(II) of the FD&C Act). We 
proposed that notice of a paragraph IV certification in an amendment or 
supplement must be provided regardless of whether the applicant has 
already given notice with respect to another paragraph IV certification 
contained in the 505(b)(2) application or ANDA or in an amendment or 
supplement to the 505(b)(2) application or ANDA (see proposed 
Sec. Sec.  314.52(d)(1) and 314.95(d)(1) and section 505(b)(3)(B)(ii) 
and (j)(2)(B)(ii)(II) of the FD&C Act).
    We proposed to require an applicant that submits an amendment or 
supplement to a 505(b)(2) application or ANDA that seeks approval for a 
different strength of the drug product and contains a paragraph IV 
certification adhere to the timing requirements for notice in 
Sec. Sec.  314.52(d)(1) or (2) and 314.95(d)(1) or (2), respectively, 
based on whether the 505(b)(2) application has been filed or the ANDA 
has been received (see proposed Sec. Sec.  314.52(d)(3) and 
314.95(d)(3)).
    We did not receive any other comments on proposed Sec. Sec.  
314.52(b)(1), (d)(1) and (2), and 314.95(b)(1), (d)(1) and (2). We are 
finalizing proposed Sec.  314.52(b)(1) and (2) and (d)(1) and (2) with 
the revisions discussed in Response 32. We are finalizing proposed 
Sec.  314.95(b)(1) and (d)(2) with clarifying revisions to consistently 
refer to ``a paragraph IV acknowledgment letter'' because these 
provisions refer to an ANDA that contains a paragraph IV certification 
before the ANDA is received and thus FDA will send the ANDA applicant a 
paragraph IV acknowledgment letter. We also are making the clarifying 
revision to proposed Sec.  314.95(d)(2) discussed in Response 31. We 
are finalizing proposed Sec.  314.95(d)(1) with a clarifying revision 
to add the phrase ``or an acknowledgment letter'' because an applicant 
may amend or supplement its ANDA to include a paragraph IV 
certification irrespective of whether the ANDA contained a paragraph IV 
certification at the time of receipt. We also are making the technical 
amendment to Sec.  314.95(d)(1) described in section V.P.1.
V.D.2. Contents of Notice
    We proposed that a 505(b)(2) or ANDA applicant's notice of a 
paragraph IV certification must include, among other things: (1) A 
statement that data from any required bioavailability or bioequivalence 
studies have been submitted; (2) a statement that the applicant has 
received an acknowledgment letter or a paragraph IV acknowledgment 
letter for its 505(b)(2) application or ANDA; (3) the patent number and 
expiration date of each patent listed in the Orange Book that is the 
subject of the paragraph IV certification; and (4) an offer of 
confidential access, if the applicant alleges that the patent will not 
be infringed and may later decide to file a civil action for 
declaratory judgment in accordance with section 505(c)(3)(D) and 
(j)(5)(C) of the FD&C Act) (see proposed Sec. Sec.  314.52(c) and 
314.95(c)). We also proposed to require the 505(b)(2) or ANDA applicant 
to cite section 505(b)(3)(D) and (j)(2)(B)(iv) of the FD&C Act, 
respectively, as amended by the MMA, in the notice of paragraph IV 
certification (see proposed Sec. Sec.  314.52(c) and 314.95(c)). In the 
proposed rule, we explained that the Agency assesses neither the 
adequacy of the contents of a 505(b)(2) or ANDA applicant's notice of 
paragraph IV certification nor the applicant's stated basis for 
certifying that a listed patent is invalid, unenforceable, or will not 
be infringed by its proposed drug product.
    In the following paragraphs, we discuss two comments on the 
proposed requirements for the content of a notice of paragraph IV 
certification. After considering these comments, we are not finalizing 
proposed Sec.  314.52(c)(3) and we are making conforming editorial 
changes to the numbering of subsequent paragraphs in Sec.  314.52(c). 
We are

[[Page 69612]]

revising proposed Sec.  314.95(c)(3) to omit the reference to an 
``acknowledgment letter'' and require that the ANDA applicant include a 
statement that the applicant has received the paragraph IV 
acknowledgment letter for the ANDA. We are making a grammatical 
correction to the introductory text of Sec. Sec.  314.52(c) and 
314.95(c) to provide that the notice must include, but is not limited 
to, the information described in Sec. Sec.  314.52(c)(1) through (8) 
and 314.95(c)(1) through (9). We are finalizing the remaining 
provisions of proposed Sec. Sec.  314.52(c) and 314.95(c) without 
change, except for a revision to proposed Sec. Sec.  314.52(c)(8) and 
314.95(c)(8) to clarify that an offer of confidential access must be 
provided by an applicant that seeks to preserve the option to file a 
civil action for declaratory judgment in accordance with section 
505(c)(3)(D) or (j)(5)(C) of the FD&C Act.
    (Comment 35) One comment asserts that FDA lacks authority to 
require a 505(b)(2) or ANDA applicant to include, in any notice of 
paragraph IV certification, a statement that the applicant has received 
an acknowledgment letter or a paragraph IV acknowledgment letter 
because section 505(b)(3)(D) and (j)(2)(B)(iv) of the FD&C Act does not 
expressly require such a statement.
    (Response 35) We disagree. FDA has the authority to establish 
regulations regarding the contents of notice of a paragraph IV 
certification to support the efficient enforcement of the FD&C Act (see 
section 701(a) of the FD&C Act). The FD&C Act requires that a notice of 
paragraph IV certification must state that the 505(b)(2) application or 
ANDA containing the certification ``has been submitted'' (see section 
505(b)(3)(D)(i) and (j)(2)(B)(iv)(I) of the FD&C Act). As discussed in 
Response 31, it is the Agency's longstanding policy that notice of a 
paragraph IV certification may not be sent unless and until we have 
notified the applicant that its 505(b)(2) application has been filed or 
its ANDA has been received because premature notice could result in 
lawsuits over applications that FDA refuses to file or receive and thus 
no longer are pending. Accordingly, our existing regulations require 
that a 505(b)(2) or ANDA applicant's notice of a paragraph IV 
certification must include a statement that FDA has filed the NDA (in 
the case of a 505(b)(2) application) or has received the ANDA (see 
Sec. Sec.  314.52(c)(1) and 314.95(c)(1)). To help ensure that notices 
of paragraph IV certifications are not sent prematurely, we also are 
requiring that an ANDA applicant's notice of paragraph IV certification 
include a statement that the applicant has received the paragraph IV 
acknowledgment letter for the ANDA (see Sec.  314.95(c)(3)). We are 
revising proposed Sec.  314.95(c)(3) to delete the reference to an 
``acknowledgment letter'' because an ANDA applicant will now receive a 
``paragraph IV acknowledgment letter'' if the ANDA contains a paragraph 
IV certification at any time before the ANDA is received (see section 
V.A.1).
    With respect to a 505(b)(2) application, we are maintaining the 
requirement that a 505(b)(2) applicant's notice of a paragraph IV 
certification must include a statement that FDA has filed the NDA (see 
Sec.  314.52(c)(1)). However, we are not requiring the 505(b)(2) 
applicant to include a statement that it has received a paragraph IV 
acknowledgment letter because we are revising our regulations to 
provide that a 505(b)(2) applicant must send notice of a paragraph IV 
certification on or after the date of filing of the 505(b)(2) 
application described in Sec.  314.101(a)(2) or (3), as applicable, 
rather than on or after the date the applicant receives a paragraph IV 
acknowledgment letter (see Sec.  314.52(b)(1) and Response 32).
    (Comment 36) One comment requests that FDA revise the regulations 
to enable any recipient of notice of paragraph IV certification to 
request that FDA confirm the adequacy of notice with respect to 
statutory and regulatory requirements (other than the factual and legal 
basis for the paragraph IV certification). This comment recommends that 
FDA provide that inadequate notice is invalid and does not trigger the 
45-day period described in section 505(c)(3)(C) or (j)(5)(B)(iii) of 
the FD&C Act. Another comment recommends that FDA provide an additional 
time period in which a 505(b)(2) or ANDA applicant can correct a 
deficient notice of paragraph IV certification that would extend the 
time for a patent holder under its duties or obligations.
    (Response 36) We decline to revise the regulations to provide for a 
ministerial review of notice of a paragraph IV certification to 
evaluate compliance with the statutory and regulatory requirements. A 
505(b)(2) or ANDA applicant is required to submit an amendment to its 
505(b)(2) application or ANDA certifying, among other things, that the 
notice of paragraph IV certification met the content requirements under 
Sec. Sec.  314.52(c) or 314.95(c), respectively (see Sec. Sec.  
314.52(b)(3) or 314.95(b)(3)). The regulations also provide that a copy 
of the notice of paragraph IV certification does not need to be 
submitted to FDA (see Sec. Sec.  314.52(b)(3) or 314.95(b)(3)). Given 
the clarifying revisions to the regulations to enhance compliance with 
the requirements for notice of a paragraph IV certification and the 
administrative burden that would be associated with a ministerial 
review of a notice of paragraph IV certification, we do not believe 
that such review is warranted. The second comment does not clearly 
describe the requested action or provide adequate support for any 
proposed change. We note, however, that an applicant may amend its 
505(b)(2) application or ANDA with a written statement that a later 
date should be used as the first day of the 45-day period provided in 
section 505(c)(3)(C) or (j)(5)(B)(iii) of the FD&C Act (see Sec. Sec.  
314.52(f) and 314.95(f)).
V.D.3. Documentation of Timely Sending and Receipt of Notice
    V.D.3.a. Acceptable methods of sending notice of paragraph IV 
certification. We proposed to expand the list of acceptable delivery 
methods that 505(b)(2) and ANDA applicants may use to send notice of 
paragraph IV certification to the NDA holder and each patent owner by 
permitting a 505(b)(2) or ANDA applicant to use a ``designated delivery 
service'' (see proposed Sec. Sec.  314.52(a) and 314.95(a)). We 
proposed to define a ``designated delivery service'' to mean a delivery 
service provided by a trade or business that FDA determines: (1) Is 
available to the general public throughout the United States; (2) 
records electronically to its database, kept in the regular course of 
its business, or marks on the cover in which any item referred to in 
this section is to be delivered, the date on which the item was given 
to the trade or business for delivery; and (3) provides overnight or 2-
day delivery service throughout the United States (see Sec. Sec.  
314.52(g)(1) and 314.95(g)(1)). We proposed to periodically issue 
guidance describing designated delivery services that meet the 
regulatory criteria (see proposed Sec. Sec.  314.52(g)(2) and 
314.95(g)(2)). We also proposed to clarify that a 505(b)(2) or ANDA 
applicant may send notice of paragraph IV certification by an 
alternative method (i.e., a method other than registered or certified 
mail, return receipt requested, or a designated delivery service) only 
if FDA has agreed in advance that the method will produce an acceptable 
form of documentation (see proposed Sec. Sec.  314.52(a)(4) and (e) and 
314.95(a)(4) and (e)).
    In the following paragraphs, we discuss a comment on these proposed 
provisions. After considering this comment, we are finalizing proposed

[[Page 69613]]

Sec. Sec.  314.52(a) and (g)(1) and 314.95(a) and (g)(1) without 
change, except for a technical amendment to add ``505(b)(2)'' before 
``applicant'' in Sec.  314.52(a) for clarity. We are revising 
Sec. Sec.  314.52(g)(2) and 314.95(g)(2) to clarify that FDA may 
periodically issue guidance regarding designated delivery services.
    (Comment 37) One comment requests that FDA clarify whether a 
505(b)(2) or ANDA applicant may use a delivery service that appears to 
satisfy the criteria in Sec. Sec.  314.52(g)(1) and 314.95(g)(1) even 
if the delivery service has not been identified by FDA in periodic 
guidance.
    (Response 37) At this time, FDA does not intend to identify 
specific designated delivery services in guidance. A 505(b)(2) or ANDA 
applicant that sends notice of a paragraph IV certification may use a 
delivery service that satisfies the regulatory criteria in Sec. Sec.  
314.52(g)(1) or 314.95(g)(1), as applicable, without FDA's prior 
approval. For purposes of the definition of ``designated delivery 
service,'' FDA is clarifying that ``United States'' means the 50 
States, the District of Columbia, and the Commonwealth of Puerto Rico, 
but not the Territories. This approach acknowledges that some delivery 
services may not routinely provide overnight or 2-day delivery services 
to each of the Territories of the United States. If a 505(b)(2) or ANDA 
applicant is required to send notice of a paragraph IV certification to 
an NDA holder or patent owner (or its representative) that resides in a 
Territory of the United States or outside the United States, the 
applicant should ensure that the designated delivery service provides 
service to the area or request permission to use an alternate method of 
delivery.
    We are revising Sec. Sec.  314.52(g)(2) and 314.95(g)(2) to clarify 
that FDA may periodically issue guidance regarding designated delivery 
services. We note that a 505(b)(2) or ANDA applicant may send notice of 
a paragraph IV certification by an alternate method that does not meet 
the criteria in Sec. Sec.  314.52(g)(1) or 314.95(g)(1) only if the 
applicant has obtained FDA's agreement in advance (see Sec. Sec.  
314.52(a)(4) and 314.95(a)(4)).
    V.D.3.b. Amendment documenting timely sending and confirmation of 
receipt of notice of paragraph IV certification. We proposed to revise 
Sec. Sec.  314.52(e) and 314.95(e) to clarify the requirements for 
submission of an amendment to a 505(b)(2) application or ANDA, 
respectively, containing documentation of timely sending of notice of 
paragraph IV certification and confirmation of receipt of same by the 
NDA holder and each patent owner.
    We proposed that an applicant must amend its 505(b)(2) application 
or ANDA at the time that it provides notice of a paragraph IV 
certification with a statement certifying that notice has been provided 
to the NDA holder and each patent owner as required by Sec. Sec.  
314.52(a) and 314.95(a) and met the content requirements described in 
Sec. Sec.  314.52(c) and 314.95(c) (see proposed Sec. Sec.  
314.52(b)(3) and 314.95(b)(3)). We also proposed to clarify that a copy 
of the notice of paragraph IV certification itself does not need to be 
submitted to FDA in the amendment (see proposed Sec. Sec.  314.52(b)(3) 
and 314.95(b)(3)).
    We proposed that an applicant must amend its 505(b)(2) application 
or ANDA with documentation that the notice of paragraph IV 
certification was sent on a date that complies with the timeframe 
required by Sec.  314.52(b) or (d) or Sec.  314.95(b) or (d), as 
applicable (see proposed Sec. Sec.  314.52(e) and 314.95(e) and section 
505(b)(3)(B) and (j)(2)(B)(ii) of the FD&C Act). For administrative 
efficiency, we proposed that a 505(b)(2) or ANDA applicant can submit a 
single amendment that contains documentation of timely sending of the 
notice(s) of paragraph IV certification and receipt of the notice(s) by 
each person provided the notice. We proposed that the amendment must be 
submitted within 30 days after the last date on which notice was 
received by a person described in Sec.  314.52(a) or Sec.  314.95(a), 
respectively (see proposed Sec. Sec.  314.52(e) and 314.95(e)). We also 
proposed to clarify the types of documentation of timely sending and 
receipt of notice of paragraph IV certification that can satisfy the 
regulatory requirements (see proposed Sec. Sec.  314.52(e) and 
314.95(e)).
    In addition, we proposed to require that ANDA applicants include in 
their amendment a dated printout of the Orange Book entry for the RLD 
that includes the patent that is the subject of the notice of paragraph 
IV certification. This proposed requirement would ensure that a 
paragraph IV certification that may qualify an ANDA applicant for 180-
day exclusivity is submitted only for a listed patent and is not sent 
before the first working day after the day the patent is listed in the 
Orange Book (see proposed Sec. Sec.  314.95(b)(2) and 
314.94(a)(12)(viii)(C)(1)(ii)).
    We did not receive any comments on these proposed revisions. 
However, for administrative efficiency, the Agency has revised 
Sec. Sec.  314.52(b)(3) and 314.95(b)(3) to remove the requirement for 
a 505(b)(2) or ANDA applicant to submit an amendment at the time it 
sends notice of paragraph IV certification. Instead, the 505(b)(2) or 
ANDA applicant may submit a single amendment that contains the 
statements required by Sec. Sec.  314.52(b)(3) and 314.95(b)(3) and 
documentation of timely sending and receipt of notice of paragraph IV 
certification if the amendment contains all of the information required 
by Sec. Sec.  314.52(b)(3) and (e) and 314.95(b)(3) and (e) and is 
submitted within 30 days of the date on which the last notice was 
received.

V.E. Amended Patent Certifications (Sec. Sec.  314.50(i)(6) and 
314.94(a)(12)(viii))

    We proposed to revise the introductory text of Sec.  
314.94(a)(12)(viii) to remove the provision that restricts an ANDA 
applicant from changing a paragraph IV certification to a paragraph III 
certification in certain circumstances. We also proposed to revise 
Sec. Sec.  314.50(i)(6) and 314.94(a)(12)(viii) to require that a 
505(b)(2) or ANDA applicant submit an amended patent certification as 
an amendment to its pending application (including a supplemental 
505(b)(2) application or supplemental ANDA) and not by letter. We 
received no comments, and we are finalizing these proposed revisions to 
Sec. Sec.  314.50(i)(6) and 314.94(a)(12)(viii) without change, except 
for the technical amendments described in sections V.P.2 and V.P.6.
V.E.1. Amended Patent Certifications After a Finding of Infringement
    We proposed to amend Sec. Sec.  314.50(i)(6)(i) and 
314.94(a)(12)(viii)(A) to reflect changes to the FD&C Act made by the 
MMA that clarify the requirements for a 505(b)(2) or ANDA applicant to 
amend its paragraph IV certification after a judicial finding of patent 
infringement (see section 505(c)(3)(C)(ii)(II) and 
(j)(5)(B)(iii)(II)(bb) of the FD&C Act). We proposed to require that a 
505(b)(2) and ANDA applicant submit an amendment to change its 
paragraph IV certification to a paragraph III certification or, if 
appropriate, to a statement under section 505(b)(2)(B) or 
(j)(2)(A)(viii) of the FD&C Act if a court enters a final decision from 
which no appeal has been or can be taken that the patent at issue is 
valid and has been infringed (see proposed Sec. Sec.  314.50(i)(6)(i) 
and 314.94(a)(12)(viii)(A)). We proposed to apply this requirement 
irrespective of whether the patent infringement action was brought 
within 45 days of receipt of the notice of paragraph IV certification 
because a 505(b)(2) or ANDA applicant can no longer lawfully maintain a 
paragraph IV certification after the final court decision.

[[Page 69614]]

    We also proposed to require a 505(b)(2) or ANDA applicant to submit 
an amendment to change its paragraph IV certification to a paragraph 
III certification or, if appropriate, to a statement under section 
505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act if a court signs a 
settlement order, or consent decree in the action that includes a 
finding that the patent is infringed, unless the final decision, 
settlement order or consent decree also finds the patent to be invalid 
(see proposed Sec. Sec.  314.50(i)(6)(i) and 314.94(a)(12)(viii)(A)). 
We noted, however, that if a settlement is reached without a finding of 
patent infringement or invalidity, then a paragraph IV certification 
may continue to be appropriate.
    We received no comments, and we are finalizing these proposed 
revisions to Sec. Sec.  314.50(i)(6)(i) and 314.94(a)(12)(viii)(A) 
without change, except for a technical amendment to clarify that a 
settlement order or consent decree must be signed and entered by the 
court as required by section 505(c)(3)(C) and (j)(5)(B)(iii) of the 
FD&C Act and the additional technical amendments described in sections 
V.P.2 and V.P.6.
V.E.2. Amended Certifications After Request by the NDA Holder To Remove 
a Patent or Patent Information From the List
    We proposed to revise Sec. Sec.  314.50(i)(6)(ii) and 
314.94(a)(12)(viii)(B) to clarify the circumstances and timeframe in 
which a 505(b)(2) or ANDA applicant must submit an amended patent 
certification to its 505(b)(2) application or ANDA after an NDA holder 
has requested removal of a patent or patent information from the list 
(patent delisting). These proposed revisions also describe our practice 
regarding patent delisting as it relates to the eligibility of one or 
more first applicants for 180-day exclusivity.
    We received one comment supporting our proposal that if an NDA 
holder has requested removal of a patent or patent information from the 
list and one or more first applicants are eligible for 180-day 
exclusivity, FDA will not remove the patent or patent information from 
the list until we have determined that no first applicant is eligible 
for 180-day exclusivity or the 180-day exclusivity is extinguished (see 
proposed Sec. Sec.  314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B)). We 
are finalizing proposed Sec. Sec.  314.50(i)(6)(ii) and 
314.94(a)(12)(viii)(B) with revisions to consistently refer to a 
request to remove a patent or patent information from the Orange Book 
and to clarify that the patent or patent information will remain listed 
until any 180-day exclusivity based on that patent has expired or has 
been extinguished. We also are making the technical amendments 
described in sections V.P.1, V.P.3, and V.P.6 and the revision to Sec.  
314.94(a)(12)(viii)(B) described in section V.E.3.
V.E.3. Amended Certifications Upon Patent Reissuance
    We proposed to revise our regulations to describe a 505(b)(2) and 
ANDA applicant's patent certification obligations with respect to a 
reissued patent. Our approach reflected our consideration of the 
original patent and the reissued patent as a ``single bundle of patent 
rights,'' albeit patent rights that may have changed with reissuance, 
for purposes of administering the patent certification requirements of 
the FD&C Act and any 30-month stay of approval or 180-day exclusivity 
that relates to a paragraph IV certification to the original patent 
(see section V.B.1.e).
    We proposed to require that a 505(b)(2) or ANDA applicant provide 
an appropriate patent certification or statement with respect to a 
reissued patent, unless the NDA holder did not timely file patent 
information with FDA on either the original patent or the reissued 
patent. We also proposed that the patent information listed for the 
reissued patent would be treated as though it had been submitted under 
505(b)(1) or 505(c)(2) of the FD&C Act at the time of listing of the 
original patent for purposes of determining the availability of a 30-
month stay if other criteria were met (see section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act).
    For a first applicant eligible for 180-day exclusivity based on a 
paragraph IV certification to an original patent that is subsequently 
reissued, we proposed that if the applicant opined that the reissued 
patent also is invalid, unenforceable, or will not be infringed, the 
applicant must submit a paragraph IV certification to the reissued 
patent within 30 days of the date on which the reissued patent is 
listed in the Orange Book to lawfully maintain its paragraph IV 
certification for purposes of eligibility for 180-day exclusivity (see 
proposed Sec.  314.94(a)(12)(viii)(B)). Otherwise, we proposed that we 
would consider the first applicant to have amended or withdrawn its 
paragraph IV certification to the original patent on which it qualified 
for 180-day exclusivity under section 505(j)(5)(D)(i)(III) of the FD&C 
Act. We indicated that if a first applicant who qualifies as such based 
on a paragraph IV certification to the original patent forfeits 180-day 
exclusivity, another applicant would not be eligible for 180-day 
exclusivity based on a paragraph IV certification to the reissued 
patent (see section 505(j)(5)(D)(iii)(II) of the FD&C Act).
    In the following paragraphs, we discuss a comment on this proposal 
(see section V.B.1.e for a discussion of comments regarding submission 
of additional information on reissued patents). After considering this 
comment, we are not finalizing this proposal.
    (Comment 38) One comment objects to FDA's proposal that a first 
applicant eligible for 180-day exclusivity based on a paragraph IV 
certification to a patent that has been reissued must submit a 
paragraph IV certification to the reissued patent within 30 days of 
listing to have lawfully maintained its paragraph IV certification for 
purposes of 180-day exclusivity. The comment asserts that failure to 
comply with this proposed requirement does not provide an adequate 
basis for FDA to extinguish a first applicant's eligibility for 180-day 
exclusivity. In the alternative, the comment requests that FDA 
expressly state that the requirement only will be applied 
prospectively. The comment also recommends that an amended patent 
certification only be required if the original certification becomes 
inaccurate.
    (Response 38) As discussed in Response 17, FDA has determined that 
the ``single bundle of patent rights'' approach reflected in its 
proposed regulations on reissued patents is no longer appropriate based 
on the recent decision in Mylan Pharms., Inc. v. FDA (594 Fed. Appx. 
791). Accordingly, the Agency is not finalizing the proposed revision 
to Sec.  314.94(a)(12)(viii)(B) regarding reissued patents because we 
now consider reissued patents as separate and distinct from the 
original patent for purposes of administering the patent certification 
requirements of the FD&C Act and any 30-month stay of approval or 180-
day exclusivity. This determination that the ``single bundle of patent 
rights'' approach is no longer appropriate means that FDA assesses 
whether a reissued patent is timely filed based solely on whether the 
NDA holder has submitted the required patent information within 30 days 
of reissuance (provided that the patent is reissued after the date of 
approval of the NDA) or otherwise meets the requirements for timely 
filing of patent information (see Sec. Sec.  314.50(i)(4) and 
314.94(a)(12)(vi)). Similarly, the date on which patent information on 
the reissued patent (and not the original patent) is submitted to FDA 
determines

[[Page 69615]]

whether a paragraph IV certification to the reissued patent could give 
rise to a 30-month stay if other criteria are met (see section 
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act). This also means that 
FDA evaluates eligibility for 180-day exclusivity based on whether the 
criteria are met for an original patent (irrespective of whether it 
subsequently is reissued) or for a reissued patent. It is unnecessary 
to address the comment requesting that FDA prospectively apply the 
proposed revision to Sec.  314.94(a)(12)(viii)(B) because we are not 
finalizing this proposed change.
    With respect to the comment regarding an ``amended'' patent 
certification, we note that an appropriate patent certification or 
statement is required for timely filed patent information submitted by 
an NDA holder for the listed drug relied upon or RLD, including timely 
filed patent information on a reissued patent (see Sec. Sec.  
314.50(i)(4) and 314.94(a)(12)(vi), and sections V.B.2.b and V.E.4; see 
also Sec. Sec.  314.60(f) and 314.96(d) and section V.F).
V.E.4. Other Amended Certifications
    We proposed to expressly require a 505(b)(2) or ANDA applicant to 
submit an appropriate patent certification or statement if, after 
submission of the 505(b)(2) application or ANDA, a new patent is issued 
by the USPTO that claims the listed drug or RLD or that claims an 
approved use for such drug, except as provided in Sec. Sec.  
314.50(i)(4) and 314.94(a)(12)(vi) (see proposed Sec. Sec.  
314.50(i)(6)(iii)(A)(2) and 314.94(a)(12)(viii)(C)(1)(ii)). We also 
explained our longstanding position that if an applicant that 
previously submitted a paragraph III certification, a paragraph IV 
certification, or a statement under section 505(b)(2)(B) or 
(j)(2)(A)(viii) of the FD&C Act fails to amend its patent certification 
to a paragraph II certification upon patent expiration, the Agency will 
consider the 505(b)(2) or ANDA applicant to have constructively changed 
its patent certification to a paragraph II certification. We proposed 
that a patent certification or statement by an ANDA applicant must not 
be submitted earlier than the first working day after the day the 
patent is published in the Orange Book (see proposed Sec.  
314.94(a)(12)(viii)(C)(1)(ii); see also proposed Sec.  314.95(b)(2) and 
section V.D.1.a). Finally, we proposed to revise our regulations to 
clarify that an applicant is not required to submit a supplement solely 
to change a submitted patent certification after approval of the 
application (see proposed Sec. Sec.  314.50(i)(6)(iii)(B) and 
314.94(a)(12)(viii)(C)(2)).
    In section V.D.1.a, we discuss comments on proposed Sec.  
314.94(a)(12)(viii)(C)(1)(ii) (see Responses 33 and 34). We received no 
other comments and are finalizing these provisions without change, 
except for the technical amendments described in section V.P.4.

V.F. Patent Certification Requirements for Amendments and Supplements 
to 505(b)(2) Applications and ANDAs (Sec. Sec.  314.60, 314.70, 314.96, 
and 314.97)

V.F.1. Types of Amendments for Which Patent Certification Is Required
    We proposed to add Sec. Sec.  314.60(f) and 314.96(d) to clarify 
and augment the patent certification requirements for amendments 
described in Sec. Sec.  314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C). 
In these provisions, we proposed to require that an applicant must 
submit patent certifications described in Sec. Sec.  314.50(i) or 
314.94(a)(12) if approval is sought for any of the following types of 
amendments to a 505(b)(2) application or ANDA: (1) To add a new 
indication or other condition of use; (2) to add a new strength; (3) to 
make other than minor changes in the product formulation; or (4) to 
change the physical form or crystalline structure of the active 
ingredient of the drug product.
    We explained that this proposed requirement would not apply to 
minor changes in product formulation that FDA would regard as resulting 
in essentially the same product (see proposed Sec. Sec.  314.60(f)(3) 
and 314.96(d)(3)). We proposed that a new patent certification would 
not be required if the new formulation in the amendment is 
qualitatively (Q1) the same as the previous formulation (i.e., contains 
all of the same inactive ingredients) and quantitatively (Q2) 
essentially the same (i.e., each inactive ingredient differs by no more 
than plus or minus 5 percent from the previous formulation). If an 
applicant submits an amendment to a 505(b)(2) application or ANDA for 
any of the categories of changes described in these provisions and does 
not submit a new patent certification, we proposed that the applicant 
would be required to verify that the proposed change described in the 
amendment is not the type of change for which a new patent 
certification or statement is required (e.g., the proposed formulation 
change meets the criteria for a ``minor'' formulation change).
    In the following paragraphs, we discuss several comments on this 
proposal. After considering these comments, we are finalizing 
Sec. Sec.  314.60(f) and 314.96(d) with revisions to clarify that the 
specified types of amendments are required to contain an appropriate 
patent certification (or recertification) or statement and to describe 
the required verification.
    (Comment 39) Three comments recommend that an amended patent 
certification should not be required if the 505(b)(2) or ANDA applicant 
determines that the change described in its amendment does not 
materially affect the factual and legal basis for a previous paragraph 
IV certification or materially affect the product in a manner that 
could be protected by a listed patent. These comments express concern 
that requiring a patent certification for the types of amendments 
described in Sec. Sec.  314.60(f) and 314.96(d) could give rise to a 
second 30-month stay of approval, contrary to the intent of the MMA. 
Two other comments opine that the proposal is under-inclusive, and 
recommend that FDA require a new patent certification in all 
circumstances in which an amendment may alter the proposed product's 
relationship to a listed patent and require that the applicant provide 
the basis for a claim of noninfringement. These comments recommend 
requiring a new patent certification (and corresponding opportunity for 
resolution of potential patent infringement claims before approval) if 
approval is sought for any of the following types of changes: Any 
change in product formulation; a change in the physical form, particle 
size, grade, purity, or crystalline structure of the active ingredient; 
or a change to a proposed drug-delivery device.
    (Response 39) We acknowledge comments suggesting that the patent 
certification requirements for amendments to a 505(b)(2) application or 
ANDA may be considered either under-inclusive or over-inclusive. 
However, we believe that our approach strikes an appropriate balance by 
protecting the patent rights of NDA holders without unnecessarily 
delaying approval of 505(b)(2) applications and ANDAs. A 505(b)(2) or 
ANDA applicant is required to amend its patent certification if, at any 
time before approval, the applicant learns that the previously 
submitted patent certification is no longer accurate with respect to 
the pending application or supplement, as amended (see Sec. Sec.  
314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C)). An applicant that 
submits a 505(b)(2) application or ANDA containing a paragraph IV 
certification to a listed patent must

[[Page 69616]]

reevaluate whether the patent certification continues to be accurate 
after a change to the proposed product submitted in an amendment to the 
505(b)(2) application or ANDA. To address concerns that the factual and 
legal basis of the applicant's opinion that a patent will not be 
infringed may have changed, we are requiring an applicant to submit an 
appropriate patent certification (or recertification, for a previously 
submitted paragraph IV certification) or statement, for the following 
types of amendments to a 505(b)(2) application or ANDA: (1) To add a 
new indication or other condition of use; (2) to add a new strength; 
(3) to make other than minor changes in the product formulation; or (4) 
to change the physical form or crystalline structure of the active 
ingredient of the drug product (see Sec. Sec.  314.60(f)(1) and 
314.96(d)(1) and Response 42). These patent certification requirements 
are intended to facilitate ongoing compliance with section 505(b)(2)(A) 
and (j)(2)(A)(vii) of the FD&C Act. We do not agree that the need for 
an appropriate patent certification (or recertification) or statement 
for the types of amendments described in Sec. Sec.  314.60(f) and 
314.96(d) should be left entirely to the applicant's discretion because 
applicants may be uncertain when it is necessary. To implement the 
proposed verification by the 505(b)(2) or ANDA applicant described in 
the proposed rule (see 80 FR 6802 at 6823), we are adding Sec. Sec.  
314.60(f)(2) and 314.96(d)(2) to require that if the amendment to the 
505(b)(2) application or ANDA does not contain a patent certification 
or statement, the applicant must verify that the proposed change 
described in the amendment is not one of the types of amendments 
described in Sec. Sec.  314.60(f)(1)(i) through (iv) and 
314.96(d)(1)(i) through (iv).
    We also do not agree that it is necessary to expressly require an 
appropriate patent certification (or recertification) with the broader 
range of changes to a proposed product described in the comments. We 
previously have explained that ``[g]iven the range of changes that may 
be the subject of a [chemistry, manufacturing, and controls] amendment, 
such a requirement would impose a significant burden without clearly 
enhancing compliance with the statutory patent certification 
requirements. Through our proposal to require a new patent 
certification and, with respect to a paragraph IV certification, a new 
notice of paragraph IV certification to be sent at the same time that 
certain types of amendments are submitted to FDA, we are upholding the 
legislative balance of the Hatch-Waxman Amendments that facilitates the 
availability of generic drug products while protecting innovator 
intellectual property rights'' (see Letter from Janet Woodcock, M.D., 
Director, CDER, to John B. Dubeck and Frederick A. Stearns, dated 
February 6, 2015, regarding Docket No. FDA-2003-P-0519, available at 
https://www.regulations.gov).
    We recognize that a 30-month stay of approval may result from 
initiation of a patent infringement action in response to a second 
notice of paragraph IV certification that is provided with an amendment 
to a 505(b)(2) application or ANDA. This scenario may occur if the 
patent at issue in the infringement action was listed before the date 
of submission of the original 505(b)(2) application or ANDA and, for 
example, the infringement action was warranted by the change proposed 
in the amendment (see, e.g., Letter from Janet Woodcock, M.D., 
Director, CDER, to Gerald F. Masoudi, dated October 19, 2010, regarding 
Docket No. FDA-2010-P-0223, available at https://www.regulations.gov 
(concluding that a new 30-month stay of approval stems from a timely 
lawsuit based on the second notice of paragraph IV certification 
submitted in connection with an amendment to the ANDA for reformulated 
doxercalciferol injection); Letter from Janet Woodcock, M.D., Director, 
CDER, to Christina M. Markus, dated June 7, 2011, regarding Docket No. 
FDA-2011-P-0127, available at https://www.regulations.gov (confirming 
that a second 30-month stay of approval stems from a timely lawsuit 
based on the second notice of paragraph IV certification submitted in 
connection with an amendment to the ANDA for desflurane liquid)).
    (Comment 40) One comment recommends that an amendment to a 
505(b)(2) application or ANDA to add a new indication or other 
condition of use should only require submission of a patent 
certification to a patent that claims the new use and for which a 
patent certification previously was not made.
    (Response 40) We agree that if an applicant amends its 505(b)(2) 
application or ANDA only to add a new indication or other condition of 
use, the applicant need only certify to listed patents that have been 
identified as claiming an approved use and relate to the change 
described in the amendment (provided that the 505(b)(2) application or 
ANDA contained an appropriate patent certification or statement to any 
other listed patent(s) prior to submission of the amendment). This 
approach preserves the NDA holder's intellectual property rights 
without requiring the 505(b)(2) or ANDA applicant to submit a 
duplicative certification to a listed patent(s) that has not been 
identified by the NDA holder as claiming a method of use and would not 
be implicated by the amendment (compare proposed Sec.  314.70(i)(2)). 
This approach also is consistent with existing patent certification 
requirements under Sec. Sec.  314.50(i)(6)(iii) and 
314.94(a)(12)(viii)(C). If any other changes described in paragraphs 
(ii) through (iv) of Sec. Sec.  314.60(f)(1) or 314.96(d)(1) are 
proposed in the amendment, the applicant would be required to address 
all timely filed listed patents for the listed drug relied upon or RLD 
with an appropriate patent certification (or recertification) or 
statement.
    An ANDA applicant would be expected to submit an amendment to add a 
new indication or other condition of use if the applicant previously 
submitted a statement described in section 505(j)(2)(A)(viii) of the 
FD&C Act and now seeks approval for the use or if the RLD was approved 
for a new indication or other condition of use after the ANDA was 
submitted (see section 505(j)(2)(A)(v) of the FD&C Act and Sec.  
314.94(a)(8)(iv)). Most requests for approval of a different indication 
or condition of use by a 505(b)(2) applicant should not be made as an 
amendment to the 505(b)(2) application (see Sec.  314.60(b)(6) and 
guidance for industry entitled ``Submitting Separate Marketing 
Applications and Clinical Data for Purposes of Assessing User Fees'' 
(December 2004) at 4 to 5, available at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm). 
Accordingly, we expect that there would be limited circumstances in 
which this provision would apply to a 505(b)(2) application (e.g., 
indication changed from prescription status to OTC use).
V.F.2. Types of Supplements for Which Patent Certification Is Required
    We proposed to add Sec. Sec.  314.70(i) and 314.97(c), and make 
conforming revisions to Sec. Sec.  314.50(i)(6)(iii)(B) and 
314.94(a)(12)(viii)(C)(2), to clarify the patent certification 
requirements for a 505(b)(2) or ANDA supplement. In these provisions, 
we proposed to require patent certifications described in Sec.  
314.50(i) or Sec.  314.94(a)(12), if the applicant requests approval to 
add a new indication or other condition of use or to add a new strength 
in a 505(b)(2) or ANDA supplement (see proposed Sec. Sec.  314.70(i) 
and 314.97(c)).

[[Page 69617]]

    For a 505(b)(2) supplement that seeks approval for a new indication 
or other condition of use, the 505(b)(2) applicant currently is 
required to submit an appropriate patent certification or statement for 
each timely filed patent that claims the listed drug(s) relied upon or 
a method of using such drug(s) for which the applicant is seeking 
approval (see section 505(b)(2) of the FD&C Act). We proposed to reduce 
these patent certification requirements by providing that a 505(b)(2) 
supplement that only seeks approval to add a new indication or other 
condition of use is required to contain an appropriate patent 
certification or statement described in Sec.  314.50(i) only for 
patents that are identified as claiming an approved use (see proposed 
Sec.  314.70(i)(2)).
    We did not propose to require a patent certification with a 
supplement to change the formulation or to change the physical form or 
crystalline structure of the active ingredient of a product approved in 
a 505(b)(2) application or ANDA. We explained that it would not be 
necessary for FDA to require patent certifications under these 
circumstances because the NDA holder for a listed drug and any patent 
owner can monitor postapproval changes in the formulation or active 
ingredient of a marketed drug product and address any patent-related 
concerns without the involvement of FDA.
    In the following paragraphs, we discuss two comments on proposed 
Sec. Sec.  314.70(i) and 314.97(c). We are continuing to consider these 
comments, and thus we are not finalizing proposed Sec. Sec.  314.70(i) 
and 314.97(c) (or the references to these provisions in proposed 
Sec. Sec.  314.50(i)(6)(iii)(B) and 314.94(a)(12)(viii)(C)(2)), 
respectively, at this time. Accordingly, FDA will maintain its current 
practice of regulating directly from the statute and general patent 
certification regulations in requiring an appropriate patent 
certification or statement with a 505(b)(2) or ANDA supplement.
    (Comment 41) Two comments disagree with FDA's proposal to not 
expressly require a new patent certification with a 505(b)(2) or ANDA 
supplement in each of the circumstances in which a new patent 
certification (or recertification) is required for amendments to a 
505(b)(2) application or ANDA. One comment maintains that the Agency's 
approach is inconsistent with the statute, which clearly describes 
patent certification requirements for 505(b)(2) and ANDA supplements. 
This comment also expresses concern that a 505(b)(2) or ANDA applicant 
could circumvent the patent certification requirements by seeking 
approval of a noninfringing product that the applicant does not intend 
to market followed by a supplement for a modified form of the active 
ingredient or a different formulation of the drug product that the 
applicant intends to market. Both comments contend that monitoring of 
postapproval changes by an NDA holder or patent owner is not a 
replacement for notice from the 505(b)(2) or ANDA applicant of a 
paragraph IV certification and the opportunity to litigate any 
potential infringement claims prior to approval of the change requested 
in the supplement.
    (Response 41) We are continuing to evaluate these comments, 
including whether our regulations should expressly require a new patent 
certification with a broader range of changes submitted in supplemental 
applications than described in the proposed rule. Accordingly, we are 
declining to finalize proposed Sec. Sec.  314.70(i) and 314.97(c) at 
this time. We will continue to implement the requirement for an 
appropriate patent certification or statement with a 505(b)(2) or ANDA 
supplement directly from the statute and our general regulations on 
patent certifications (see Sec. Sec.  314.50(i)(6)(iii) and 
314.94(a)(12)(viii)(C) (requiring a 505(b)(2) or ANDA applicant to 
amend its patent certification if, at any time before approval, the 
applicant learns that the previously submitted patent certification is 
no longer accurate with respect to the pending application or 
supplement)).
V.F.3. Requirements for Notice of Paragraph IV Certifications and 
Implications for 180-Day Exclusivity
    We proposed that notice to the NDA holder and each patent owner 
would be required for all paragraph IV certifications, irrespective of 
whether the 505(b)(2) or ANDA applicant previously provided notice of 
paragraph IV certification to the same patent or to another patent 
claiming the listed drug relied upon or RLD (see section 505(b)(3)(B) 
and (j)(2)(B)(ii) of the FD&C Act and proposed Sec. Sec.  314.52(d)(1) 
and 314.95(d)(1)). We proposed that a first applicant that submits an 
amendment to its pending ANDA or a supplement would be considered to 
have lawfully maintained a paragraph IV certification to the patent 
upon which eligibility for 180-day exclusivity was based if the 
amendment is accompanied by another paragraph IV certification to the 
patent and notice of paragraph IV certification is sent in accordance 
with proposed Sec.  314.95(d).
    In the following paragraphs, we discuss two comments on this topic. 
After considering these comments, we are revising proposed Sec.  
314.96(d) regarding amendments to an ANDA to clarify that a paragraph 
IV certification to a patent or patent claim for which an ANDA 
applicant previously submitted a paragraph IV certification is a 
``recertification'' rather than an ``amendment'' of the paragraph IV 
certification. We are making conforming revisions to Sec.  314.60(f). 
We are finalizing Sec.  314.52(d)(1) with the changes described in 
Response 32, and we are finalizing Sec.  314.95(d)(1) with the changes 
described in section V.D.1.b and the technical amendments described in 
section V.P.1.
    (Comment 42) One comment expresses concern that a first applicant 
could inadvertently forfeit its eligibility for 180-day exclusivity if, 
pursuant to proposed Sec.  314.96(d), the first applicant submits a new 
paragraph IV certification to the patent that qualified the applicant 
for 180-day exclusivity (see section 505(j)(5)(D)(i)(III) of the FD&C 
Act). The comment suggests that FDA require an ANDA applicant to 
provide a new notice of its paragraph IV certification to the NDA 
holder and each patent owner instead of submitting a new patent 
certification to the Agency. Another comment recommends that FDA not 
require an ANDA applicant to submit a new patent certification with an 
amendment to the ANDA if a patent infringement action already has been 
filed against the applicant with respect to the ANDA.
    (Response 42) FDA interprets the statute to mean that a first 
applicant ``lawfully maintains'' a paragraph IV certification to the 
patent or patent claim upon which eligibility for 180-day exclusivity 
is based if any subsequent amendment to the ANDA that requires a patent 
certification contains a paragraph IV certification to the qualifying 
patent or patent claim and notice of the paragraph IV certification is 
sent in accordance with Sec.  314.95(d). This interpretation is 
supported by our longstanding requirement that an ANDA applicant must 
amend a submitted certification if, at any time before approval of the 
ANDA, the applicant learns that the submitted certification is no 
longer accurate (see Sec.  314.94(a)(12)(viii)(C)(1)(i)). A subsequent 
paragraph IV certification to the qualifying patent or patent claim is 
not an ``amendment'' of the previously submitted paragraph IV 
certification under section 505(j)(5)(D)(i)(III) of the FD&C Act 
because the type of certification remains the same; rather, it is a 
reaffirmation of the patent challenge

[[Page 69618]]

notwithstanding the amendment to the ANDA. Therefore, we are using the 
term ``recertification'' to describe this scenario (see Sec.  
314.96(d)(1); see also Sec.  314.60(f)(1)).
    We decline to adopt the comment's proposal to require a new notice 
of paragraph IV certification--but not a new patent certification--with 
an amendment to the ANDA. Notice of a paragraph IV certification is 
inextricably linked to the submission of a corresponding paragraph IV 
certification. The statute expressly requires that an applicant that 
submits a paragraph IV certification in an amendment to the ANDA 
provide the required notice at the time of submission of the amendment 
regardless of whether the applicant has already given notice with 
respect to another such certification contained in the application (see 
section 505(j)(2)(B)(ii)(II) of the FD&C Act). Notice of a new 
paragraph IV certification submitted with an amendment to the ANDA must 
be updated to correspond to the proposed product as changed by the 
amendment. However, we believe that the concern described in the 
comment is addressed by our explanation that a paragraph IV 
certification to a patent or patent claim for which an ANDA applicant 
previously submitted a paragraph IV certification is a 
``recertification'' rather than an ``amendment'' of the paragraph IV 
certification and by the corresponding changes to Sec.  314.96(d)(1).
    We also do not agree with the suggestion that a new notice of 
paragraph IV certification should not be required if the NDA holder or 
owner of the relevant patent(s) already is litigating claims of patent 
infringement against the ANDA applicant. As previously discussed, the 
statute requires an ANDA applicant to provide notice with all paragraph 
IV certifications (see section 505(j)(2)(B)(ii)(II) of the FD&C Act). 
Moreover, if the factual and legal bases for the paragraph IV 
certification have changed, it would be particularly important to 
timely provide this information to the NDA holder and each patent owner 
to support the efficient use of judicial resources.

V.G. Amendments or Supplements to a 505(b)(2) Application for a 
Different Drug and Amendments or Supplements to an ANDA That Reference 
a Different Listed Drug (Sec. Sec.  314.60, 314.70, 314.96, and 314.97)

V.G.1. Amendments and Supplements to an ANDA (Sec. Sec.  314.96(c) and 
314.97(b))
    We proposed to establish a regulation that would implement section 
505(j)(2)(D)(i) of the FD&C Act by providing that an ANDA applicant may 
not amend or supplement an ANDA to seek approval of a drug referring to 
a listed drug that is different from the RLD identified in the ANDA 
(see proposed Sec. Sec.  314.96(c) and 314.97(b)). For example, we 
proposed that if at any time before approval of the ANDA, an NDA is 
approved for a drug product that is pharmaceutically equivalent to the 
proposed product in the pending ANDA and that NDA is designated as an 
RLD, the applicant would not be permitted to amend its pending ANDA to 
reference the new RLD (see proposed Sec.  314.96(c)). We proposed that 
this restriction also would apply if one or more changes proposed in an 
amendment or a supplement to an ANDA would result in the proposed 
product being a pharmaceutical equivalent to a different listed drug 
than the RLD identified in the ANDA. In these scenarios, we proposed 
that the ANDA applicant would be required to submit a new ANDA to 
identify the pharmaceutically equivalent product as the new RLD (see 
proposed Sec. Sec.  314.96(c) and 314.97(b) and section 505(j)(2)(D)(i) 
of the FD&C Act).
    In the proposed rule, we confirmed that different strengths of an 
approved drug product continue to be regarded as different listed 
drugs. However, to implement section 505(j)(2)(D)(ii) of the FD&C Act, 
we proposed to codify our practice that permits an applicant to amend 
or supplement an ANDA to seek approval of a different strength of the 
drug (see proposed Sec. Sec.  314.96(c) and 314.97(b)).
    We received no comments on proposed Sec.  314.97(b) regarding 
supplements. In the following paragraphs, we discuss three comments on 
proposed Sec.  314.96(c) regarding amendments. After considering these 
comments, we are finalizing proposed Sec. Sec.  314.96(c) and 314.97(b) 
without change.
    (Comment 43) One comment requests that FDA modify the proposed 
regulation to require that if, at any time before submission (rather 
than any time before approval) of the ANDA, an NDA is approved for a 
drug product that is pharmaceutically equivalent to the proposed 
product and that NDA is designated as an RLD, the ANDA applicant would 
be required to submit an ANDA that identifies the pharmaceutically 
equivalent product as the RLD. The comment suggests that this proposed 
revision (and a similar proposal discussed in comment 49) would 
harmonize FDA's proposed requirements for ANDAs and 505(b)(2) 
applications by imposing limitations up until the time of ANDA 
submission rather than approval. Another comment expresses concern that 
requiring an ANDA applicant to submit a new ANDA that identifies the 
pharmaceutically equivalent product as the RLD may unnecessarily 
require additional data and delay ANDA approval, although the comment 
acknowledges that this may be appropriate and efficient in some 
circumstances.
    (Response 43) We decline to adopt the suggested modification to 
proposed Sec.  314.96(c). Under existing practice, FDA will refuse to 
receive an ANDA that does not cite an appropriate RLD or rely on an 
approved suitability petition as its basis for ANDA submission (see 
Sec.  314.94(a)(3)). In addition, there are circumstances in which an 
ANDA that has been received, but not approved, may be required to 
submit a new ANDA that identifies a pharmaceutically equivalent product 
as the RLD. This may occur, for example: (1) If a pharmaceutically 
equivalent product is approved after an ANDA is submitted pursuant to 
an approved suitability petition (petitioned ANDA) or (2) if changes 
are proposed in an amendment or a supplement to the ANDA such that the 
proposed product is pharmaceutically equivalent to a different listed 
drug than the RLD identified in the original ANDA (modified ANDA). 
Before enactment of the MMA, FDA required an applicant to amend its 
ANDA in these scenarios to cite the pharmaceutically equivalent product 
as its RLD. However, the MMA prohibits an ANDA applicant from amending 
its ANDA to change the RLD (see section 505(j)(2)(D)(i) of the FD&C 
Act). Accordingly, for the applicant to obtain approval of the proposed 
product under section 505(j) of the FD&C Act in these scenarios, we 
require the applicant to submit a new ANDA that identifies the 
pharmaceutically equivalent product as its RLD and complies with 
applicable statutory and regulatory requirements.
    We require an ANDA applicant to identify as its RLD a 
pharmaceutically equivalent product approved any time before approval, 
rather than submission, of the ANDA, because a generic drug product 
must demonstrate, among other things, that it is bioequivalent to the

[[Page 69619]]

RLD to obtain approval (see section 505(j)(2)(A)(iv) of the FD&C Act 
and Sec.  314.127(a)(6)(i)). We disagree that an ANDA applicant should 
only be required to identify a pharmaceutically equivalent product as 
its RLD until submission of the ANDA, because this approach would not 
ensure that an ANDA applicant cites an appropriate RLD in the context 
of a petitioned ANDA or modified ANDA unless the RLD was approved 
before submission of the ANDA. Such an approach would foster a 
potentially confusing proliferation of pharmaceutically equivalent drug 
products that have not demonstrated therapeutic equivalence to the RLD. 
The additional data and time that may be needed for an ANDA applicant 
to identify a pharmaceutically equivalent drug product as the RLD is 
warranted by the need for a clear determination of therapeutic 
equivalence. The modification requested in the comment would ``diminish 
the utility and accuracy of FDA's therapeutic equivalence 
determinations and potentially allow ANDA applicants to circumvent 
otherwise applicable patent and exclusivity rights accorded the NDA 
holder for the pharmaceutically equivalent RLD'' (see Letter from Janet 
Woodcock, M.D., Director, CDER, to Mark S. Aikman, Pharm.D., Osmotica 
Pharmaceutical Corp., dated November 25, 2008, regarding Docket No. 
FDA-2008-P-0329, at 11-12, available at https://www.regulations.gov) 
(Venlafaxine ER CP Response).
    Unlike an ANDA that relies on a single RLD, a 505(b)(2) application 
may rely for approval on one or more listed drugs and is not required 
to demonstrate bioequivalence or pharmaceutical equivalence to a listed 
drug on which it relies for approval. Although the Agency requires a 
505(b)(2) applicant to rely upon a drug product approved in an NDA that 
is pharmaceutically equivalent to the proposed product, the basis and 
timeframe for this requirement for 505(b)(2) applications differs from 
that of ANDAs.
    (Comment 44) One comment recommends that FDA permit an ANDA 
applicant to amend its ANDA if FDA changes the RLD or the ANDA 
applicant petitions to change the RLD.
    (Response 44) The comment is unclear because the Agency's 
designation of an additional RLD or selection of a new reference 
standard generally would not require an ANDA applicant to change its 
RLD. The RLD is the listed drug identified by FDA as the drug product 
upon which an applicant relies in seeking approval of its ANDA (see 
Sec.  314.3(b)). An ANDA applicant is prohibited from amending or 
supplementing its ANDA to change the RLD after the ANDA has been 
submitted (see Sec. Sec.  314.96(c) and 314.97(b) and section 
505(j)(2)(D)(i) of the FD&C Act).
    We note that if there are two or more approved NDAs for 
pharmaceutically equivalent products, a person may submit a citizen 
petition requesting that FDA designate an additional RLD, provided that 
there is adequate justification (see ``Abbreviated New Drug Application 
Regulations; Final Rule,'' 57 FR 17950 at 17958, April 28, 1992, and 
section 1.4 of the preface to the Orange Book (36th Edition, 2016, at 
ix) (recognizing that a listed drug that is not designated as the RLD 
may be shielded from generic competition)). An ANDA would not be 
ineligible for approval because it relied on one of two or more RLDs 
that were approved under section 505(c) of the FD&C Act based on full 
reports of investigations of safety and effectiveness, provided that 
other statutory and regulatory requirements are met. Thus, an applicant 
is not required to change its RLD upon FDA designation of the 
additional RLD.
    Generally, the RLD also will be the reference standard, which is 
the drug product selected by FDA that an ANDA applicant must use in 
conducting an in vivo bioequivalence study required for ANDA approval 
(see Sec. Sec.  314.3(b) and 314.94(a)(3)). FDA usually selects as the 
reference standard the highest strength available for drug products 
with multiple approved strengths. However, a person may petition the 
Agency to request that FDA designate a new reference standard for 
conducting bioequivalence testing if, for example, the person believes 
that another drug product would be a scientifically appropriate 
reference standard, or if the drug product selected as the reference 
standard has been discontinued and FDA has not selected a new reference 
standard. FDA also may select a reference standard in the absence of a 
citizen petition (see Letter from Janet Woodcock, M.D., Director, CDER, 
to Paul A. Braier, Ph.D., J.D., dated September 5, 2014, regarding 
Docket No. FDA-2014-P-0417, at 11, available at https://www.regulations.gov). For example, if the RLD has been withdrawn from 
marketing for reasons other than safety or effectiveness, FDA may 
select a different drug product (e.g., a different strength of a drug 
product that is the RLD) or a therapeutically equivalent drug product 
(e.g., an approved ANDA that cited the RLD as its basis of submission) 
as the reference standard. Even if FDA selects a reference standard 
that is a drug product other than the RLD for use in conducting an in 
vivo bioequivalence study, the proposed drug product will be evaluated 
against the RLD to determine whether it meets the statutory 
requirements for approval under section 505(j) of the FD&C Act. An 
applicant also may request, with appropriate scientific justification, 
that FDA waive the requirement to use the drug selected by FDA as the 
reference standard in an in vivo bioequivalence study required for 
approval (see Sec.  314.99(b)).
    FDA's selection of a different reference standard or waiver of the 
requirement to use the reference standard generally would not result in 
a change to the RLD. An ANDA would not be ineligible for approval 
because it relied upon an RLD that was not selected as a reference 
standard.
    We acknowledge that FDA's practice of identifying the reference 
standard in the Orange Book by the word ``yes'' in the ``RLD'' column 
has resulted in confusion, and we are revising the column heading in 
the Orange Book from ``RLD'' to ``RS'' for clarity.
V.G.2. Amendments and Supplements to a 505(b)(2) Application 
(Sec. Sec.  314.60(e) and 314.70(h))
    We proposed to establish a regulation that would implement section 
505(b)(4)(A) of the FD&C Act by providing that an applicant may not 
amend or supplement a 505(b)(2) application to seek approval of a drug 
that is a different drug from the drug in the original submission of 
the 505(b)(2) application (see proposed Sec. Sec.  314.60(e) and 
314.70(h)). We proposed that a drug will be considered a ``different 
drug'' for purposes of section 505(b)(4)(A) of the FD&C Act if it has 
been modified to have a different active ingredient, different route of 
administration, different dosage form, or different excipients that 
require either a separate clinical study to establish safety or 
effectiveness or, for topical products, that require a separate in vivo 
demonstration of bioequivalence (see proposed Sec. Sec.  314.60(e) and 
314.70(h)). These proposed modifications would result in a different 
drug for which approval must be requested in a new 505(b)(2) 
application.
    In the proposed rule, we explained that the statutory restriction 
on amending a 505(b)(2) application to seek approval of a drug that is 
a different drug from the drug in the original submission of the 
505(b)(2) application applies to any proposed amendment, even if the 
amendment is submitted before the Agency's decision regarding whether 
the 505(b)(2) application can be filed in accordance with Sec.  
314.101(a). However, notwithstanding these

[[Page 69620]]

restrictions on amendments to a 505(b)(2) application, we proposed that 
an applicant is permitted to amend or supplement a 505(b)(2) 
application to identify a new or additional listed drug upon which the 
application relies for approval as long as the applicant is not seeking 
approval for a different drug from the drug in the original submission 
of the 505(b)(2) application. In addition, we proposed that an 
applicant is permitted to amend or supplement a 505(b)(2) application 
to seek approval for a different strength of the drug product (see 
section 505(b)(4)(B) of the FD&C Act and proposed Sec. Sec.  314.60(e) 
and 314.70(h)).
    We received no comments on proposed Sec.  314.70(h) regarding 
supplements. In the following paragraphs, we discuss a comment on 
proposed Sec.  314.60(e) regarding amendments. After considering this 
comment, we are finalizing proposed Sec. Sec.  314.60(e) and 314.70(h) 
without change.
    (Comment 45) One comment recommends that FDA return to its initial 
interpretation of section 505(b)(4)(A) of the FD&C Act and revise Sec.  
314.60(e) to prohibit a 505(b)(2) applicant from amending its 
application to rely upon a new or different listed drug for approval. 
The comment observes that if a new or different listed drug is 
identified in an amendment to the 505(b)(2) application, and the 
505(b)(2) applicant submits a paragraph IV certification for a patent 
that is timely filed after submission of the 505(b)(2) application, a 
30-month stay would not be available should the NDA holder or patent 
owner initiate patent infringement litigation within the statutory 
timeframe.
    (Response 45) We decline to revise Sec.  314.60(e) as requested 
because the comment does not provide any basis for a different 
interpretation of section 505(b)(4)(A) of the FD&C Act that FDA did not 
expressly consider in the proposed rule. The preamble to the proposed 
rule contains an extensive discussion of the Agency's initial 
interpretation of section 505(b)(4)(A) of the FD&C Act and explains why 
FDA proposed narrowing that interpretation of section 505(b)(4)(A) of 
the FD&C Act as reflected in Sec. Sec.  314.60(e) and 314.70(h) (see 80 
FR 6802 at 6850 through 6852). The comment has not persuaded us to 
return to that initial interpretation.

V.H. Procedure for Submission of a 505(b)(2) Application Requiring 
Investigations for Approval of a New Indication for, or Other Change 
From, a Listed Drug (Sec.  314.54)

    We proposed to require that the listed drug(s) identified as relied 
upon by a 505(b)(2) applicant must include any approved drug product 
that: (1) Is pharmaceutically equivalent to the drug product for which 
the 505(b)(2) application is submitted and (2) was approved before the 
505(b)(2) application was submitted (see proposed Sec. Sec.  
314.50(i)(1)(i)(C), 314.54(a)(1), and 314.125(b)(19)).
    In the following paragraphs, we discuss a comment on these proposed 
provisions. After considering this comment, we are finalizing proposed 
Sec.  314.54(a)(1) with revisions to clarify that a 505(b)(2) applicant 
must identify a pharmaceutically equivalent drug product approved in an 
NDA as a listed drug (or an additional listed drug) relied upon if the 
pharmaceutically equivalent drug product was approved before the date 
of submission of the original 505(b)(2) application, and to codify the 
basis for this requirement. If there is more than one drug product that 
is pharmaceutically equivalent to the drug product for which the 
original 505(b)(2) application is submitted and was approved in one or 
more NDAs before the original 505(b)(2) application was submitted, the 
505(b)(2) applicant is only required to identify one such 
pharmaceutically equivalent drug product as a listed drug relied upon. 
We are finalizing proposed Sec. Sec.  314.50(i)(1)(i)(C) and 
314.125(b)(19) with conforming revisions.
    (Comment 46) One comment suggests that FDA require a 505(b)(2) 
applicant to identify any approved pharmaceutically equivalent drug 
product as a listed drug relied upon to support approval of the 
proposed product irrespective of whether the pharmaceutically 
equivalent product was approved before or during the review of the 
505(b)(2) application. The comment proposes that if a pharmaceutically 
equivalent product is approved after a 505(b)(2) application is 
submitted, the 505(b)(2) applicant--like an ANDA applicant--should be 
required to file a new 505(b)(2) application to ensure that the NDA 
holder for the pharmaceutically equivalent drug product has a 
reasonable opportunity for a 30-month stay and that any non-patent 
exclusivity is meaningful.
    (Response 46) We decline to modify the regulations as suggested. If 
a pharmaceutically equivalent drug product is approved before an 
original 505(b)(2) application is submitted, we consider the 505(b)(2) 
applicant to implicitly rely upon FDA's finding of safety and 
effectiveness for one such pharmaceutically equivalent drug product for 
approval even if the proposed drug product was developed independently 
of that pharmaceutically equivalent drug product. Accordingly, we 
require the 505(b)(2) applicant to identify one pharmaceutically 
equivalent drug product approved in an NDA as a listed drug (or an 
additional listed drug) relied upon and comply with applicable 
regulatory requirements. A 505(b)(2) applicant that identifies a listed 
drug solely to comply with Sec.  314.54(a)(1)(vi) must provide an 
appropriate patent certification or statement for any patents that are 
listed in the Orange Book for the pharmaceutically equivalent drug 
product, but the 505(b)(2) applicant is not required to submit bridging 
data to justify the scientific appropriateness of reliance on the 
pharmaceutically equivalent drug product if it is scientifically 
unnecessary to support approval. Given that there cannot be any 
implicit reliance on FDA's finding of safety and effectiveness for a 
drug product that has not yet been approved, this rationale would not 
support a requirement for a 505(b)(2) applicant to identify a 
pharmaceutically equivalent drug product approved in an NDA after the 
505(b)(2) application is submitted. We are revising Sec.  
314.54(a)(1)(vi) to clarify the basis for this requirement, which 
establishes a bright line requirement for administering the patent 
certification requirements of the FD&C Act and is unrelated to our 
approach to implementing section 505(b)(4)(A) of the FD&C Act. We are 
further revising the regulations to clarify that the requirement to 
identify one pharmaceutically equivalent drug product approved in an 
NDA as a listed drug (or an additional listed drug) relied upon applies 
before the date of submission of an original 505(b)(2) application and 
not a resubmission or a supplement (see, e.g., Sec.  314.54(a)(1); see 
also Sec.  314.3(b) (definitions of ``original NDA'' and 
``resubmission'')). We also are making conforming revisions to Sec.  
314.54(a)(1)(iii) and (vi) to clarify that a 505(b)(2) application may 
rely on FDA's finding of safety and/or effectiveness for one or more 
listed drugs.
    We recognize that a 505(b)(2) applicant that does not amend its 
pending 505(b)(2) application to rely upon a pharmaceutically 
equivalent listed drug would have no occasion to submit a patent 
certification or

[[Page 69621]]

statement with respect to any patents listed for the listed drug (and 
could be subject to patent infringement litigation after approval). 
This illustrates one of many circumstances in which the timing of 
submission of an application has certain statutory or regulatory 
implications (see, e.g., untimely filing of patent information). 
However, to the extent that the 505(b)(2) application is seeking 
approval for the exclusivity-protected conditions of approval for the 
listed drug, approval of the 505(b)(2) application would be delayed by 
any applicable 3-year exclusivity for the listed drug irrespective of 
reliance (see Veloxis Pharms. v. FDA, 109 F. Supp. 3d 104, 120 (D.D.C. 
2015)).
    (Comment 47) One comment suggests that FDA require a 505(b)(2) 
applicant to identify any approved drug product that is a 
pharmaceutical alternative to the proposed product as a listed drug(s) 
relied upon to support approval of the proposed product.
    (Response 47) We decline to modify the regulations as suggested. 
Pharmaceutical alternatives are drug products that contain the 
identical therapeutic moiety, or its precursor, but not necessarily in 
the same amount or dosage form or as the same salt or ester (see Sec.  
314.3(b)). Accordingly, there may be numerous pharmaceutical 
alternatives to a particular drug product. Given that a proposed drug 
product intended for submission in a 505(b)(2) application may differ 
in various respects from the listed drug(s) on which it relies for 
approval, there is insufficient justification to require a 505(b)(2) 
applicant to identify any pharmaceutical alternative (in addition to 
one pharmaceutical equivalent) as a listed drug upon which the 
505(b)(2) application relies in the absence of explicit reliance (see 
Letter from Janet Woodcock, M.D., Director, CDER, to David B. Clissold, 
J.D., dated September 18, 2013, regarding Docket Nos. FDA-2011-P-0869 
and FDA-2013-P-0995, at 8, available at https://www.regulations.gov) 
(``except where a pharmaceutical equivalent already has been approved, 
the 505(b)(2) applicant should determine which listed drug(s) is most 
appropriate for its development program'').
    We consider the 505(b)(2) applicant to implicitly rely for approval 
upon FDA's finding of safety and effectiveness for one such 
pharmaceutically equivalent listed drug approved in an NDA because the 
proposed product shares key characteristics (active ingredient, dosage 
form, route of administration, and strength) in common with the listed 
drug despite being ineligible for approval under section 505(j) of the 
FD&C Act (see Sec.  314.101(d)(9)). As we explained in the proposed 
rule, the requirement to identify a pharmaceutically equivalent product 
approved in an NDA as a listed drug upon which the 505(b)(2) 
application relies ``is intended to help ensure that the 505(b)(2) 
pathway is not used to circumvent the statutory obligation that would 
have applied if the proposed product was submitted as an ANDA--namely, 
submission of a patent certification for a listed patent that 
corresponds to the protected aspects of the pharmaceutically equivalent 
listed drug'' (80 FR 6802 at 6856).
    (Comment 48) One comment recommends that FDA clarify that the 
requirement for a 505(b)(2) applicant to identify an approved 
pharmaceutically equivalent product as a listed drug relied upon does 
not extend to a complex drug product for which there may be uncertainty 
about whether the drug contains the ``identical'' or ``same'' active 
drug ingredient.
    (Response 48) We acknowledge that a 505(b)(2) applicant may be 
uncertain whether to identify a listed drug solely to comply with 
Sec. Sec.  314.50(i)(1)(i)(C), 314.54(a)(1), and 314.125(b)(19) due to 
the applicant's uncertainty about whether the drug contains the 
``identical'' active drug ingredient or meets other criteria for a 
pharmaceutical equivalent. FDA intends to consider on a case-by-case 
basis any assertions by a prospective 505(b)(2) applicant that there is 
uncertainty about whether a previously approved drug product contains 
the ``identical'' active drug ingredient as the proposed product.

V.I. Petition To Request a Change From a Listed Drug (Sec.  314.93)

    We proposed to codify FDA's policy that the listed drug identified 
in an approved suitability petition can no longer be the basis for 
submission for an unapproved ANDA after a drug product is approved in 
an NDA for the change described in the petition, irrespective of 
whether FDA has withdrawn approval of the suitability petition (see 
proposed Sec.  314.93(f)). We proposed that an applicant may not amend 
its ANDA to change the basis for submission to the new RLD (see section 
505(j)(2)(D)(i) of the FD&C Act and proposed Sec.  314.96(c)), and 
would be required to submit a new ANDA that relies on the 
pharmaceutically equivalent RLD if the applicant seeks approval for the 
drug product. Accordingly, we proposed to add Sec.  314.127(a)(14) to 
state that FDA will refuse to approve a petitioned ANDA if an NDA 
subsequently has been approved for the change described in the 
suitability petition. We also proposed to add Sec.  314.93(e)(1)(vi) to 
codify our longstanding policy that FDA will not approve a suitability 
petition if a drug product is approved in an NDA for the change 
requested in the petition.
    One comment agreed with these proposed revisions to our regulations 
on suitability petitions. In the following paragraph, we discuss two 
other comments on the proposal. After considering these comments, we 
are finalizing proposed Sec.  314.93(e) and (f) with the technical 
amendment described in section V.P.1. We are also finalizing proposed 
Sec.  314.127(a)(14) with technical amendments to describe an approved 
``suitability petition'' as an approved petition under 21 CFR 10.30 and 
Sec.  314.93, and we are making conforming revisions to Sec.  
314.94(a)(3)(i) and (iii).
    (Comment 49) Two comments recommend that FDA revise the proposed 
regulation to require that if, at any time before submission (rather 
than any time before approval) of an ANDA based on a suitability 
petition, an NDA is approved for the change described in the 
suitability petition, the ANDA applicant would be required to submit an 
ANDA that identifies the drug product approved in the NDA as the RLD. 
One comment suggests that this proposed revision would harmonize FDA's 
proposed requirements for ANDAs and 505(b)(2) applications with respect 
to the timeframe in which an applicant must rely upon a 
pharmaceutically equivalent product. The other comment observes that 
there still may be multiple versions of a drug product because one or 
more ANDAs may have been approved pursuant to the suitability petition 
before an NDA is approved for the change described in the petition.
    (Response 49) We decline to adopt the suggested modification to 
Sec. Sec.  314.93 and 314.127(a)(14). FDA's longstanding practice, as 
described in the letter granting a suitability petition, is that once a 
drug product is approved in an NDA for the change described in the 
petition, that drug product will be the RLD and thereafter the approved 
suitability petition may not be used as the basis for submission of an 
ANDA. Accordingly, if an NDA is approved for the change described in 
the suitability petition before submission of an ANDA pursuant to an 
approved suitability petition, FDA would refuse to receive the ANDA. If 
an NDA is approved for the change described in the suitability petition 
after submission or receipt of an ANDA and is designated as the RLD, 
the applicant would be required to submit a new ANDA that cites the RLD 
as its basis for submission, and complies with

[[Page 69622]]

applicable statutory and regulatory requirements for approval. As we 
explained in the proposed rule, our requirement that an applicant with 
a pending ANDA subject to an approved suitability petition change the 
RLD upon FDA approval of an NDA for the same drug product described in 
the approved suitability petition ``reflects the Agency's judgment that 
considerations regarding an ANDA's limited reliance on an approved 
suitability petition are outweighed by the need for a clear 
determination of therapeutic equivalence for a generic drug product and 
protection of intellectual property rights accorded an NDA holder'' (80 
FR 6802 at 6853, quoting Venlafaxine ER CP Response at 9).

V.J. Filing an NDA and Receiving an ANDA (Sec.  314.101)

V.J.1. Notification of Filing of a 505(b)(2) Application or Receipt of 
an ANDA
    We proposed to clarify that FDA will notify the applicant that the 
505(b)(2) application is regarded as filed or the ANDA is regarded as 
received by means of a paragraph IV acknowledgment letter if the 
505(b)(2) application or ANDA contains a paragraph IV certification 
(see proposed Sec.  314.101(a)(2) and (b)(2); see also sections V.A.1 
and V.D.1.a). We received no comments regarding these proposed 
revisions, and we are finalizing proposed Sec.  314.101(a)(2) without 
change, and Sec.  314.101(b)(2) with the clarifying revisions discussed 
in section V.J.2.
V.J.2. Refuse-to-Receive Decisions for ANDAs
    We proposed to revise Sec.  314.101(b)(1) and (2) regarding ANDAs 
to incorporate the statutory definition of a ``substantially complete 
application,'' which was added by the MMA for purposes of section 
505(j)(5) of the FD&C Act (see section 505(j)(5)(B)(iv)(II)(cc) of the 
FD&C Act and section V.A.5). We proposed that receipt of an ANDA means 
that FDA has made a threshold determination that the ANDA is 
substantially complete (see proposed Sec.  314.101(b)(1)). We proposed 
to revise Sec.  314.101(b)(2) to clarify that if an ANDA is determined 
to have been substantially complete as of the date on which it was 
submitted, the date of submission is considered to be the date of 
receipt. We also proposed to amend Sec.  314.101(b)(3) to update the 
regulations to reflect our current practice for advising an ANDA 
applicant that FDA has refused to receive the ANDA under Sec.  
314.101(d) or (e).
    In the following paragraphs, we discuss three comments on these 
proposed revisions. After considering these comments, we are making 
clarifying revisions to proposed Sec.  314.101(b)(2). We are finalizing 
proposed Sec.  314.101(b)(3) and (d)(3) with revisions to more 
precisely describe the factors that FDA considers in determining 
whether an ANDA is incomplete on its face, and the actions that an ANDA 
applicant may take following a refuse-to-receive decision.
    (Comment 50) Two comments recommend that FDA clarify its 
regulations regarding refuse-to-receive standards in light of the 
policy described in its guidance for industry entitled ``ANDA 
Submissions--Refuse-to-Receive Standards'' (May 2015), available at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. One of these comments maintains that the current 
regulation permits applicants to amend an ANDA to address deficiencies 
irrespective of the number of deficiencies or whether the deficiencies 
are major or minor. This comment asserts that FDA would need to reissue 
the proposed rule to incorporate the standards described in the 
guidance. Another comment suggests that FDA limit the time for a 
completeness evaluation to 90 days, and permit applicants to amend an 
ANDA to address minor deficiencies that can be corrected within 30 
days.
    (Response 50) FDA agrees with the recommendations to clarify its 
regulations regarding refuse-to-receive standards for ANDAs. To address 
these comments, FDA is revising Sec.  314.101(d)(3) to codify its 
current practice of considering the nature (e.g., major or minor) of 
the deficiencies, including the number of deficiencies in the ANDA, in 
determining whether an ANDA is incomplete on its face. This approach 
reflects the goal of FDA's filing regulations, which encourage 
applicants to submit complete ANDAs and conserve FDA resources by 
permitting FDA reviewers to devote their time to examining reviewable 
applications (57 FR 17950 at 17965).
    To clarify the actions that an ANDA applicant may take following a 
refuse-to-receive decision, FDA is revising Sec.  314.101(b)(3)(ii) to 
state that if the ANDA is not received, the applicant may correct the 
deficiencies and resubmit the ANDA. This amendment reflects the 
statutory procedures for ANDAs that FDA considers not to have been 
received (see section 744B(a)(3)(E) of the FD&C Act (21 U.S.C. 379j-
42(a)(3)(E) (describing the user fee requirements for resubmission of 
an ANDA that FDA considers not to have been received or that has been 
withdrawn)). FDA also is revising Sec.  314.101(b)(3)(iii) to clarify 
that if the ANDA is not received, the applicant may take no action, in 
which case FDA may consider the ANDA withdrawn after 1 year. An ANDA 
applicant's failure to take action after a refuse-to-receive decision 
on an ANDA may be considered a request by the applicant to withdraw the 
ANDA, unless the applicant requests an extension of time in which to 
resubmit the ANDA. This revision eliminates the circularity of the 
former text, which provided that if the ANDA is refused for receipt and 
the applicant takes no action, FDA will refuse to receive the ANDA.
    Finally, FDA is revising Sec.  314.101(b)(2) to clarify that if FDA 
determines, upon evaluation, that an ANDA was substantially complete as 
of the date it was submitted to FDA, FDA will consider the ANDA to have 
been received as of the date of submission. We are making a conforming 
revision to Sec.  314.101(b)(1) to change ``reviewed'' to ``evaluated'' 
to clarify that FDA's evaluation does not involve a substantive review 
of the data in the ANDA. We disagree with the comment's suggestion that 
reissuance of the proposed rule is necessary for these clarifying 
revisions to Sec.  314.101 because the revisions are not changing the 
standard for refuse-to-receive decisions, but are merely clarifying how 
FDA has been implementing the standard.
    (Comment 51) One comment recommends that FDA provide a mechanism 
for ANDA applicants to challenge a refuse-to-receive decision analogous 
to the procedures described in Sec.  314.101(a)(3) for NDA applicants.
    (Response 51) FDA declines to adopt the suggestion because a 
revision to the regulations is not necessary to provide a mechanism for 
ANDA applicants to dispute a refuse-to-receive decision. ANDA 
applicants can avail themselves of existing mechanisms to discuss or 
dispute a refuse-to-receive action, including the dispute resolution 
procedure in Sec.  314.103.
V.J.3. Administrative Consequence for Late Notice
    We proposed to establish an administrative consequence for an ANDA 
applicant that fails to timely provide notice of a paragraph IV 
certification (see section 505(j)(2)(B)(ii) of the FD&C Act). We 
proposed that if FDA determines that an ANDA applicant did not send 
notice of a paragraph IV certification within the timeframe described 
in Sec.  314.95(b) or (d), as applicable, FDA will deem the

[[Page 69623]]

date that the ANDA was submitted to be delayed by the number of days by 
which the timeframe for sending notice of a paragraph IV certification 
was exceeded (see proposed Sec.  314.101(b)(4)). This proposal created 
the potential for an ANDA applicant to lose its first-applicant status 
and thus its eligibility for 180-day exclusivity as a result of 
providing late notice, if another applicant were to submit a 
substantially complete ANDA containing a paragraph IV certification on 
the same first day and were to provide timely notice (see section 
505(j)(5)(B)(iv) of the FD&C Act). We noted that this proposed 
administrative consequence would not reduce the 30-month timeframe set 
forth in section 505(j)(5)(D)(i)(I)(aa)(BB) and (j)(5)(D)(i)(IV) of the 
FD&C Act in the forfeiture calculus for a first applicant; rather, the 
30-month period would begin on the revised date of submission.
    Two comments support FDA's proposed administrative consequence for 
failure to send notice of paragraph IV certification within the 
required timeframe. In the following paragraphs, we discuss two other 
comments on this proposal. After considering these comments, we are not 
finalizing proposed Sec.  314.101(b)(4).
    (Comment 52) One comment asserts that the statutory consequence for 
an ANDA applicant's delay in sending notice of paragraph IV 
certification is a commensurate delay in the start of any resultant 30-
month stay of approval. The comment contends that the Agency has no 
legal authority to impose an additional sanction, and that the proposal 
should be withdrawn. Another comment recommends that the administrative 
consequence for a first applicant be modified to reduce the 180-day 
exclusivity period by the number of days that notice was late and avoid 
the potential loss of eligibility for 180-day exclusivity.
    (Response 52) Although we believe that the Agency has the authority 
to establish an administrative consequence for an ANDA applicant's 
failure to comply with the statutory timeframe for sending notice of 
paragraph IV certification, we currently do not consider the 
administrative consequence to be necessary in light of other incentives 
for ANDA applicants to timely provide notice of a paragraph IV 
certification. Based on the Agency's implementation of the Generic Drug 
User Fee Amendments of 2012 (GDUFA) in Title III of FDASIA and the 
GDUFA goals for expeditious review of ANDAs, FDA is approving ANDAs 
more quickly and ANDA applicants are unlikely to delay sending notice 
of paragraph IV certification because such a delay might result in a 
delay in ANDA approval. A 505(b)(2) or ANDA applicant that provides 
late notice of a paragraph IV certification risks that the NDA holder 
or patent owner will file an action for patent infringement within the 
45-day period after notice, and that any resultant 30-month stay will 
delay approval by a period of time commensurate with the 505(b)(2) or 
ANDA applicant's delay in sending notice. We believe this potential 
delay in approval will incentivize 505(b)(2) and ANDA applicants to 
comply with the statutory timeframe for sending notice, and provide 
adequate opportunity for an NDA holder or patent owner to assert 
certain intellectual property rights prior to approval. Accordingly, we 
are declining to finalize the proposed administrative consequence as 
unnecessary at this time.
V.J.4. Other Proposed Revisions
    We proposed several clarifying revisions to Sec.  314.101. First, 
we proposed to delete the reference to section 507 of the FD&C Act in 
Sec.  314.101(d)(3) to reflect statutory changes made by the Food and 
Drug Administration Modernization Act of 1997 (Pub. L. 105-115). 
Second, we proposed to replace the term ``application'' in Sec.  
314.101(d)(6) and (7) with ``NDA or ANDA'' to clarify that these 
provisions apply to ANDAs as well as NDAs. Third, we proposed to 
replace the current text of Sec.  314.101(e)(2) with a statement that 
FDA will refuse to file a 505(b)(2) application or will consider an 
ANDA not to have been received if submission of a 505(b)(2) application 
or an ANDA is not permitted under Sec.  314.108(b)(2).
    We received no comments regarding these proposed revisions, and we 
are finalizing these revisions to Sec.  314.101(d)(3), (6), and (7) 
without change. We are making conforming revisions to Sec.  
314.101(d)(5) and the paragraph heading for Sec.  314.101(d). As 
discussed in section V.A.7, we are revising Sec.  314.101(e)(2) to 
remove the cross-reference to Sec.  314.108(b)(2) because that section 
does not address all of the potential exclusivities that would preclude 
a 505(b)(2) application or ANDA from being filed or received. We are 
also revising Sec.  314.101(e)(2) to expressly state that FDA will 
refuse to file an NDA or will consider an ANDA not to have been 
received if submission of a 505(b)(2) application or an ANDA is not 
permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), 
505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 505E(a) of the FD&C Act.

V.K. Approval of an NDA and ANDA (Sec.  314.105)

    We proposed to revise Sec.  314.105(a) and (d) regarding approval 
of an NDA and an ANDA to remove the references to a ``delayed effective 
date'' and clarify that an application is approved on the date of 
issuance of an approval letter. We explained in the proposed rule that 
the Agency does not issue approval letters with delayed effective 
dates. Rather, the Agency will issue a tentative approval letter when 
an NDA or ANDA that is otherwise eligible for approval cannot be 
approved because of unexpired patents, certain circumstances related to 
patent litigation, or various types of exclusivity.
    In addition, we proposed to revise Sec.  314.105(a) and (d) to 
expressly state that FDA's tentative approval of a drug product is 
based on information available to FDA at the time of the tentative 
approval letter (i.e., information in the 505(b)(2) application or ANDA 
and the status of current good manufacturing practices of the 
facilities used in the manufacturing and testing of the drug product) 
and is therefore subject to change on the basis of new information that 
may come to FDA's attention.
    We received no comments regarding these proposed revisions. We are 
finalizing Sec.  314.105 without change, except for the technical 
amendments described in section V.A.3 and V.A.7 to reflect the 
enactment of GAIN and IRTNMTA, respectively.

V.L. Refusal To Approve an NDA or ANDA (Sec. Sec.  314.125 and 314.127 
and Related Provisions in Sec. Sec.  314.90 and 314.99)

    We proposed to revise Sec. Sec.  314.90 and 314.99 to clarify that 
if FDA grants an applicant's request for waiver of a requirement under 
Sec. Sec.  314.50 through 314.81 or Sec. Sec.  314.92 through 314.99, 
respectively, the applicant's failure to comply with the requirement 
that is the subject of the waiver request will not constitute a basis 
for refusal to approve the NDA under Sec.  314.125 or the ANDA under 
Sec.  314.127. We also proposed corresponding revisions to Sec. Sec.  
314.125(b) and 314.127(a), which address permissive refusal to approve 
an NDA and mandatory refusal to approve an ANDA, respectively. We 
received no comments regarding these proposed revisions, and we are 
finalizing these provisions without change.

[[Page 69624]]

V.M. Date of Approval of a 505(b)(2) Application or ANDA (Sec.  
314.107)

V.M.1. General (Sec.  314.107(a))
    We proposed to revise the general regulation that describes the 
``effective date of approval'' of a 505(b)(2) application or ANDA and 
the date on which the approval of a 505(b)(2) application or ANDA 
``becomes effective'' to simply refer to the date the 505(b)(2) 
application or ANDA ``is approved'' (see proposed Sec.  314.107(a)). In 
the proposed rule, we explained that FDA does not issue approval 
letters with delayed effective dates. We received no comments on these 
revisions, and we are finalizing proposed Sec.  314.107(a) without 
change.
V.M.2. Effect of Patent(s) on the Listed Drug (Sec.  314.107(b))
    We proposed to revise the regulation that describes the effect of 
one or more patents on the listed drug(s) relied upon or the RLD on the 
timing of approval of a 505(b)(2) application or ANDA, respectively 
(see proposed Sec.  314.107(b)). We proposed to clarify that an 
analysis is required for each relevant patent to determine the first 
possible date on which the 505(b)(2) application or ANDA can be 
approved based on the patent certification(s) and/or statement(s) 
submitted by the applicant (see proposed Sec.  314.107(b)). We proposed 
that the 505(b)(2) application or ANDA may be eligible for approval on 
the last applicable date for all relevant patents listed in the Orange 
Book (see proposed Sec.  314.107(b) and proposed deletion of Sec.  
314.107(b)(4)). In the proposed rule, we explained that an analysis of 
the effect of one or more patents on the timing of approval of a 
505(b)(2) application or ANDA is made when the 505(b)(2) application or 
ANDA is otherwise eligible for approval. We received no comments on 
these revisions, and we are finalizing the introductory text of 
proposed Sec.  314.107(b) with the IRTNTMA-related revisions described 
in section V.A.3.
    V.M.2.a. Timing of approval based on patent certification or 
statement (Sec.  314.107(b)(1)). We proposed to describe the timing of 
approval of a 505(b)(2) application or ANDA based on the patent 
certification(s) and/or statement(s) submitted by the applicant for 
each relevant patent (see proposed Sec.  314.107(b)(1)). We proposed to 
reorganize the regulation and describe the types of patent 
certifications or statements that would result in an immediate first 
possible date on which a 505(b)(2) application or ANDA may be approved 
(see proposed Sec.  314.107(b)(1)(i) and (ii)) or in a delay in the 
first possible approval date until the date on which a patent will 
expire (see proposed Sec.  314.107(b)(1)(iii)).
    We proposed to clarify that, except as provided in Sec.  
314.107(b)(3) and (c), a 505(b)(2) application or ANDA containing a 
paragraph IV certification may be eligible for immediate approval only 
if the 45-day period provided for in section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act has expired (see proposed Sec.  
314.107(b)(1)(i)(C)). We also proposed to clarify that if a 505(b)(2) 
or ANDA applicant submits a statement under Sec.  314.50(i)(1)(iii) or 
Sec.  314.94(a)(12)(iii), respectively, explaining that a method-of-use 
patent does not claim an indication or other condition of use for which 
the applicant is seeking approval and submits proposed labeling that 
appropriately carves out information related to the patented method of 
use, then the 505(b)(2) application or ANDA may be eligible for 
immediate approval (see proposed Sec.  314.107(b)(1)(ii)). In the 
proposed rule, we explained that a listed patent may claim the drug 
substance and/or drug product in addition to one or more methods of 
use, and if the 505(b)(2) or ANDA applicant submitted a statement with 
respect to one or more methods of use and a paragraph IV certification 
with respect to the remaining claims, the first possible date on which 
the 505(b)(2) application or ANDA can be approved would be analyzed in 
accordance with proposed Sec.  314.107(b)(1)(i)(C) and (b)(1)(ii).
    We received no comments on proposed Sec.  314.107(b)(1). However, 
we are revising Sec.  314.107(b)(1)(ii) to expressly state that if a 
505(b)(2) or ANDA applicant submits a paragraph IV certification for 
certain patent claims in addition to a statement under Sec.  
314.50(i)(1)(iii) or Sec.  314.94(a)(12)(iii) for other patent claims, 
a determination of the first possible date on which the 505(b)(2) 
application or ANDA can be approved also would require an analysis 
under Sec.  314.107(b)(1)(i)(C). We also are making a minor editorial 
revision to proposed Sec.  314.107(b)(1) to clarify that the provision 
applies to a 505(b)(2) application or an ANDA.
    V.M.2.b. Patent information filed after submission of 505(b)(2) 
application or ANDA (Sec.  314.107(b)(2)). We proposed to clarify the 
effect of patent information filed after submission of a 505(b)(2) 
application or ANDA on the timing of approval of the 505(b)(2) 
application or ANDA (see proposed Sec.  314.107(b)(2)). We proposed 
that if an NDA holder submits patent information for a listed drug 
after the date on which a 505(b)(2) application or ANDA relying upon 
such drug was submitted to FDA, the 505(b)(2) or ANDA applicant must 
comply with the requirements of Sec. Sec.  314.50(i)(4) and (i)(6) and 
314.94(a)(12)(vi) and (a)(12)(viii) regarding amendment of its patent 
certification or statement. We also proposed that if the 505(b)(2) or 
ANDA applicant submits an amendment containing a paragraph IV 
certification to a newly listed patent, the 505(b)(2) application or 
ANDA may be approved immediately upon the submission of an amendment 
containing documentation that the NDA holder and each patent owner have 
received notice of the paragraph IV certification, if the 505(b)(2) 
application or ANDA is otherwise eligible for approval (see proposed 
Sec.  314.107(b)(2)). We proposed that there is no need to delay 
approval until the expiration of the 45-day period described in section 
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act because a 30-month stay 
of approval is not available in these circumstances.
    We received no comments on these revisions. However, we are 
revising Sec.  314.107(b)(2) to clarify that a 505(b)(2) or ANDA 
applicant must comply with the regulatory requirements regarding 
``submission of an appropriate patent certification or statement'' to a 
newly listed patent rather than an ``amendment of its patent 
certification or statement'' because the latter phrase may incorrectly 
suggest a change to an existing patent certification or statement, 
which would not exist in the case of a newly listed patent. We are 
making conforming revisions to Sec. Sec.  314.50(i)(4) and 
314.94(a)(12)(vi).
    V.M.2.c. Disposition of patent litigation: Approval upon expiration 
of 30-month stay or 7\1/2\ years from date of listed drug approval 
(Sec.  314.107(b)(3)(i)). We proposed that a 30-month stay (or a delay 
in approval for a 7\1/2\-year period where applicable) would be 
available only when the patent owner or exclusive patent licensee 
initiates a patent infringement action within the statutory timeframe 
in response to notice of a paragraph IV certification to a patent 
submitted to FDA before the date on which the 505(b)(2) application or 
ANDA was submitted (see proposed Sec.  314.107(b)(3)(i)(A) and section 
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act). We proposed to 
clarify that a 30-month stay (or 7\1/2\ years where applicable) begins 
on the later of the date of receipt of the notice of paragraph IV 
certification by any owner of the listed patent, the NDA holder who is 
an exclusive patent licensee, or its representative(s) (see proposed 
Sec.  314.107(b)(3)(i)(A)). In the proposed rule, we noted that a 
period of pediatric

[[Page 69625]]

exclusivity under section 505A of the FD&C Act also may affect the 
timing of approval of a 505(b)(2) application or ANDA in the 
circumstances described in proposed Sec.  314.107(b)(3) (see 80 FR 6802 
at 6863).
    In the following paragraphs, we discuss a comment on proposed Sec.  
314.107(b)(3)(i). After considering this comment, we are finalizing 
proposed Sec.  314.107(b)(3)(i) with the IRTNMTA-related revisions 
described in section V.A.3 and a revision to conform with Sec.  
314.107(f)(1) and clarify that a 30-month stay begins on the later of 
the date of receipt of the notice of paragraph IV certification by any 
owner of the listed patent, the NDA holder, or its representative(s). 
We also are making a technical amendment to the paragraph heading 
described in section V.P.3.
    (Comment 53) One comment recommended that FDA revise Sec.  
314.107(b)(3)(i) to accept any reason a court provides for reducing the 
30-month stay, and not solely an extension or reduction of the 30-month 
stay because of a failure of the applicant or patent owner to cooperate 
reasonably in expediting the action.
    (Response 53) We agree that if, before the expiration of the stay, 
the court enters an order requiring the 30-month or 7\1/2\-year period 
to be terminated, the 505(b)(2) application or ANDA may be approved in 
accordance with the court's order (see Sec.  314.107(b)(3)(vii) and 
section V.M.2.i). However, we are not revising the regulation because 
Sec.  314.107(b)(3)(vii) adequately addresses the concern described in 
the comment by providing for termination of the 30-month stay if the 
court enters an order requiring the 30-month stay to be terminated. Our 
regulation governing this scenario is consistent with the statutory 
purpose of the stay, which allows time for claims of patent 
infringement to be litigated prior to approval of the potentially 
infringing drug product.
    V.M.2.d. Federal district court decision of invalidity, 
unenforceability, or non-infringement (Sec.  314.107(b)(3)(ii)). The 
MMA amended section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act to 
describe certain types of court decisions in patent litigation that 
will terminate a 30-month stay (or 7\1/2\ years where applicable) and 
lead to approval of a 505(b)(2) application or ANDA that is otherwise 
eligible for approval. We proposed to revise our regulations to 
implement section 505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of the FD&C Act 
by providing that if, before the expiration of the 30-month stay (or 
7\1/2\ years where applicable), the district court decides that the 
patent is invalid, unenforceable, or not infringed (including any 
substantive determination that there is no cause of action for patent 
infringement or invalidity), the 505(b)(2) application or ANDA may be 
approved on the date on which the court enters judgment reflecting the 
decision pursuant to Federal Rule of Civil Procedure (Fed. R. Civ. P.) 
Rule 58, or the date of a settlement order or consent decree signed and 
entered by the court stating that the patent that is the subject of the 
certification is invalid or not infringed (see proposed Sec.  
314.107(b)(3)(ii)). We also proposed that a Federal district court 
decision that the applicable patent is unenforceable (for example, 
because of inequitable conduct in patent prosecution) would terminate a 
30-month stay or 7\1/2\ years where applicable (see proposed Sec.  
314.107(b)(3)(ii)).
    We received no comments on these proposed revisions. We are 
finalizing proposed Sec.  314.107(b)(3)(ii) with a technical amendment 
to add the term ``unenforceable'' to Sec.  314.107(b)(3)(ii)(B) for 
consistency and completeness.
    V.M.2.e. Appeal of Federal district court judgment of infringement 
(Sec.  314.107(b)(3)(iii)). We proposed to revise our regulations to 
implement section 505(c)(3)(C)(ii)(I) and (j)(5)(B)(iii)(II)(aa) of the 
FD&C Act by providing that if, before the expiration of the 30-month 
stay (or 7\1/2\ years where applicable), the Federal district court 
decides that the patent has been infringed and the judgment is 
appealed, the 505(b)(2) application or ANDA may be approved on: (1) The 
date on which the mandate is issued by the court of appeals entering 
judgment that the patent is invalid or not infringed (including any 
substantive determination that there is no cause of action for patent 
infringement or invalidity) or (2) the date of a settlement order or 
consent decree signed and entered by the court of appeals stating that 
the patent that is the subject of the certification is invalid or not 
infringed.
    We received no comments on these proposed revisions. We are 
finalizing proposed Sec.  314.107(b)(3)(iii) with technical amendments 
to add the term ``unenforceable'' to Sec.  314.107(b)(3)(iii)(A) and 
(B) for consistency and completeness. We are also deleting the 
parenthetical reference to a substantive determination by a Federal 
district court that there is no cause of action for patent invalidity 
for the reason discussed in section V.M.2.d.
    V.M.2.f. Affirmation or non-appeal of Federal district court 
judgment of infringement (Sec.  314.107(b)(3)(iv)). We proposed to 
establish a regulation that would implement section 
505(c)(3)(C)(ii)(II) and (j)(5)(B)(iii)(II)(bb) of the FD&C Act by 
providing that if, before the expiration of the 30-month stay (or 7\1/
2\ years where applicable), the Federal district court decides that the 
patent that is the subject of the paragraph IV certification is 
infringed and this judgment is not appealed or is affirmed on appeal, 
the 505(b)(2) application or ANDA may be approved no earlier than the 
date specified by the district court in an order under 35 U.S.C. 
271(e)(4)(A) (see proposed Sec.  314.107(b)(3)(iv)). We proposed to 
clarify that the 505(b)(2) application or ANDA may be approved no 
earlier than the date specified by the district court in a 35 U.S.C. 
271(e)(4)(A) order because the order may not take into account any 
other unexpired patents or unexpired exclusivity (or deficiencies in 
the application) that would delay approval of the 505(b)(2) application 
or ANDA beyond the expiration date of the infringed patent (see 
proposed Sec.  314.107(b)(3)(iv)). In the following paragraphs, we 
discuss a comment related to this provision. After considering this 
comment, we are finalizing proposed Sec.  314.107(b)(3)(iv) without 
change.
    (Comment 54) One comment recommends that FDA revise Sec.  
314.107(b)(3) to provide that FDA will not approve a pending 505(b)(2) 
application or ANDA if a district court decides after the 30-month stay 
or 7\1/2\-year period has expired that the patent that is the subject 
of the paragraph IV certification is infringed. The comment expresses 
concern that the regulatory focus on court decisions before the 
expiration of the 30-month stay or 7\1/2\-year period may be 
interpreted to mean that FDA can approve a 505(b)(2) application or 
ANDA if a district court decides after the 30-month stay or 7\1/2\-year 
period has expired that the proposed product would infringe a listed 
patent.
    (Response 54) We decline to revise Sec.  314.107(b)(3) as suggested 
because other regulations address the concern described in the comment 
(see, e.g., Sec. Sec.  314.50(i)(6)(i) and 314.94(a)(12)(viii)(A) 
(requiring a 505(b)(2) or ANDA applicant to amend a previously 
submitted paragraph IV certification after a finding of patent 
infringement)). We are enhancing our regulations to impose a duty on 
505(b)(2) and ANDA applicants to notify FDA of any court judgment, 
settlement order, or consent decree regarding a patent described in 
Sec.  314.107(b)(3) (see Sec.  314.107(e)(1)(i); see also Sec.  
314.107(e)(1)(ii)). We are also requiring an applicant to submit a copy

[[Page 69626]]

of any court order under 35 U.S.C. 271(e)(4)(A) providing that the 
505(b)(2) application or ANDA may be approved no earlier than the date 
specified in the order, irrespective of whether the injunction relates 
to a patent described in Sec.  314.107(b)(3), within 14 days of the 
court's entry of the order (see Sec.  314.107(e)(1)(vi)). In addition, 
the Agency routinely contacts an applicant after the 30-month stay (or 
7\1/2\ years where applicable) has expired to confirm the status of any 
pending litigation prior to an action on the 505(b)(2) application or 
ANDA.
    V.M.2.g. Grant of preliminary injunction by Federal district court 
(Sec.  314.107(b)(3)(v)). We proposed to revise our regulations to 
implement section 505(c)(3)(C)(iii) and (iv) and (j)(5)(B)(iii)(III) 
and (IV) of the FD&C Act by providing that if a preliminary injunction 
is entered before the expiration of the 30-month stay (or 7\1/2\ years 
where applicable), the stay of approval would be extended until the 
court decides the issues of patent infringement and validity. In the 
proposed rule, we explained that proposed Sec.  314.107(b)(3)(v) cross-
references the applicable paragraph of Sec.  314.107(b)(3) that would 
address the timing of approval of the 505(b)(2) application or ANDA 
based on the court's decision regarding patent validity and 
infringement. We proposed that if the court later decides that the 
patent is invalid, unenforceable, or not infringed, the 505(b)(2) 
application or ANDA may be approved as provided in Sec.  
314.107(b)(3)(iii) or (iv), whichever is applicable (see proposed Sec.  
314.107(b)(3)(v)). In addition, we proposed to clarify that the court 
referred to in Sec.  314.107(b)(3)(v) is the Federal district court 
hearing the patent infringement action.
    In the following paragraphs, we discuss two comments on the timing 
of approval of a 505(b)(2) application or ANDA after a preliminary 
injunction has been entered. After considering these comments, we are 
revising Sec.  314.107(b)(3)(v) to more clearly describe the timing of 
approval of a 505(b)(2) application or ANDA when a preliminary 
injunction is entered before the expiration of a 30-month stay (or 7\1/
2\ years where applicable) and to cross-reference the applicable 
paragraphs of Sec.  314.107(b)(3). We are redesignating a portion of 
proposed Sec.  314.107(b)(3)(v) as paragraph (b)(3)(v)(A) and adding 
paragraph (b)(3)(v)(B) to implement section 505(c)(3)(C)(iv) and 
(j)(5)(B)(iii)(IV) of the FD&C Act. With these revisions, the 
regulation provides:
     If a preliminary injunction is entered before the 
expiration of a 30-month stay (or 7\1/2\ years where applicable) and 
the Federal district court later decides that the patent is invalid, 
unenforceable, or not infringed, the 505(b)(2) application or ANDA may 
be approved as provided in Sec.  314.107(b)(3)(ii) (see Sec.  
314.107(b)(3)(v)(A) and section 505(c)(3)(C)(iii) and 
(j)(5)(B)(iii)(III) of the FD&C Act).
     If a preliminary injunction is entered before the 
expiration of a 30-month stay (or 7\1/2\ years where applicable) and 
the Federal district court later decides that the patent is infringed, 
the 505(b)(2) application or ANDA may be approved as provided in Sec.  
314.107(b)(3)(iii) or (iv), whichever is applicable (see Sec.  
314.107(b)(3)(v)(B) and section 505(c)(3)(C)(iv) and (j)(5)(B)(iii)(IV) 
of the FD&C Act).
    (Comment 55) One comment asserts that if a preliminary injunction 
is entered before the expiration of the 30-month stay, the stay should 
not be extended until the court decides the issues of patent 
infringement and validity because the preliminary injunction serves the 
purpose of the stay. The comment recommends that FDA issue a final 
approval of the 505(b)(2) application or ANDA (if otherwise eligible 
for approval) after the 30-month stay expires so that the product can 
be marketed without delay at such time as the injunction is lifted.
    (Response 55) We disagree with the comment. If a preliminary 
injunction is entered before the expiration of the 30-month stay (or 
7\1/2\ years where applicable), FDA interprets section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act to require an extension of the stay 
until the court decides the issues of patent infringement and validity 
because all of the outcomes described in the statute presume that 
approval will not occur until a later date.
    (Comment 56) One comment requests that FDA revise the regulation to 
clarify the timing of approval if the district court enters a 
preliminary injunction after the 30-month stay expires. The comment 
recommends that FDA not approve a pending 505(b)(2) application or ANDA 
in this scenario unless the court later decides the patent is invalid, 
unenforceable, or not infringed. The comment also asserts that FDA's 
view that a preliminary injunction entered before the expiration of the 
30-month stay would extend the stay until the court decides the issues 
of patent infringement and validity suggests that the issuance of a 
preliminary injunction after expiry of the 30-month or 7\1/2\-year 
period, combined with a district court finding of infringement, stays 
approval through at least the appeal.
    (Response 56) We decline to adopt the recommendations in the 
comment. It is unnecessary for FDA to establish a regulation that 
addresses the timing of approval of a 505(b)(2) application or ANDA if 
a district court enters a preliminary injunction after the 30-month 
stay (or 7\1/2\-year period where applicable) has expired. If a party 
to a patent infringement action involving a patent described in Sec.  
314.107(b)(3) seeks to ensure that a 505(b)(2) application or ANDA is 
not approved while the litigation is pending, the party may request a 
preliminary injunction before the 30-month stay (or 7\1/2\-year period 
where applicable) expires. If a court enters a preliminary injunction 
after the 30-month stay (or 7\1/2\-year period where applicable) has 
expired, parties should ensure that the court specifies the duration 
and effect of the injunction.
    (Comment 57) One comment suggests that if a court requests an 
applicant to voluntarily agree not to begin marketing the drug product 
or to provide pre-launch notice instead of issuing a preliminary 
injunction, FDA should treat these agreements as equivalent to a 
preliminary injunction and similarly extend the 30-month stay or 7\1/
2\-year period.
    (Response 57) We decline to adopt this suggestion. The FD&C Act 
provides that if the district court grants a preliminary injunction 
before the expiration of the 30-month stay (or 7\1/2\ years where 
applicable) to preserve the status quo until the court decides the 
issues of patent infringement and validity, the stay must be extended 
until the applicable date described in section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act. A voluntary agreement not to begin 
marketing the drug product or to provide pre-launch notice does not 
fall within this statutory exception to the termination of the stay at 
the end of the 30-month period (or 7\1/2\ year-period where 
applicable). Accordingly, we do not consider such agreements to be 
equivalent to a preliminary injunction for purposes of extending the 
stay. Moreover, it is unnecessary for the Agency to address these 
circumstances through regulation because the parties to the litigation 
can specify the desired terms of the agreement.
    V.M.2.h. Written consent to approval by patent owner or exclusive 
patent licensee (Sec.  314.107(b)(3)(vi)). We proposed to clarify that 
if the patent owner or exclusive patent licensee (or their 
representatives) agreed in writing that the 505(b)(2) application or 
ANDA may be approved, the 30-month stay (or 7\1/2\ years where 
applicable) would be terminated and the approval may be granted on or 
after the date of the

[[Page 69627]]

consent (see proposed Sec.  314.107(b)(3)(vi)). In the proposed rule, 
we noted that this scenario may arise, for example, if settlement of 
the patent litigation results in a license to the 505(b)(2) or ANDA 
applicant. One comment agrees with the addition of this provision 
because it expressly permits the party that receives the benefit of the 
statutory 30-month stay to waive that benefit. We agree with the 
comment and we are finalizing proposed Sec.  314.107(b)(3)(vi) without 
change.
    V.M.2.i. Court order terminating 30-month or 7\1/2\-year period 
(Sec.  314.107(b)(3)(vii)). We proposed to clarify that if a court 
enters an order requiring the termination of the 30-month stay (or 7\1/
2\ years where applicable), the 505(b)(2) application or ANDA, if 
otherwise eligible for approval, may be approved in accordance with the 
court order (see proposed Sec.  314.107(b)(3)(vii)). We received no 
comments on this provision, and we are finalizing proposed Sec.  
314.107(b)(3)(vii) without change.
    V.M.2.j. Court order of dismissal without a finding of infringement 
(Sec.  314.107(b)(3)(viii)). We proposed to codify FDA's policy that a 
Federal district court's entry of an order of dismissal, with or 
without prejudice, of patent infringement litigation that was timely 
initiated in response to the 505(b)(2) or ANDA applicant's notice of a 
paragraph IV certification will terminate the 30-month period (or 7\1/
2\ years where applicable) if such order does not state a finding of 
patent infringement (see proposed Sec.  314.107(b)(3)(viii)).
    In the following paragraphs, we discuss two comments on proposed 
Sec.  314.107(b)(3)(viii). After considering these comments, we are 
revising Sec.  314.107(b)(3)(viii) to clarify that the 30-month period 
(or 7\1/2\ years where applicable) will be terminated if the court(s) 
enter(s) an order of dismissal without a finding of infringement in 
each pending suit for patent infringement brought within 45 days of 
receipt of the notice of paragraph IV certification sent by the 
505(b)(2) or ANDA applicant.
    (Comment 58) One comment opines that proposed Sec.  
314.107(b)(3)(viii) should be withdrawn because the statute does not 
specify that an order of dismissal without a finding of infringement 
will terminate a 30-month stay (see section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act).
    (Response 58) We decline to withdraw our proposal. The MMA's 
amendments to the FD&C Act clarify the timing of approval of a 
505(b)(2) application or ANDA, respectively, in relation to a 
settlement order or consent decree stating that the patent that is the 
subject of the paragraph IV certification is invalid or not infringed 
(see section 505(c)(3)(C)(i)(II), (c)(3)(C)(ii)(I)(bb), 
(j)(5)(B)(iii)(I)(bb), and (j)(5)(B)(iii)(II)(aa)(BB) of the FD&C Act). 
However, the MMA does not address whether a 30-month stay may be 
terminated and a 505(b)(2) application or ANDA may be approved if the 
court enters an order of dismissal without a finding of patent 
infringement. Because this issue was not addressed by Congress, the 
Agency is using its authority to establish rules for the efficient 
enforcement of the FD&C Act to clarify the effect of a Federal district 
court's entry of an order of dismissal without a finding of 
infringement on a 30-month stay of approval. The Agency's approach is 
consistent with the statutory scheme because it avoids unwarranted 
delays in approval of a 505(b)(2) application or ANDA while protecting 
innovator intellectual property rights. As we explained in the proposed 
rule, it is appropriate that a 30-month stay be terminated under these 
circumstances because the statutory purpose of the stay is to allow 
time for claims of patent infringement to be litigated prior to 
approval of the potentially infringing drug product. If the patent 
owner or exclusive patent licensee dismisses the patent infringement 
action on terms that the court considers proper (see Fed. R. Civ. P. 
Rule 41(a)(2)), then there should be no further delay of approval of a 
505(b)(2) application or ANDA otherwise eligible for approval.
    (Comment 59) One comment recommends that FDA revise proposed Sec.  
314.107(b)(3)(viii) to exclude dismissals that do not terminate all 
timely filed litigation with respect to the patent(s) in suit. The 
comment explains that parallel suits for patent infringement may be 
filed in different Federal district courts within the 45-day period 
described in section 505(j)(5)(B)(iii) of the FD&C Act, and one or more 
suits may be dismissed because of lack of jurisdiction or other 
reasons. The comment maintains that the 30-month stay should remain in 
effect if one of multiple patent infringement actions filed in response 
to notice of a paragraph IV certification is dismissed while at least 
one of the timely filed lawsuits continues to be litigated.
    (Response 59) We agree that the 30-month stay should remain in 
effect if a patent infringement action that was timely filed in 
response to a paragraph IV certification continues to be litigated 
after the dismissal of a parallel action. We are revising Sec.  
314.107(b)(3)(viii) to clarify that the 30-month period (or 7\1/2\ 
years where applicable) will be terminated if the court(s) enter(s) an 
order of dismissal without a finding of infringement in each pending 
suit for patent infringement brought within 45 days of receipt of the 
notice of paragraph IV certification sent by the 505(b)(2) or ANDA 
applicant.
    (Comment 60) One comment recommends that FDA revise proposed Sec.  
314.107(b)(3)(viii) to provide that if the court enters an order of 
dismissal without a finding of patent infringement based on an 
agreement not to make or sell the drug until a specified future date, 
the stay should continue until the date provided in the agreement.
    (Response 60) We decline to adopt this suggestion. If the court(s) 
enter(s) an order of dismissal without a finding of infringement in 
each pending suit for patent infringement brought within 45 days of 
receipt of the notice of paragraph IV certification sent by the 
505(b)(2) or ANDA applicant, FDA may approve the 505(b)(2) application 
or ANDA on or after the date of the order. If a 505(b)(2) or ANDA 
applicant has entered into an agreement not to make or sell the drug 
until a specified future date and the 505(b)(2) application or ANDA 
receives final approval, the applicant can choose not to make or sell 
the product until the specified date.
V.M.3. Timing of Approval of Subsequent ANDA (Sec.  314.107(c))
    We proposed to revise Sec.  314.107(c) to remove provisions that 
have been superseded by the FD&C Act as revised by the MMA and to 
generally conform with the FD&C Act. We proposed to revise Sec.  
314.107(c)(1) to incorporate the statutory term ``first applicant'' and 
to distinguish a ``first applicant'' from a ``subsequent applicant'' 
(see section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act and proposed 
Sec.  314.3(b)). We proposed that an ANDA has been submitted by a 
subsequent applicant if the ANDA has not been submitted by a first 
applicant and contains a paragraph IV certification to a relevant 
patent that has been listed for the drug product for which a first 
applicant has submitted an ANDA (see proposed Sec.  314.107(c)(1)). We 
proposed that a subsequent applicant's ANDA will not be approved during 
the period when any first applicant for the drug product is eligible 
for 180-day exclusivity or during the 180-day exclusivity period of any 
first applicant (see proposed Sec.  314.107(c)(1) and section 
505(j)(5)(B)(iv)(I) of the FD&C Act).

[[Page 69628]]

    We proposed to delete the definition of the ``applicant submitting 
the first application'' in existing Sec.  314.107(c)(2) because it was 
superseded by the statutory definition of ``first applicant'' added by 
the MMA. We also proposed to delete Sec.  314.107(c)(3), which 
described the potential consequences of a first applicant's failure to 
actively pursue approval of its ANDA (see section 505(j)(5)(D) of the 
FD&C Act).
    We proposed to revise Sec.  314.107(c)(4) (redesignated as proposed 
Sec.  314.107(c)(2)) to conform with the statutory change to the event 
that triggers the start of the 180-day exclusivity period for a first 
applicant (see section 505(j)(5)(B)(iv)(I) of the FD&C Act). Given that 
the 180-day exclusivity period begins on the date of the first 
commercial marketing of the drug product (including the commercial 
marketing of the listed drug) by any first applicant, we proposed to 
require a first applicant to submit correspondence to its ANDA 
notifying FDA within 30 days of the date of first commercial marketing 
of the drug product (see proposed Sec.  314.107(c)(2) and section 
505(j)(5)(B)(iv)(I) of the FD&C Act). If the first applicant does not 
notify FDA within this timeframe, we proposed to deem the date of first 
commercial marketing to be the date of the ANDA's approval. In the 
proposed rule, we noted that this may have the effect of shortening the 
180-day period of exclusivity in a manner similar to existing Sec.  
314.107(c)(4). We also proposed to remove the description of 
``commercial marketing'' from Sec.  314.107(c)(4) because we proposed 
to define ``commercial marketing'' in proposed Sec.  314.3(b) with 
certain modifications to the scope of the exclusion for transfer of the 
drug product for reasons other than sale.
    In the following paragraphs, we discuss three comments on proposed 
Sec.  314.107(c). After considering these comments, we are finalizing 
proposed Sec.  314.107(c)(1) without change and we are finalizing 
proposed Sec.  314.107(c)(2) with a technical amendment to include a 
reference to first commercial marketing of the RLD for consistency with 
section 505(j)(5)(B)(iv)(I) of the FD&C Act. We also are making an 
editorial correction to remove the introductory phrase in Sec.  
314.107(c)(2) referring to Sec.  314.107(c)(1). We are not finalizing 
our proposal to delete Sec.  314.107(c)(3) because we want to retain 
flexibility to ensure that approval of ANDAs of subsequent applicants 
is not blocked, for example, by a first applicant that is nonresponsive 
to repeated inquiries from the Agency regarding its ANDA. In addition, 
we are making clarifying revisions to this provision. As revised, Sec.  
314.107(c)(3) explains that if FDA concludes that a first applicant is 
not actively pursuing approval of its ANDA, FDA may immediately approve 
an ANDA(s) of a subsequent applicant(s) if the ANDA(s) is otherwise 
eligible for approval.
    (Comment 61) One comment asserts that FDA's proposal to deem the 
date of first commercial marketing to be the date of the drug product's 
approval if a first applicant fails to timely notify FDA is 
inconsistent with the statute, FDA's proposed and existing definitions 
of ``commercial marketing,'' and the predecessor regulation at Sec.  
314.107(c)(3), because the product was not actually marketed on the 
deemed date. Another comment maintains that FDA's proposal to deem the 
date of first commercial marketing to be the date of the drug product's 
approval if a first applicant fails to timely notify FDA is a penalty 
that is not warranted by the statutory change in the commercial 
marketing trigger of the 180-day exclusivity period.
    (Response 61) We do not find these comments persuasive. Section 
505(j)(5)(B)(iv)(I) of the FD&C Act provides that the period of 180-day 
exclusivity will begin on the date of the first commercial marketing of 
the drug (including the commercial marketing of the listed drug) by any 
first applicant. This commercial marketing trigger differs from the 
version of section 505(j)(5)(B)(iv)(I) in effect prior to enactment of 
the MMA, which provided that the 180-day exclusivity period will begin 
on the earlier of two events, one of which was the date the Secretary 
receives notice from the applicant of the first commercial marketing of 
the drug eligible for 180-day exclusivity. Based on the change in the 
commercial marketing trigger from the date on which FDA receives notice 
from the applicant of the first commercial marketing to the date of the 
first commercial marketing of the drug, we are requiring the first 
applicant to notify FDA within 30 days of the date of first commercial 
marketing. This requirement is intended to facilitate the efficient 
enforcement of the FD&C Act and provide FDA with adequate notice to 
inform the timing of approval for ANDAs submitted by subsequent 
applicants. If a first applicant does not notify FDA within this 
timeframe, we will deem the date of first commercial marketing to be 
the date of the ANDA's approval. This consequence of a first 
applicant's failure to provide timely notification to FDA is similar to 
the consequence described in the predecessor regulation at Sec.  
314.107(c)(4), which provided that if an applicant does not promptly 
notify FDA of commercial marketing, the effective date of approval 
shall be deemed to be the date of the commencement of first commercial 
marketing. We expect that the regulation will encourage first 
applicants to provide timely notification to FDA. Given that the date 
of notification is within a first applicant's control, we expect that 
there will be few instances in which there is a need to deem the date 
of first commercial marketing to be the date of the ANDA's approval.
    (Comment 62) One comment expresses concern that FDA may deem the 
date of first commercial marketing to be the date of the drug product's 
approval if a first applicant does not launch its drug product within 
30 days after ANDA approval. The comment proposes that FDA require a 
first applicant to notify FDA if the applicant will not launch the drug 
product within 30 days after ANDA approval, but intends to launch the 
drug product within 75 days after ANDA approval.
    (Response 62) We decline to adopt this suggestion because it is 
unnecessary. FDA would only deem the date of first commercial marketing 
to be the date of the ANDA's approval if a first applicant began 
commercial marketing of the drug product described in the ANDA or of 
the reference listed drug and failed to notify FDA within 30 days of 
the first commercial marketing (see Sec.  314.107(c)(2)). This 
provision would not apply if commercial marketing had not yet 
commenced. FDA's requirement for a first applicant to timely notify the 
Agency of the date of first commercial marketing is intended to 
facilitate implementation of the statutory change in the commercial 
marketing trigger of the 180-day exclusivity period (section 
505(j)(5)(B)(iv)(I) of the FD&C Act). This notification requirement is 
unrelated to the statutory conditions under which a first applicant 
would forfeit the 180-day exclusivity period for failure to market the 
product (see section 505(j)(5)(D)(i)(I) of the FD&C Act). We will 
determine whether additional rulemaking related to 180-day exclusivity 
is necessary in the future.
V.M.4. Delay of Approval Due to Exclusivity (Sec.  314.107(d))
    We proposed to clarify that approval of a 505(b)(2) application or 
ANDA may be delayed by orphan drug exclusivity under 21 CFR 316.31 or 
pediatric exclusivity under section 505A of the FD&C Act, in addition 
to the exclusivities described in Sec.  314.108 (see proposed Sec.  
314.107(d)).

[[Page 69629]]

    In section V.A.7, we discuss a comment on proposed Sec.  314.107(d) 
(see Comment 8). After considering this comment, we are revising Sec.  
314.107(d) to indicate that approval of a 505(b)(2) application or ANDA 
also may be delayed by a period of exclusivity for the listed drug 
under section 505E of the FD&C Act. We are also making a technical edit 
to refer to section 527 of the FD&C Act in the context of a delay in 
approval of a 505(b)(2) application or ANDA because of orphan drug 
exclusivity.
V.M.5. Notification of Court Actions or Written Consent to Approval 
(Sec.  314.107(e))
    We proposed to revise Sec.  314.107(e) to expand the scope of 
documentation that an applicant must submit to FDA regarding court 
actions and settlements related to patents that may affect the timing 
of approval of a 505(b)(2) application or ANDA. We proposed to require 
a 505(b)(2) or ANDA applicant to submit a copy of any judgment by the 
court (Federal district court or mandate of the court of appeals) 
finding a patent described in Sec.  314.107(b)(3) invalid, 
unenforceable, or not infringed, or finding the patent valid and 
infringed (see proposed Sec.  314.107(e)(1)(i)). We also proposed to 
require a 505(b)(2) or ANDA applicant to submit to FDA a copy of 
specified documented agreements and court actions other than judgments 
to facilitate FDA's administration of the FD&C Act (see Sec.  
314.107(e)(1)(i) through (vi)).
    We explained that the proposed requirement to submit a copy of any 
documented agreement described in Sec.  314.107(b)(3)(vi) would require 
submission of written documentation that the parties have entered into 
a settlement that terminated the patent infringement litigation, but 
would not require applicants to send copies of the actual settlement 
agreement to FDA (see proposed Sec.  314.107(e)(1)(iv)). To ensure 
timely notification to FDA, we proposed to require a 505(b)(2) or ANDA 
applicant to submit all required information to the appropriate 
division in OND or to OGD, within 14 calendar days of the date of entry 
by the court, the date of appeal or expiration of the time for appeal, 
or the date of documented agreement, as applicable (see proposed Sec.  
314.107(e)(2)).
    In the following paragraphs, we discuss a comment on proposed Sec.  
314.107(e)(1)(iv). After considering this comment, we are revising 
Sec.  314.107(e)(1)(iv) to require submission of a copy of any 
``written consent to approval'' by the patent owner or exclusive patent 
licensee, and we are making a conforming revision to Sec.  
314.107(e)(2) and to the paragraph heading for Sec.  314.107(e). We 
also are clarifying that a copy of any order entered by the court 
terminating the 30-month or 7\1/2\-year period includes an order 
described in Sec.  314.107(b)(3)(vii) and (viii). Finally, for 
administrative convenience, we are revising Sec.  314.107(e)(2) to 
provide that all information required by Sec.  314.107(e)(1) must be 
sent to the applicant's NDA or ANDA rather than to OGD or the 
appropriate division in OND.
    (Comment 63) One comment agrees with FDA's proposal to require 
submission of written documentation that the parties have entered into 
a settlement that has terminated the patent infringement litigation, 
and recommends that FDA revise proposed Sec.  314.107(e)(1)(iv) to 
expressly state that a ``documented agreement'' does not refer to the 
settlement agreement, and that a copy of the actual settlement 
agreement need not be submitted. The comment also requests that FDA 
clarify the content of the documentation that should be submitted.
    (Response 63) We agree that the proposal to require applicants to 
submit a copy of any ``documented agreement'' has been the source of 
confusion, notwithstanding the statement in the proposed rule that 
applicants are not required to send copies of the actual settlement 
agreement to FDA. We are revising Sec.  314.107(e)(1)(iv) to require 
submission of a copy of any ``written consent to approval'' by the 
patent owner or exclusive patent licensee. This revision is intended to 
clarify the requested information and align with the text of Sec.  
314.107(b)(3)(vi). A letter to FDA from the patent owner(s) or 
exclusive patent licensee that provides consent to approval of the 
505(b)(2) application or ANDA any time on or after the date of consent 
would be acceptable. Although FDA does not require a copy of the actual 
settlement agreement, we note that generic drug applicants are required 
to file certain agreements with the FTC (see section 1112 of the MMA).
V.M.6. Computation of the 45-Day Time Clock (Sec.  314.107(f))
    We proposed to revise Sec.  314.107(f)(1) and (2) to clarify the 
computation of the 45-day period after receipt of notice of paragraph 
IV certification and to enhance the requirements for notifying FDA of 
any legal action filed within this timeframe. We proposed to add Sec.  
314.107(f)(2)(iii) to clarify that a 505(b)(2) application or ANDA may 
be approved upon expiration of the 45-day period (if the 505(b)(2) or 
ANDA applicant confirms that a legal action for patent infringement has 
not been filed within the 45-day period) or upon completion of FDA's 
review of the 505(b)(2) application or ANDA, whichever is later. We 
also proposed to revise Sec.  314.107(f)(3) to expressly permit a 
representative of the patent owner or NDA holder who is an exclusive 
patent licensee to waive the opportunity to file a patent infringement 
action within the 45-day period.
    We received no comments regarding these proposed revisions, and we 
are finalizing proposed Sec.  314.107(f) without change, except for the 
technical amendments described in section V.P.5 regarding the location 
to which the notification must be sent.
V.M.7. Conversion of Approval to Tentative Approval (Sec.  314.107(g))
    We proposed to add Sec.  314.107(g) to clarify that if FDA issues 
an approval letter in error or a court enters an order requiring that 
the date of approval be delayed for an already approved 505(b)(2) 
application or ANDA, FDA will convert the approval to a tentative 
approval if appropriate. In the following paragraphs, we discuss a 
comment on this proposed provision. After considering this comment, we 
are finalizing proposed Sec.  314.107(g) without change.
    (Comment 64) One comment recommends that FDA remove the qualifier 
``if appropriate'' from proposed Sec.  314.107(g). The comment also 
requests that FDA clarify that ``court'' refers to either a district 
court or an appellate court for consistency with Mylan Labs., Inc. v. 
Thompson, 389 F.3d 1272 (D.C. Cir. 2004).
    (Response 64) FDA declines to adopt the suggestion to remove the 
qualifier ``if appropriate'' from proposed Sec.  314.107(g) because 
there are circumstances in which it may not be appropriate to convert 
an approval to a tentative approval (e.g., a stay of the district 
court's order pending appeal). Moreover, the qualifier ``if 
appropriate'' also modifies FDA's issuance of an approval letter in 
error, and the appropriateness of conversion to tentative approval may 
depend on a variety of factors. If either a district court or appellate 
court enters an order requiring that the date of approval of an already 
approved 505(b)(2) application or ANDA be delayed, FDA will convert the 
approval to a tentative approval if appropriate.

[[Page 69630]]

V.N. Assessing Bioavailability and Bioequivalence for Drugs Not 
Intended To Be Absorbed Into the Bloodstream (Sec.  320.23)

    We proposed to revise Sec.  320.23 to reflect the MMA's amendments 
to section 505(j)(8) of the FD&C Act, which permit use of 
scientifically valid methods for assessing bioavailability and 
bioequivalence for drugs that are not intended to be absorbed into the 
bloodstream and essentially codify our existing practice. We received 
no comments regarding these proposed revisions, and we are finalizing 
proposed Sec.  320.23 without change.

V.O. Miscellaneous

    We proposed several clarifying revisions and editorial changes 
throughout the sections of parts 314 and 320 that were the subject of 
the proposed rule. These changes were intended to promote consistency 
throughout our regulations, incorporate ``plain language,'' employ 
grammatically correct phrasing, and otherwise clarify the text of these 
regulations. We also proposed certain revisions to provisions that 
contemplated the submission of paper to facilitate the transition to 
electronic submissions in the future. We did not receive any comments 
on these proposed revisions, and we are finalizing them without change.

V.P. Technical Amendments

    We are making several technical amendments in the sections of parts 
314 and 320 that are the subject of this rulemaking. These changes are 
intended to promote clarity and consistency throughout our regulations 
and correct certain outdated or incorrect information. Examples of 
revisions that are not otherwise described are provided in sections 
V.P.1 through V.P.6.
V.P.1. Consistent Use of Defined Terms
    We are replacing the terms ``application'' and ``abbreviated 
application'' with the commonly used abbreviations ``NDA'' and/or 
``ANDA,'' as appropriate, in the following sections: Sec. Sec.  
314.3(b) (definitions of ``original application or original NDA'' and 
``tentative approval''); 314.50(h); 314.53(b)(1); 314.93(b); 
314.94(a)(3), (a)(12)(i)(A)(4)(i), (a)(12)(ii), (a)(12)(viii)(B), and 
introductory text to Sec.  314.94; 314.95(d)(1) and (f); 314.97(a); 
314.107(b)(4) and (f)(3); and 314.127(a)(2) and (a)(8)(ii)(B) and (C).
    We are replacing the term ``act'' with ``Federal Food, Drug, and 
Cosmetic Act'' in the following sections: Sec. Sec.  314.50(d); 
314.60(b)(1) and (4), (c)(1)(i), and (c)(2); 314.93(d)(3) and 
(e)(1)(iii)(C); 314.94(a)(3)(ii), (a)(5)(ii)(A), (a)(7)(ii)(C), and 
(a)(8)(iv); 314.125(a) and (b)(2), (11), and (18); and 
314.127(a)(3)(iii)(A)(2) and (a)(12).
    We are defining ``Agency'' as an alternate term for ``FDA'' for 
clarity (see Sec.  314.3(b)).
    We are replacing references to the ``holder of [an or the] approved 
application'' with the defined term ``NDA holder'' in the following 
sections: Sec. Sec.  314.50(i)(1)(i)(A)(4)(ii); 314.70(a)(2); and 
314.94(a)(12)(i)(A)(4)(ii).
    We are revising the proposed definition of ``resubmission'' in 
Sec.  314.3(b) to clarify that the definition applies only in the 
context of a complete response letter (compare Sec.  314.101(b)(3)(ii), 
which uses the term ``resubmit'' with a different meaning and in a 
different context).
    We are replacing the term ``right of reference'' with the defined 
term ``right of reference or use'' in Sec.  314.60(c)(1)(iii).
    We are making an editorial correction to the proposed definition of 
``therapeutic equivalents'' in Sec.  314.3(b) to combine the sentences 
into a single-sentence definition to be consistent with the definition 
in the Orange Book. As revised, ``therapeutic equivalents'' are 
approved drug products that are pharmaceutical equivalents for which 
bioequivalence has been demonstrated, and that can be expected to have 
the same clinical effect and safety profile when administered to 
patients under the conditions specified in the labeling.
    We are replacing the reference to a ``use patent'' with the term 
``method-of-use patent'' (see Sec. Sec.  314.50(i)(1)(iii)(A) and (B), 
314.52(a)(3), 314.53(e), 314.94(a)(12)(iii)(A) and (B), and 
314.95(a)(3)).
V.P.2. Alignment of Certain Regulations for 505(b)(2) Applications and 
ANDAs
    We are making conforming revisions between certain provisions in 
Sec. Sec.  314.50 and 314.94 to align the requirements for 505(b)(2) 
applications and ANDAs and enhance clarity.
    We are expressly providing, with respect to a 505(b)(2) applicant 
that amends its paragraph IV certification after a finding of patent 
infringement, that once an amendment for the change has been submitted, 
the 505(b)(2) application will no longer be considered to contain a 
paragraph IV certification to the patent (see Sec.  314.50(i)(6)(i)). 
However, we explain that if a final decision finds the patent to be 
invalid and infringed, an amended certification is not required. This 
revision to Sec.  314.50(i)(6)(i) corresponds to the parallel 
regulation for ANDAs in Sec.  314.94(a)(12)(viii)(A) and clarifies the 
general statement in the introductory text of Sec.  314.50(i)(6) 
regarding amended patent certifications for 505(b)(2) applications.
    We are revising Sec.  314.94(a)(12)(viii)(A) to expressly provide 
that, after a finding of patent infringement, an ANDA applicant must 
submit a paragraph III certification or, with respect to a method-of-
use patent, the applicant may instead provide a statement under Sec.  
314.94(a)(12)(iii) if the applicant amends its ANDA such that the 
applicant is no longer seeking approval for a method of use claimed by 
the patent. This revision to Sec.  314.94(a)(12)(viii)(A) corresponds 
to the parallel regulation for 505(b)(2) applications in Sec.  
314.50(i)(6)(i) and describes an acceptable approach under the statute 
and existing regulations.
    We are revising Sec. Sec.  314.50(i)(1)(i)(A)(4)(ii) and 
314.94(a)(12)(i)(A)(4)(ii) to conform with Sec. Sec.  314.52(a)(2) and 
314.95(a)(2), respectively, and provide that if the NDA holder does not 
reside or maintain a place of business in the United States, notice of 
a paragraph IV certification must be sent to its attorney, agent, or 
other authorized official.
    We are revising Sec.  314.94(a)(12)(viii) to clarify that a patent 
certification or statement may be amended at any time ``before the 
approval of the ANDA,'' rather than ``before the date of approval of 
the ANDA'' for consistency with Sec.  314.50(i)(6).
V.P.3. Technical Corrections to Regulatory Concepts
    We are revising the definition of ``505(b)(2) application'' to 
clarify that it is an NDA for which ``at least some of'' the 
investigations relied upon by the applicant for approval were not 
conducted by or for the applicant and for which the applicant has not 
obtained a right of reference or use (see Sec.  314.3(b)).
    We are replacing the term ``filed'' with ``submitted'' in the first 
sentence of Sec.  314.50(i)(4)(ii) to use consistent terminology in 
this paragraph and to accurately describe FDA's longstanding practice. 
As revised, an applicant whose 505(b)(2) application is submitted after 
the NDA holder's untimely filing of patent information must submit an 
appropriate patent certification or statement as to that patent.
    We are deleting the phrase ``or changed'' from Sec. Sec.  
314.50(i)(5) and 314.94(a)(12)(vii) because a 505(b)(2) or ANDA 
applicant must submit an appropriate patent certification or statement 
for changes to patent information that are timely filed. We also are 
changing ``each relevant patent''

[[Page 69631]]

to ``each listed patent'' in Sec. Sec.  314.50(i)(5) and 
314.94(a)(12)(vii) for clarity.
    We are revising the titles of Sec. Sec.  314.52 and 314.95 to 
clarify that these sections relate to a notice of certification of 
invalidity, unenforceability, or non-infringement of a patent, as 
reflected in the text of these sections and FDA's definition of a 
paragraph IV certification.
    We are revising the paragraph headings of Sec. Sec.  314.52(f) and 
314.95(f) to change them from ``Approval'' to ``Forty-five day period 
after receipt of notice'' to more clearly describe the content of these 
sections. We are also revising Sec. Sec.  314.52(f) and 314.95(f) to 
add the NDA holder's attorney, agent, or other authorized official as 
potential recipients of the 505(b)(2) or ANDA applicant's notice of 
paragraph IV certification for consistency with Sec. Sec.  314.52(a)(2) 
and 314.95(a)(2).
    We are changing ``a drug product'' to ``the drug product'' in Sec.  
314.53(b)(1) to clarify that for patents that claim a drug product, the 
applicant must submit information only on those patents that claim the 
drug product, as is defined in Sec.  314.3, that is described in the 
pending or approved NDA.
    We are revising the description of required patent information for 
drug substance patents to clarify that information must include whether 
the patent claims ``a'' drug substance that is ``an'' active ingredient 
in the drug product described in the NDA or supplement to reflect 
submission of patent information on drug products that contain more 
than one active ingredient (see Sec.  314.53(c)(2)(i)(M)(1) and 
(c)(2)(ii)(N)(1)).
    We are deleting the phrase ``including a 505(b)(2) application'' in 
Sec.  314.53(d)(1) because the provision refers to an original NDA, 
which describes ``stand-alone'' applications submitted under section 
505(b)(1) of the FD&C Act and 505(b)(2) applications.
    We are adding the word ``active'' to a parenthetical reference to 
``ingredient'' for clarity and consistency with the regulations 
governing submission of patent information on drug substances (see 
Sec.  314.53(d)(1)).
    We are replacing a reference to the provisions regarding ``untimely 
filed patents'' with the phrase ``untimely filed patent information'' 
for consistency with the paragraph headings of Sec. Sec.  314.50(i)(4) 
and 314.94(a)(12)(vi) (see Sec.  314.53(d)(3)).
    We are replacing a reference to a request to ``delist a patent'' 
with the phrase ``remove a patent from the list'' for clarity (see 
Sec.  314.53(f)(2)(iv)).
    We are replacing a reference to an ``NDA'' in Sec.  314.60(a) with 
a reference to an ``NDA, supplement, or resubmission'' for clarity and 
consistency with the content of this regulation.
    We are replacing the phrase ``the listed drug approved in the 
petition'' in Sec.  314.93 with the phrase ``the listed drug referenced 
in the approved petition'' for accuracy (see Sec.  314.94(a)(3)(i)).
    We are revising the paragraph heading of Sec.  314.94(a)(12)(i) to 
describe ``patents claiming drug substance, drug product, or method of 
use'' for clarity and consistency with the regulation.
    We are deleting the word ``who'' in the phrase ``letter 
acknowledging receipt by the person who provided the notice'' because 
the letter described in Sec.  314.95(e) must acknowledge receipt by the 
person who received the notice, not the person who provided the notice.
    We are deleting the phrase ``for the active moiety'' in the phrase 
``[s]ubmission of a 505(b)(2) application or an ANDA for the active 
moiety'' because applicants submit 505(b)(2) applications and ANDAs for 
drug products, not active moieties, and the restriction on submission 
is described in the cited statutory references (see Sec.  
314.101(e)(2)).
    We are revising the paragraph heading of Sec.  314.107(b)(3)(i) to 
refer to the date of ``listed drug approval'' rather than the 
``reference product approval'' because a 505(b)(2) application or ANDA 
may rely on a listed drug approved under the FD&C Act.
    We are revising Sec.  314.94(a)(12)(viii)(B) to clarify that if 
removal of a patent from the list results in there being no patents 
listed for the listed drug identified in the ANDA, the applicant must 
submit an amended certification reflecting that there are ``no relevant 
patents,'' rather than ``no listed patents,'' to incorporate the 
terminology used in Sec.  314.94(a)(12)(ii).
    We are revising the reference to an approval that ``will become 
effective'' to an approval that ``will occur'' because the Agency no 
longer uses this terminology (see Sec.  314.108(b)(3)).
V.P.4. Technical Corrections to Statutory or Regulatory References
    We are correcting statutory and regulatory citations in the 
sections of part 314 and 320 that are the subject of this rulemaking, 
as illustrated by the following examples:
     Delete the reference to ``section 505 of the act'' as 
unnecessary in the context of an approved NDA (see Sec.  314.70(a)(2));
     Correct the statutory reference to the definition of ``new 
drug'' in section 201(p) of the FD&C Act (21 U.S.C. 321(p)) (see Sec.  
314.93(d)(3));
     Change ``section 505(j)(4)(D)'' to ``section 
505(j)(5)(F)'' of the FD&C Act to correctly cite the relevant 
exclusivity provision (see Sec.  314.94(a)(3)(ii));
     Update the citation for the definition ``same drug product 
formulation'' from Sec.  320.1(g) to Sec.  314.3(b) to reflect the 
relocation of the definition (see Sec.  314.94(a)(7)(i));
     Add a reference to Sec.  314.94(a)(12)(iii) to align with 
text regarding an ANDA applicant's submission of an appropriate patent 
certification or statement (see Sec.  314.94(a)(12)(i)(B) and 
(a)(12)(viii)(C)(1)(ii));
     Change ``section 505(j)(4)(B)(iii)'' to ``section 
505(j)(5)(B)(iii)'' of the FD&C Act to correctly cite the statutory 
provision regarding the 45-day period after receipt of notice of a 
paragraph IV certification (see Sec.  314.95(f)); and
     Revise Sec.  314.105(a) regarding approval of an NDA to 
delete the reference to Sec.  314.107(c), which only applies to ANDAs.
V.P.5. Changes to Location for Sending Information
    We are revising Sec. Sec.  314.52(a)(2) and 314.95(a)(2) to clarify 
that the name and address of the NDA holder or its attorney, agent, or 
authorized official may also be obtained by sending an electronic 
communication to the Orange Book staff. As revised, Sec. Sec.  
314.52(a)(2) and 314.95(a)(2) provide that this information may be 
obtained by sending a written or electronic communication to the Orange 
Book Staff, Office of Generic Drugs, 7620 Standish Pl., Rockville, MD 
20855, or to the Orange Book Staff at the email address listed on the 
Agency's Web site at https://www.fda.gov.
    We are revising Sec.  314.53(c)(2)(i)(B) and (c)(2)(ii)(B) to 
request the NDA applicant's full address, phone number, and, if 
available, fax number and email address in addition to the applicant's 
name to facilitate communication.
    We are revising Sec.  314.107(f)(2) to clarify that notification of 
the filing of any legal action within 45 days of the receipt of notice 
of a paragraph IV certification must be sent by a 505(b)(2) applicant 
to its NDA (rather than to the appropriate OND Review Division) and 
must be sent by an ANDA applicant to its ANDA (rather than to OGD).
V.P.6. Grammatical Corrections
    We are making certain revisions to correct or improve grammar or 
punctuation in the sections of parts 314 and 320 that are the subject 
of this rulemaking, as illustrated by the following examples:

[[Page 69632]]

     Change ``which'' to ``that'' (see Sec. Sec.  
314.50(i)(1)(i)(A)(4)(ii) and 314.95(a)(1));
     Change ``method of use patent'' to ``method-of-use 
patent'' (see Sec. Sec.  314.50(i)(1)(iii) and 314.94(a)(12)(iii));
     Change ``[o]nce an amendment for the change in 
certification has been submitted'' to ``[o]nce an amendment is 
submitted to change the certification'' (see Sec.  314.50(i)(6));
     Change ``will no longer be considered to be one 
containing'' to ``will no longer be considered to contain'' (see 
Sec. Sec.  314.50(i)(6) and 314.94(a)(12)(viii)(A) and (B));
     Delete the word ``use'' in the phrase ``one or more 
methods of using the drug product for which use approval is being 
sought'' for clarity (see Sec.  314.53(c)(2)(i)(O)(1));
     Change ``United States'' to ``U.S.'' (see Sec.  
314.53(c)(2)(ii)(H));
     Change ``shall'' to ``must'' as appropriate (see 
Sec. Sec.  314.53(d)(1) and 314.94(a), (a)(1), (a)(12)(i)(A)(4)(i) and 
(ii), (b), and (d)(2));
     Change ``except that Sec.  314.50(d)(1)(ii)(c) must 
contain'' to ``except that the [technical] section described in Sec.  
314.50(d)(1)(ii)(c) must contain'' or ``except that the information 
required under Sec.  314.50(d)(1)(ii)(c) must contain'' for clarity 
(see Sec. Sec.  314.54(a)(2) and 314.94(a)(9)(i));
     Change ``any bioavailability of bioequivalence testing'' 
to ``any bioavailability or bioequivalence testing'' to correct a 
typographical error (see Sec.  314.94(a)(7)(ii));
     Change ``it'' to ``the study'' for clarity (see Sec. Sec.  
314.94(a)(7)(iii)(B) and 314.101(d)(6) and (7));
     Change ``amendment to Sec.  314.94(a)(9)'' to ``amendment 
under Sec.  314.94(a)(9)'' for clarity (see Sec.  314.96(b));
     Change ``their representatives'' to ``its representative'' 
or ``its representative(s)'' (see Sec. Sec.  314.94(a)(12)(i)(A)(4)(ii) 
and 314.107(f)(2)(ii) and (iii) and (f)(3));
     Delete the words ``is or'' from the phrase ``is or has 
been removed'' (see Sec.  314.94(a)(12)(viii)(B)); and
     Add appropriate descriptors (e.g., ``section'' and 
``paragraph'') to modify statutory and regulatory references (see Sec.  
314.94(d)(2)).

VI. Effective Date

    This final rule is effective December 5, 2016. The final rule 
applies to any new submission (including but not limited to an NDA or 
ANDA, an amendment or supplement (including any patent certifications 
or statements), submission of patent information and requests by the 
NDA holder to amend or withdraw a patent or patent information, 
submission of a new patent listing dispute, and notification of court 
actions or written consent to approval) received by FDA on or after the 
effective date. In addition, a person (including a 505(b)(2) or ANDA 
applicant) may submit a request under Sec.  314.53(f)(1) for an NDA 
holder to confirm the accuracy or relevance of previously submitted 
patent information in light of requirements for submission of patent 
information on and after the effective date of this final rule.

VII. Economic Analysis of Impacts

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct us to assess all costs 
and benefits of available regulatory alternatives and, when regulation 
is necessary, to select regulatory approaches that maximize net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). We 
have developed a comprehensive Economic Analysis of Impacts that 
assesses the impacts of the final rule. We believe that this final rule 
is not a significant regulatory action as defined by Executive Order 
12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because average costs per entity are small, and the 
regulatory requirement with the highest cost per instance would affect 
few if any of the smallest entities, we certify that the final rule 
will not have a significant economic impact on a substantial number of 
small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before issuing ``any rule that includes 
any Federal mandate that may result in the expenditure by State, local, 
and tribal governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation) in any one 
year.'' The current threshold after adjustment for inflation is $146 
million, using the most current (2015) Implicit Price Deflator for the 
Gross Domestic Product. This final rule would not result in an 
expenditure in any year that meets or exceeds this amount.
    Many provisions of this final rule codify current practice, but 
some elements will lead to changes that generate additional benefits 
and costs. Table 2 summarizes the benefits and costs of this final 
rule. The estimated annualized monetized benefits of this final rule 
are $215,247 at a 3 percent or 7 percent discount rate, while the 
estimated annualized monetized costs are $266,947 at a 3 percent 
discount rate and $275,925 at a 7 percent discount rate. We have also 
identified, but are unable to quantify, additional impacts from changes 
to submitted patent information.

                  Table 2--Summary of Benefits and Costs
------------------------------------------------------------------------
                                             Benefits          Costs
------------------------------------------------------------------------
One-time (Year 1) Cost for Reading the               N/A        $466,450
 Rule...................................
Annually Recurring Compliance Costs or          $215,247         213,858
 Savings (Years 1-10)...................
Present Value at 3 Percent..............       1,836,098       2,277,116
Present Value at 7 Percent..............       1,511,803       1,937,983
Annualized Value at 3 Percent...........         215,247         266,947
Annualized Value at 7 Percent...........         215,247         275,925
------------------------------------------------------------------------

    The full analysis of economic impacts is available in the docket 
for this final rule (Ref. 2) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

VIII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(h) and 25.31(a) and (g) that 
this action is of a type that does not individually or cumulatively 
have a significant effect on the human environment. Therefore, neither 
an environmental assessment nor an environmental impact statement is 
required.

[[Page 69633]]

IX. Paperwork Reduction Act of 1995

    The final rule contains information collection requirements that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3520). 
The title, description, and respondent description of the information 
collection provisions are shown in the following paragraphs with an 
estimate of the annual reporting burden. The estimate includes the time 
for reviewing instructions, searching existing data sources, gathering 
and maintaining the data needed, and completing and reviewing each 
collection of information.
    Title: Abbreviated New Drug Applications and 505(b)(2) 
Applications.
    Description of Respondents: Respondents to this collection of 
information are NDA applicants (including 505(b)(2) applicants) and 
ANDA applicants, patent owners, and their representatives.
    Burden Estimate: This final rule implements portions of Title XI of 
the MMA that pertain to a 505(b)(2) or ANDA applicant's provision of 
notice of paragraph IV certification to each patent owner and the NDA 
holder; the availability of 30-month stays of approval on 505(b)(2) 
applications and ANDAs that are otherwise ready to be approved; 
submission of amendments and supplements to 505(b)(2) applications and 
ANDAs; and the types of bioavailability and bioequivalence data that 
can be used to support these applications. This final rule also amends 
certain regulations regarding 505(b)(2) applications and ANDAs to 
facilitate compliance with and efficient enforcement of the FD&C Act.
    FDA currently has OMB approval for the collection of information 
entitled ``Application for Food and Drug Administration Approval to 
Market a New Drug'' (OMB control number 0910-0001). This collection of 
information includes, among other things:
     The requirements in Sec. Sec.  314.50(i) and 314.94(a)(12) 
for submission of an appropriate patent certification or statement in a 
505(b)(2) application or ANDA;
     the requirements in Sec. Sec.  314.52 and 314.95 for a 
505(b)(2) or ANDA applicant to send notice of any paragraph IV 
certification to each patent owner and the NDA holder and to amend its 
505(b)(2) application or ANDA to certify that notice has been provided 
and to document receipt of the notice;
     the content requirements in Sec.  314.54 for a 505(b)(2) 
application;
     the requirements in Sec. Sec.  314.60 and 314.96 for 
applicants that amend an unapproved 505(b)(2) application or ANDA, 
respectively;
     the requirements in Sec. Sec.  314.70 and 314.97 for 
supplements submitted to FDA for certain changes to an approved 
505(b)(2) application or ANDA;
     the requirements in Sec. Sec.  314.90 and 314.99 for 
applicants that request waivers from FDA for compliance with Sec. Sec.  
314.50 through 314.81 or Sec. Sec.  314.92 through 314.99, 
respectively;
     the procedures in Sec.  314.107(c) by which a first 
applicant notifies FDA of the date of first commercial marketing;
     the requirement in Sec.  314.107(e) for an applicant to 
submit to FDA a copy of certain court decisions related to a patent 
that is the subject of a paragraph IV certification;
     the requirement in Sec.  314.107(f) for a 505(b)(2) or 
ANDA applicant to notify FDA immediately of the filing of any legal 
action within 45 days of receipt of the notice of paragraph IV 
certification by each patent owner or the NDA holder; and
     the requirement in Sec.  314.107(f) for a patent owner or 
NDA holder who is an exclusive patent licensee that waives its 
opportunity to file a legal action for patent infringement within the 
45-day period to submit to FDA a waiver in the specified format.
    In addition, FDA has OMB approval for the collection of information 
entitled ``General Administrative Procedures: Citizen Petitions; 
Petition for Reconsideration or Stay of Action; Advisory Opinions'' 
(OMB control number 0910-0191). This collection of information 
includes, among other things, the requirements in Sec.  314.93 for 
submitting a suitability petition in accordance with 21 CFR 10.20 and 
10.30.
    FDA also has OMB approval for the collection of information 
entitled ``Applications for Food and Drug Administration Approval to 
Market a New Drug: Patent Submission and Listing Requirements and 
Application of 30-Month Stays on Approval of Abbreviated New Drug 
Applications Certifying That a Patent Claiming a Drug Is Invalid or 
Will Not Be Infringed'' (OMB control number 0910-0513). This collection 
of information includes the requirements in Sec.  314.50(h) for 
submission of patent information in an NDA, an amendment, or a 
supplement, as described in Sec.  314.53. Section 314.53 requires that 
an applicant submitting an NDA, an amendment, or a supplement, except 
as provided in Sec.  314.53(d)(2), submit on Forms FDA 3542a and 3542 
the required patent information described in this section.
    Under section 505(b), (c), and (j) of the FD&C Act and this final 
rule, the following information must be submitted to FDA but is not 
currently approved by OMB under the PRA.
    Section 314.50(i)(1)(i)(C) requires a 505(b)(2) applicant to submit 
an appropriate patent certification or statement for each patent listed 
in the Orange Book for one drug product approved in an NDA that is 
pharmaceutically equivalent to the proposed drug product for which the 
original 505(b)(2) application is submitted and was approved before the 
original 505(b)(2) application was submitted. Section 314.54 also 
describes this requirement. In general, 505(b)(2) applications 
submitted for a proposed drug product for which there is an approved 
pharmaceutical equivalent already cite the pharmaceutically equivalent 
product as a listed drug relied upon to support approval. However, 
based on our experience reviewing 505(b)(2) applications, we estimate 
that Sec.  314.50(i)(1)(i)(C) may result in two instances per year in 
which an applicant is required to identify a pharmaceutically 
equivalent drug product as a listed drug relied upon and to comply with 
applicable regulatory requirements (including submission of an 
appropriate patent certification or statement for each patent listed in 
the Orange Book for a pharmaceutically equivalent drug product approved 
in an NDA). Based on an average of 3.4 patents submitted by an NDA 
holder for listing in the Orange Book, we calculate that the two 
instances in which a 505(b)(2) applicant is required to identify a 
pharmaceutically equivalent drug product as a listed drug relied upon 
will result in 6.8 patent certifications or statements per year. The 
burden associated with this requirement in Sec.  314.50(i)(1)(i)(C) is 
approximately 2 hours per response. In addition, if the patent 
certification submitted pursuant to Sec.  314.50(i)(1)(i)(C) is a 
paragraph IV certification, the applicant also must comply with the 
requirements in Sec.  314.52 for notice of paragraph IV certification.
    The burden estimate for sending notice of a paragraph IV 
certification reflects other changes that reduce the currently approved 
burden for Sec.  314.52 from 16 hours per response to 15 hours per 
response, and the additional content requirement in Sec.  314.52(c) 
that increases the estimated burden by 0.33 hours per response. We are 
providing an estimate of 15 respondents for Sec.  314.52(a), (b), and 
(e) to reflect the additional burden that may arise from the 
requirement in Sec.  314.50(i)(1)(i)(C) if the two 505(b)(2)

[[Page 69634]]

applicants submit paragraph IV certifications and to update data 
regarding the estimated number of 505(b)(2) applications that contain 
one or more paragraph IV certifications, which adds approximately 675 
hours (15 hours per response) to the currently approved burden. We 
separately describe and estimate the burden of the additional content 
requirement in Sec.  314.52(c).
    Sections 314.52(a) and 314.95(a) expand the acceptable delivery 
methods that may be used to send notice of paragraph IV certification 
to the NDA holder and each patent owner, and thereby reduce the burden 
on applicants to submit, under existing Sec.  314.52(a) and (e), a 
request to FDA to use common alternate delivery methods. We receive 
approximately 390 written inquiries per year from 505(b)(2) or ANDA 
applicants requesting permission to send notice of paragraph IV 
certification by an overnight delivery service. Sections 314.52(a) and 
314.95(a) eliminate the requirement to submit a request to use a 
designated delivery service, as defined in Sec. Sec.  314.52(g) and 
314.95(g). We estimate that approximately 97.5 percent of these written 
inquiries will no longer be required because the alternate delivery 
method would fall within the definition of a ``designated delivery 
service'' in Sec. Sec.  314.52(g) and 314.95(g).
    Sections 314.50(i)(6) and 314.94(a)(12)(viii) require a 505(b)(2) 
or ANDA applicant to amend its patent certification from a paragraph IV 
certification to a paragraph III certification after the court enters a 
final decision from which no appeal has been or can be taken, or signs 
and enters a settlement order or consent decree with a finding of 
infringement (unless the patent also is found invalid). Sections 
314.50(i)(6) and 314.94(a)(12)(viii) also require a 505(b)(2) or ANDA 
applicant to submit an amended patent certification in certain 
circumstances after the NDA holder has requested to remove a patent or 
patent information from the list.
    Based on our experience receiving submissions of court decisions or 
orders with a finding of infringement, and instances in which the 
patent or patent information has been removed from the list at the 
request of the NDA holder, we estimate that this requirement may result 
in approximately 17 and 153 instances per year in which an applicant 
amends its 505(b)(2) application or ANDA, respectively, to submit a 
revised patent certification. The burden hours associated with this 
requirement will be approximately 2 hours per response.
    Sections 314.50(i)(6)(iii)(A)(2) and 314.94(a)(12)(viii)(C)(1)(ii) 
expressly codify the current requirement for a 505(b)(2) or ANDA 
applicant to submit a patent certification or statement if, after 
submission of the application, a new patent is issued by the USPTO that 
in the opinion of the applicant and to the best of its knowledge, 
claims the listed drug or an approved use for such listed drug and for 
which information is required to be filed by the NDA holder.
    Section 314.95(c) requires that the notice of paragraph IV 
certification contain a statement that the applicant has received the 
paragraph IV acknowledgment letter. In addition, Sec.  314.52(c) 
requires that the notice of paragraph IV certification contain a 
statement that a 505(b)(2) application that contains any required 
bioavailability or bioequivalence data has been submitted by the 
applicant and filed by FDA, as required by section 505(b)(3)(D)(i) of 
the FD&C Act. We estimate that these additional content requirements 
for the notice of paragraph IV certification would increase the burden 
of providing notice of paragraph IV certification by approximately 20 
minutes. Based on an estimated average of 20 505(b)(2) applications 
filed per year that contain one or more paragraph IV certifications 
(plus the additional burden that may arise from the requirement in 
Sec.  314.50(i)(1)(i)(C) if the 2 505(b)(2) applicants submit paragraph 
IV certifications) and 400 ANDAs received per year that contain one or 
more paragraph IV certifications, we estimate that there will be 60 and 
1,200 responses per year, respectively, and the burden hours associated 
with this requirement will be approximately 20 minutes per response.
    Sections 314.52(d)(1) and 314.95(d)(1) require notice of paragraph 
IV certification regardless of whether notice has already been provided 
for another paragraph IV certification contained in the 505(b)(2) 
application or ANDA or an amendment or supplement to the 505(b)(2) 
application or ANDA, as required by section 505(b)(3)(B)(ii) and 
(j)(2)(B)(ii)(II) of the FD&C Act. Since enactment of the MMA in 2003, 
FDA has regulated directly from the statute and required notice of 
paragraph IV certification in these circumstances, and the burden 
associated with this statutory requirement is currently approved under 
OMB control number 0910-0001.
    Sections 314.52(e) and 314.95(e) would permit a 505(b)(2) or ANDA 
applicant to submit a single amendment containing documentation of 
timely sending and receipt of notice of paragraph IV certification. 
Currently, an applicant is required to amend its 505(b)(2) application 
or ANDA both at the time of sending notice of paragraph IV 
certification and after the notice was received by each patent owner 
and the NDA holder (see existing Sec. Sec.  314.52(b) and (e) and 
314.95(b) and (e)). Section 314.95(e) also requires an ANDA applicant 
to include in its amendment a dated printout of the Orange Book entry 
for the RLD. The burden associated with this statutory requirement is 
currently approved under OMB control number 0910-0001.
    Section 314.53(c)(2) decreases the patent information that NDA 
applicants are currently required to submit for listing in the Orange 
Book. Section 314.53(c)(2) requires submission of patent information on 
whether a drug substance patent claims a polymorph only if such patent 
claims only a polymorph that is the same active ingredient described in 
the NDA or supplement. Section 314.53(c)(2) also provides that an 
applicant that submits information for a patent that claims either the 
drug substance or drug product and meets the requirements for patent 
listing on that basis is not required to provide information on whether 
that patent also claims the drug product or drug substance, 
respectively. Section 314.53(c)(2) also modifies requirements for 
submission of patent information on method-of-use patents. The 
information collection resulting from existing Sec.  314.50(h) (citing 
Sec.  314.53) and Form FDA 3542a has been approved by OMB under control 
number 0910-0513 for FDA's estimate of 20 hours per response. We 
previously estimated that the burden of Form FDA 3542a would fall by 3 
hours per response. We now estimate that the burden for Form FDA 3542a 
will be reduced by 5 hours from 20 hours to 15 hours per response; we 
further estimate that the burden for Form FDA 3542 will increase by 5 
hours from 5 to 10 hours per response. We have shifted a portion of the 
time spent preparing Form FDA 3542a to the estimated time preparing 
Form FDA 3542 to reflect the additional time spent by the NDA holder to 
develop the use code in accordance with FDA's revised regulations and 
identify the specific section(s) and subsection(s) of labeling that 
describe the specific approved method of use claimed by the patent.
    Section 314.53(d)(2) avoids duplicative submission of patent 
information that would accompany supplements to NDAs and requires such 
information only for a supplement to add or change the dosage form or 
route of administration, to add or change the strength, to change the 
drug product

[[Page 69635]]

from prescription to OTC use, or to revise previously submitted patent 
information that differently or no longer claims the changed product.
    Section 314.53(f)(1) provides a more detailed description of the 
procedure for patent listing disputes directed to the accuracy or 
relevance of submitted patent information, and establishes additional 
requirements for patent listing disputes directed to method-of-use 
claims. Based on our experience, we estimate that there may be 
approximately 12 instances per year in which a person submits a patent 
listing dispute, and a corresponding 12 instances per year in which the 
NDA holder is required to respond to the patent listing dispute. In 
light of the additional requirements for patent listing disputes 
directed to method-of-use claims, we estimate that the burden 
associated with Sec.  314.53(f)(1) will be approximately 10 hours per 
response.
    Section 314.53(f)(2) expressly requires correction or change of 
patent information if the NDA holder determines that a patent or patent 
claim no longer meets the statutory requirements for listing, if the 
NDA holder is required by court order to amend patent information or 
withdraw a patent from the list, or if the term of a listed patent is 
extended under 35 U.S.C. 156(e). We estimate that these corrections and 
changes of patent information would result in approximately 39 
submissions of Form FDA 3542 or other written submission, as provided 
in Sec.  314.53(f)(2), by approximately 27 NDA holders. We further 
estimate that the burden hours associated with the requirement in Sec.  
314.53(f)(2) would be approximately 1 hour per response.
    Section 505(b)(4)(A) and (j)(2)(D)(i) of the FD&C Act generally 
prohibits the submission of certain types of changes in an amendment or 
a supplement to a 505(b)(2) application or an ANDA, respectively. 
Sections 314.60(e) and 314.70(h) would prohibit an applicant from 
amending or supplementing a 505(b)(2) application to seek approval of a 
drug that has been modified to have a different active ingredient, 
different route of administration, different dosage form, or certain 
differences in excipients than the drug proposed in the original 
submission of the 505(b)(2) application. These changes must be 
requested in a new 505(b)(2) application. This final requirement 
conforms with FDA's current policy regarding the types of proposed 
changes to a drug product that should be submitted as a separate 
application (see guidance for industry on ``Submitting Separate 
Marketing Applications and Clinical Data for Purposes of Assessing User 
Fees'' (December 2004), available at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm). 
Accordingly, the burden associated with this statutory requirement is 
currently approved under OMB control number 0910-0001.
    Sections 314.60(f) and 314.96(d) require an applicant to submit a 
patent certification if approval is sought for the following types of 
amendments to a 505(b)(2) application or ANDA: (1) To add a new 
indication or other condition of use; (2) to add a new strength; (3) to 
make other than minor changes in product formulation; or (4) to change 
the physical form or crystalline structure of the active ingredient. 
Although currently the submission of a patent certification is required 
if, at any time before approval, the applicant learns that the 
previously submitted patent certification is no longer accurate with 
respect to the pending application or supplement, as amended, the 
patent certification requirements would be broadened under this 
regulation. We estimate that this broadened requirement may result in 
approximately six instances per year in which an applicant is required 
to submit a patent certification with an amendment to its 505(b)(2) 
application. We further estimate that this requirement may result in 
approximately 100 instances per year in which an applicant is required 
to submit a patent certification with an amendment to its ANDA. The 
burden hours associated with these requirements are estimated to be 
approximately 2 hours per response.
    Sections 314.96(c) and 314.97(b) prohibit an ANDA applicant from 
amending or supplementing an ANDA to seek approval of a drug referring 
to a listed drug that is different from the RLD identified in the ANDA. 
An applicant must submit a change of the RLD in a new ANDA. We estimate 
that approximately one ANDA applicant per year will be required to 
submit a new ANDA instead of submitting an amendment for a change of 
the RLD. We also estimate that approximately one ANDA applicant per 
year will be required to submit a new ANDA instead of submitting a 
supplement for a change of the RLD. We further estimate that the burden 
of submitting an ANDA and complying with applicable regulatory 
requirements, including any required study to demonstrate 
bioequivalence to the new RLD, will be approximately 300 hours for each 
of the estimated two responses per year.
    Section 314.107(e) expands the scope of the court actions and 
written consent to approval related to a patent described in Sec.  
314.107(b)(3) that are required to be submitted to FDA. Section 
314.107(e) also requires submission of any court order pursuant to 35 
U.S.C. 271(e)(4)(A) ordering that a 505(b)(2) application or ANDA may 
be approved no earlier than the date specified. Based on our 
experience, we estimate that 247 505(b)(2) and ANDA applicants will be 
required to submit a copy of a court action, written consent to 
approval, or written notification of appeal in approximately 494 
instances per year. We continue to estimate that the burden associated 
with submitting a copy of these documents to FDA (as approved in OMB 
control number 0910-0001) is approximately 30 minutes per response.
    The estimated burden of this collection of information is described 
in Table 3.

                                                     Table 3--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                 Number of
               21 CFR section                    Number of     responses per   Total annual     Average burden per response (in hours)      Total hours
                                                respondents     respondent       responses
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.50(i)(1)................................               2             3.4             6.8  2.........................................              14
314.50(i)(6)................................              17               1              17  2.........................................              34
314.52(a), (b), and (e).....................              15               3              45  15........................................             675
314.52(c)...................................              22               3              66  0.33 (20 minutes).........................              22
314.53(f)(1)................................              24               1              24  10........................................             240
314.53(f)(2)................................              27             1.4              39  1.........................................              39
314.60(f)...................................               6               1               6  2.........................................              12
314.94(a)(12)(viii).........................             153               1             153  2.........................................             306
314.95(c)...................................             400               3           1,200  0.33 (20 minutes).........................             400

[[Page 69636]]

 
314.96(c)...................................               1               1               1  300.......................................             300
314.96(d)...................................             100               1             100  2.........................................             200
314.97(b)...................................               1               1               1  300.......................................             300
314.107(e)..................................             247               2             494  0.5 (30 minutes)..........................             247
                                             -----------------------------------------------------------------------------------------------------------
    Total Reporting Burden Hours............  ..............  ..............  ..............  ..........................................           2,789
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    The information collection provisions in this final rule have been 
submitted to OMB for review as required by section 3507(d) of the 
Paperwork Reduction Act of 1995.
    Before the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions in this 
final rule. An Agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

X. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. We have determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, we conclude that the rule 
does not contain policies that have federalism implications as defined 
in the Executive Order and, consequently, a federalism summary impact 
statement is not required.

XI. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the Web site addresses, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

1. Federal Trade Commission, Report on ``Generic Drug Entry Prior to 
Patent Expiration: An FTC Study'' (July 2002), available at https://www.ftc.gov/sites/default/files/documents/reports/generic-drug-entry-prior-patent-expiration-ftc-study/genericdrugstudy_0.pdf.
2. Final Regulatory Impact Analysis, Final Regulatory Flexibility 
Analysis, and Unfunded Mandates Reform Act Analysis for Abbreviated 
New Drug Applications and 505(b)(2) Applications; Final Rule, 
available at https://www.fda.gov/aboutfda/reportsmanualsforms/
reports/economicanalyses/default.htm.

List of Subjects

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 320

    Drugs, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
314 and 320 are amended as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
1. The authority citation for part 314 is revised to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f, 
356, 356a, 356b, 356c, 356e, 360cc, 371, 374, 379e, 379k-1.

0
2. Section 314.3 is revised to read as follows:


Sec.  314.3  Definitions.

    (a) The definitions and interpretations contained in section 201 of 
the Federal Food, Drug, and Cosmetic Act apply to those terms when used 
in this part and part 320 of this chapter.
    (b) The following definitions of terms apply to this part and part 
320 of this chapter:
    180-day exclusivity period is the 180-day period beginning on the 
date of the first commercial marketing of the drug (including the 
commercial marketing of the reference listed drug) by any first 
applicant. The 180-day period ends on the day before the date on which 
an ANDA submitted by an applicant other than a first applicant could be 
approved.
    505(b)(2) application is an NDA submitted under section 505(b)(1) 
of the Federal Food, Drug, and Cosmetic Act for a drug for which at 
least some of the investigations described in section 505(b)(1)(A) of 
the Federal Food, Drug, and Cosmetic Act and relied upon by the 
applicant for approval of the NDA were not conducted by or for the 
applicant and for which the applicant has not obtained a right of 
reference or use from the person by or for whom the investigations were 
conducted.
    Abbreviated application, abbreviated new drug application, or ANDA 
is the application described under Sec.  314.94, including all 
amendments and supplements to the application.
    Acknowledgment letter is a written, postmarked communication from 
FDA to an applicant stating that the Agency has determined that an ANDA 
is sufficiently complete to permit a substantive review. An 
acknowledgment letter indicates that the ANDA is regarded as received.
    Act is the Federal Food, Drug, and Cosmetic Act (section 201 et 
seq. (21 U.S.C. 301 et seq.)).
    Active ingredient is any component that is intended to furnish 
pharmacological activity or other direct effect in the diagnosis, cure, 
mitigation, treatment, or prevention of disease, or to affect the 
structure or any function of the body of man or other animals. The term 
includes those components that may undergo chemical change in the 
manufacture of the drug product and be present in the drug product in a 
modified form intended to furnish the specified activity or effect.
    Active moiety is the molecule or ion, excluding those appended 
portions of the molecule that cause the drug to be an ester, salt 
(including a salt with hydrogen or coordination bonds), or other 
noncovalent derivative (such as a complex, chelate, or clathrate) of 
the molecule, responsible for the physiological or pharmacological 
action of the drug substance.

[[Page 69637]]

    ANDA holder is the applicant that owns an approved ANDA.
    Applicant is any person who submits an NDA (including a 505(b)(2) 
application) or ANDA or an amendment or supplement to an NDA or ANDA 
under this part to obtain FDA approval of a new drug and any person who 
owns an approved NDA (including a 505(b)(2) application) or ANDA.
    Application, new drug application, or NDA is the application 
described under Sec.  314.50, including all amendments and supplements 
to the application. An NDA refers to ``stand-alone'' applications 
submitted under section 505(b)(1) of the Federal Food, Drug, and 
Cosmetic Act and to 505(b)(2) applications.
    Approval letter is a written communication to an applicant from FDA 
approving an NDA or an ANDA.
    Assess the effects of the change is to evaluate the effects of a 
manufacturing change on the identity, strength, quality, purity, and 
potency of a drug product as these factors may relate to the safety or 
effectiveness of the drug product.
    Authorized generic drug is a listed drug, as defined in this 
section, that has been approved under section 505(c) of the Federal 
Food, Drug, and Cosmetic Act and is marketed, sold, or distributed 
directly or indirectly to the retail class of trade with labeling, 
packaging (other than repackaging as the listed drug in blister packs, 
unit doses, or similar packaging for use in institutions), product 
code, labeler code, trade name, or trademark that differs from that of 
the listed drug.
    Bioavailability is the rate and extent to which the active 
ingredient or active moiety is absorbed from a drug product and becomes 
available at the site of drug action. For drug products that are not 
intended to be absorbed into the bloodstream, bioavailability may be 
assessed by scientifically valid measurements intended to reflect the 
rate and extent to which the active ingredient or active moiety becomes 
available at the site of drug action.
    Bioequivalence is the absence of a significant difference in the 
rate and extent to which the active ingredient or active moiety in 
pharmaceutical equivalents or pharmaceutical alternatives becomes 
available at the site of drug action when administered at the same 
molar dose under similar conditions in an appropriately designed study. 
Where there is an intentional difference in rate (e.g., in certain 
extended-release dosage forms), certain pharmaceutical equivalents or 
alternatives may be considered bioequivalent if there is no significant 
difference in the extent to which the active ingredient or moiety from 
each product becomes available at the site of drug action. This applies 
only if the difference in the rate at which the active ingredient or 
moiety becomes available at the site of drug action is intentional and 
is reflected in the proposed labeling, is not essential to the 
attainment of effective body drug concentrations on chronic use, and is 
considered medically insignificant for the drug. For drug products that 
are not intended to be absorbed into the bloodstream, bioequivalence 
may be assessed by scientifically valid measurements intended to 
reflect the rate and extent to which the active ingredient or active 
moiety becomes available at the site of drug action.
    Bioequivalence requirement is a requirement imposed by FDA for in 
vitro and/or in vivo testing of specified drug products that must be 
satisfied as a condition of marketing.
    Class 1 resubmission is the resubmission of an NDA or efficacy 
supplement, following receipt of a complete response letter, that 
contains one or more of the following: Final printed labeling, draft 
labeling, certain safety updates, stability updates to support 
provisional or final dating periods, commitments to perform 
postmarketing studies (including proposals for such studies), assay 
validation data, final release testing on the last lots used to support 
approval, minor reanalyses of previously submitted data, and other 
comparatively minor information.
    Class 2 resubmission is the resubmission of an NDA or efficacy 
supplement, following receipt of a complete response letter, that 
includes any item not specified in the definition of ``Class 1 
resubmission,'' including any item that would require presentation to 
an advisory committee.
    Commercial marketing is the introduction or delivery for 
introduction into interstate commerce of a drug product described in an 
ANDA, outside the control of the ANDA applicant, except that the term 
does not include transfer of the drug product for investigational use 
under part 312 of this chapter or transfer of the drug product to 
parties identified in the ANDA for reasons other than sale. Commercial 
marketing includes the introduction or delivery for introduction into 
interstate commerce of the reference listed drug by the ANDA applicant.
    Complete response letter is a written communication to an applicant 
from FDA usually describing all of the deficiencies that the Agency has 
identified in an NDA or ANDA that must be satisfactorily addressed 
before it can be approved.
    Component is any ingredient intended for use in the manufacture of 
a drug product, including those that may not appear in such drug 
product.
    Date of approval is the date on the approval letter from FDA 
stating that the NDA or ANDA is approved, except that the date of 
approval for an NDA described in section 505(x)(1) of the Federal Food, 
Drug, and Cosmetic Act is determined as described in section 505(x)(2) 
of the Federal Food, Drug, and Cosmetic Act. ``Date of approval'' 
refers only to a final approval and not to a tentative approval.
    Dosage form is the physical manifestation containing the active and 
inactive ingredients that delivers a dose of the drug product. This 
includes such factors as:
    (1) The physical appearance of the drug product;
    (2) The physical form of the drug product prior to dispensing to 
the patient;
    (3) The way the product is administered; and
    (4) The design features that affect frequency of dosing.
    Drug product is a finished dosage form, e.g., tablet, capsule, or 
solution, that contains a drug substance, generally, but not 
necessarily, in association with one or more other ingredients.
    Drug substance is an active ingredient that is intended to furnish 
pharmacological activity or other direct effect in the diagnosis, cure, 
mitigation, treatment, or prevention of disease or to affect the 
structure or any function of the human body, but does not include 
intermediates used in the synthesis of such ingredient.
    Efficacy supplement is a supplement to an approved NDA proposing to 
make one or more related changes from among the following changes to 
product labeling:
    (1) Add or modify an indication or claim;
    (2) Revise the dose or dose regimen;
    (3) Provide for a new route of administration;
    (4) Make a comparative efficacy claim naming another drug product;
    (5) Significantly alter the intended patient population;
    (6) Change the marketing status from prescription to over-the-
counter use;
    (7) Provide for, or provide evidence of effectiveness necessary 
for, the traditional approval of a product originally approved under 
subpart H of this part; or
    (8) Incorporate other information based on at least one adequate 
and well-controlled clinical study.

[[Page 69638]]

    FDA or Agency is the Food and Drug Administration.
    First applicant is an ANDA applicant that, on the first day on 
which a substantially complete application containing a paragraph IV 
certification is submitted for approval of a drug, submits a 
substantially complete application that contains, and for which the 
applicant lawfully maintains, a paragraph IV certification for the 
drug.
    Inactive ingredient is any component other than an active 
ingredient.
    Listed drug is a new drug product that has been approved under 
section 505(c) of the Federal Food, Drug, and Cosmetic Act for safety 
and effectiveness or under section 505(j) of the Federal Food, Drug, 
and Cosmetic Act, which has not been withdrawn or suspended under 
section 505(e)(1) through (5) or section 505(j)(6) of the Federal Food, 
Drug, and Cosmetic Act, and which has not been withdrawn from sale for 
what FDA has determined are reasons of safety or effectiveness. Listed 
drug status is evidenced by the drug product's identification in the 
current edition of FDA's ``Approved Drug Products With Therapeutic 
Equivalence Evaluations'' (the list) as an approved drug. A drug 
product is deemed to be a listed drug on the date of approval for the 
NDA or ANDA for that drug product.
    NDA holder is the applicant that owns an approved NDA.
    Newly acquired information is data, analyses, or other information 
not previously submitted to the Agency, which may include (but is not 
limited to) data derived from new clinical studies, reports of adverse 
events, or new analyses of previously submitted data (e.g., meta-
analyses) if the studies, events, or analyses reveal risks of a 
different type or greater severity or frequency than previously 
included in submissions to FDA.
    Original application or original NDA is a pending NDA for which FDA 
has never issued a complete response letter or approval letter, or an 
NDA that was submitted again after FDA had refused to file it or after 
it was withdrawn without being approved.
    Paragraph IV acknowledgment letter is a written, postmarked 
communication from FDA to an applicant stating that the Agency has 
determined that a 505(b)(2) application or ANDA containing a paragraph 
IV certification is sufficiently complete to permit a substantive 
review. A paragraph IV acknowledgment letter indicates that the 
505(b)(2) application is regarded as filed or the ANDA is regarded as 
received.
    Paragraph IV certification is a patent certification of invalidity, 
unenforceability, or noninfringement described in Sec.  
314.50(i)(1)(i)(A)(4) or Sec.  314.94(a)(12)(i)(A)(4).
    Patent owner is the owner of the patent for which information is 
submitted for an NDA.
    Pharmaceutical alternatives are drug products that contain the 
identical therapeutic moiety, or its precursor, but not necessarily in 
the same amount or dosage form or as the same salt or ester. Each such 
drug product individually meets either the identical or its own 
respective compendial or other applicable standard of identity, 
strength, quality, and purity, including potency and, where applicable, 
content uniformity, disintegration times, and/or dissolution rates.
    Pharmaceutical equivalents are drug products in identical dosage 
forms and route(s) of administration that contain identical amounts of 
the identical active drug ingredient, i.e., the same salt or ester of 
the same therapeutic moiety, or, in the case of modified-release dosage 
forms that require a reservoir or overage or such forms as prefilled 
syringes where residual volume may vary, that deliver identical amounts 
of the active drug ingredient over the identical dosing period; do not 
necessarily contain the same inactive ingredients; and meet the 
identical compendial or other applicable standard of identity, 
strength, quality, and purity, including potency and, where applicable, 
content uniformity, disintegration times, and/or dissolution rates.
    Postmark is an independently verifiable evidentiary record of the 
date on which a document is transmitted, in an unmodifiable format, to 
another party. For postmarks made by the U.S. Postal Service or a 
designated delivery service, the date of transmission is the date on 
which the document is received by the domestic mail service of the U.S. 
Postal Service or by a designated delivery service. For postmarks 
documenting an electronic event, the date of transmission is the date 
(in a particular time zone) that FDA sends the electronic transmission 
on its host system as evidenced by a verifiable record. If the sender 
and the intended recipient are located in different time zones, it is 
the sender's time zone that provides the controlling date of electronic 
transmission.
    Reference listed drug is the listed drug identified by FDA as the 
drug product upon which an applicant relies in seeking approval of its 
ANDA.
    Reference standard is the drug product selected by FDA that an 
applicant seeking approval of an ANDA must use in conducting an in vivo 
bioequivalence study required for approval.
    Resubmission, in the context of a complete response letter, is 
submission by the applicant of all materials needed to fully address 
all deficiencies identified in the complete response letter. An NDA or 
ANDA for which FDA issued a complete response letter, but which was 
withdrawn before approval and later submitted again, is not a 
resubmission.
    Right of reference or use is the authority to rely upon, and 
otherwise use, an investigation for the purpose of obtaining approval 
of an NDA, including the ability to make available the underlying raw 
data from the investigation for FDA audit, if necessary.
    Same drug product formulation is the formulation of the drug 
product submitted for approval and any formulations that have minor 
differences in composition or method of manufacture from the 
formulation submitted for approval, but are similar enough to be 
relevant to the Agency's determination of bioequivalence.
    Specification is the quality standard (i.e., tests, analytical 
procedures, and acceptance criteria) provided in an approved NDA or 
ANDA to confirm the quality of drug substances, drug products, 
intermediates, raw materials, reagents, components, in-process 
materials, container closure systems, and other materials used in the 
production of a drug substance or drug product. For the purpose of this 
definition, acceptance criteria means numerical limits, ranges, or 
other criteria for the tests described.
    Strength is the amount of drug substance contained in, delivered, 
or deliverable from a drug product, which includes:
    (1)(i) The total quantity of drug substance in mass or units of 
activity in a dosage unit or container closure (e.g., weight/unit dose, 
weight/volume or weight/weight in a container closure, or units/volume 
or units/weight in a container closure); and/or, as applicable.
    (ii) The concentration of the drug substance in mass or units of 
activity per unit volume or mass (e.g., weight/weight, weight/volume, 
or units/volume); or
    (2) Such other criteria the Agency establishes for determining the 
amount of drug substance contained in, delivered, or deliverable from a 
drug product if the weights and measures described in paragraph (i) of 
this definition do not apply (e.g., certain drug-device combination 
products for

[[Page 69639]]

which the amount of drug substance is emitted per use or unit time).
    Substantially complete application is an ANDA that on its face is 
sufficiently complete to permit a substantive review. Sufficiently 
complete means that the ANDA contains all the information required 
under section 505(j)(2)(A) of the Federal Food, Drug, and Cosmetic Act 
and does not contain a deficiency described in Sec.  314.101(d) and 
(e).
    Tentative approval is notification that an NDA or ANDA otherwise 
meets the requirements for approval under the Federal Food, Drug, and 
Cosmetic Act, but cannot be approved because there is a 7-year period 
of orphan exclusivity for a listed drug under section 527 of the 
Federal Food, Drug, and Cosmetic Act and Sec.  316.31 of this chapter, 
or that a 505(b)(2) application or ANDA otherwise meets the 
requirements for approval under the Federal Food, Drug, and Cosmetic 
Act, but cannot be approved until the conditions in Sec.  
314.107(b)(1)(iii), (b)(3), or (c) are met; because there is a period 
of exclusivity for the listed drug under Sec.  314.108; because there 
is a period of pediatric exclusivity for the listed drug under section 
505A of the Federal Food, Drug, and Cosmetic Act; because there is a 
period of exclusivity for the listed drug under section 505E of the 
Federal Food, Drug, and Cosmetic Act; or because a court order pursuant 
to 35 U.S.C. 271(e)(4)(A) orders that the NDA or ANDA may be approved 
no earlier than the date specified. A drug product that is granted 
tentative approval is not an approved drug and will not be approved 
until FDA issues an approval letter after any necessary additional 
review of the NDA or ANDA.
    The list is the list of approved drug products published in FDA's 
current ``Approved Drug Products With Therapeutic Equivalence 
Evaluations,'' available electronically on FDA's Web site at https://www.fda.gov/cder.
    Therapeutic equivalents are approved drug products that are 
pharmaceutical equivalents for which bioequivalence has been 
demonstrated, and that can be expected to have the same clinical effect 
and safety profile when administered to patients under the conditions 
specified in the labeling.

0
3. Amend Sec.  314.50 as follows:
0
a. Remove the word ``shall'' and add in its place the word ``must'' 
wherever it appears in paragraphs (a) introductory text, (a)(5), 
(d)(1)(v), (d)(5)(v), (d)(5)(vi)(a) and (b), (e)(2) introductory text, 
(f)(3), (g)(2), and (k);
0
b. Remove the word ``application'' and add in its place ``NDA'' 
wherever it appears in paragraphs (a)(5), (b), (c)(1), (c)(2)(i), 
(c)(2)(iv) through (viii), (d) introductory text, (d)(1)(i), 
(d)(1)(ii)(a), (d)(1)(iii) through (v), (d)(3)(ii), (d)(5)(iv), 
(d)(5)(vi)(b), (e)(1)(i) introductory text, (e)(2) introductory text, 
(f) introductory text, (f)(1) through (3), (g)(2), (h), (j)(4) 
introductory text, (j)(4)(i) and (ii), (k), (l) heading, (l)(1) 
introductory text, and (l)(4);
0
c. Remove the word ``act'' and add in its place ``Federal Food, Drug, 
and Cosmetic Act'' in paragraphs (d) introductory text, (d)(5)(vi)(b), 
and (j)(3);
0
d. Remove the phrase ``Prior to the submission of'' and add in its 
place the words ``Before submitting'' and remove the phrase ``are 
required to'' and add in its place the word ``must'' wherever it 
appears in paragraph (d)(5)(vi)(b);
0
e. Remove the word ``shall'' and add in its place the word ``must'' and 
remove the phrase ``new drug application'' and add in its place ``NDA'' 
in paragraph (j) introductory text; and
0
f. Revise the section heading, introductory text, and paragraphs 
(a)(1), (e)(1) introductory text, (f)(4), (g)(3), (i), the first two 
sentences of paragraph (j)(4)(iii), and (l)(2) and (3).
    The revisions read as follows:


Sec.  314.50  Content and format of an NDA.

    NDAs and supplements to approved NDAs are required to be submitted 
in the form and contain the information, as appropriate for the 
particular submission, required under this section. Three copies of the 
NDA are required: An archival copy, a review copy, and a field copy. An 
NDA for a new chemical entity will generally contain an application 
form, an index, a summary, five or six technical sections, case report 
tabulations of patient data, case report forms, drug samples, and 
labeling, including, if applicable, any Medication Guide required under 
part 208 of this chapter. Other NDAs will generally contain only some 
of those items, and information will be limited to that needed to 
support the particular submission. These include an NDA of the type 
described in section 505(b)(2) of the Federal Food, Drug, and Cosmetic 
Act, an amendment, and a supplement. The NDA is required to contain 
reports of all investigations of the drug product sponsored by the 
applicant, and all other information about the drug pertinent to an 
evaluation of the NDA that is received or otherwise obtained by the 
applicant from any source. FDA will maintain guidance documents on the 
format and content of NDAs to assist applicants in their preparation.
    (a) * * *
    (1) The name and address of the applicant; the date of the NDA; the 
NDA number if previously issued (for example, if the NDA is a 
resubmission or an amendment or supplement); the name of the drug 
product, including its established, proprietary, code, and chemical 
names; the dosage form and strength; the route of administration; the 
identification numbers of all INDs (as defined in Sec.  312.3(b) of 
this chapter) that are referenced in the NDA; the identification 
numbers of all drug master files and other applications under this part 
that are referenced in the NDA; and the drug product's proposed 
indications for use.
* * * * *
    (e) * * * (1) Upon request from FDA, the applicant must submit the 
samples described below to the places identified in the Agency's 
request. FDA generally will ask applicants to submit samples directly 
to two or more Agency laboratories that will perform all necessary 
tests on the samples and validate the applicant's analytical 
procedures.
* * * * *
    (f) * * *
    (4) Presentation and format. Applicants are invited to meet with 
FDA before submitting an NDA to discuss the presentation and format of 
supporting information. If the applicant and FDA agree, the applicant 
may submit tabulations of patient data and case report forms in an 
alternate form.
    (g) * * *
    (3) If an applicant who submits an NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act obtains a ``right of reference or 
use,'' as defined under Sec.  314.3(b), to an investigation described 
in clause (A) of section 505(b)(1) of the Federal Food, Drug, and 
Cosmetic Act, the applicant must include in its NDA a written statement 
signed by the owner of the data from each such investigation that the 
applicant may rely on in support of the approval of its NDA, and 
provide FDA access to, the underlying raw data that provide the basis 
for the report of the investigation submitted in its NDA.
* * * * *
    (i) Patent certification--(1) Contents. A 505(b)(2) application is 
required to contain the following:
    (i) Patents claiming drug substance, drug product, or method of 
use. (A) An appropriate patent certification or statement with respect 
to each patent issued by the U.S. Patent and Trademark Office that, in 
the opinion of the applicant and to the best of its knowledge, claims 
the drug substance or drug product on which investigations that are 
relied upon by the applicant for approval of its 505(b)(2) application

[[Page 69640]]

were conducted or that claims an approved use for such drug and for 
which information is required to be filed under section 505(b) and (c) 
of the Federal Food, Drug, and Cosmetic Act and Sec.  314.53. For each 
such patent, the applicant must provide the patent number and certify, 
in its opinion and to the best of its knowledge, one of the following 
circumstances:
    (1) That the patent information has not been submitted to FDA. The 
applicant must entitle such a certification ``Paragraph I 
Certification'';
    (2) That the patent has expired. The applicant must entitle such a 
certification ``Paragraph II Certification'';
    (3) The date on which the patent will expire. The applicant must 
entitle such a certification ``Paragraph III Certification''; or
    (4)(i) That the patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for 
which the 505(b)(2) application is submitted. The applicant must 
entitle such a certification ``Paragraph IV Certification''. This 
certification must be submitted in the following form:

    I, (name of applicant), certify that Patent No. ____ (is 
invalid, unenforceable, or will not be infringed by the manufacture, 
use, or sale of) (name of proposed drug product) for which this 
505(b)(2) application is submitted.

    (ii) The certification must be accompanied by a statement that the 
applicant will comply with the requirements under Sec.  314.52(a) with 
respect to providing a notice to each owner of the patent or its 
representative and to the NDA holder (or, if the NDA holder does not 
reside or maintain a place of business within the United States, its 
attorney, agent, or other authorized official) for the drug product 
that is claimed by the patent or a use of which is claimed by the 
patent and with the requirements under Sec.  314.52(b) with respect to 
sending the notice and under Sec.  314.52(c) with respect to the 
content of the notice.
    (B) If the drug on which investigations that are relied upon by the 
applicant were conducted is itself a licensed generic drug of a 
patented drug first approved under section 505(b) of the Federal Food, 
Drug, and Cosmetic Act, an appropriate patent certification or 
statement under this section with respect to each patent that claims 
the first-approved patented drug or that claims an approved use for 
such a drug.
    (C) If, before the date of submission of an original 505(b)(2) 
application, there is a drug product approved in an NDA that is 
pharmaceutically equivalent to the drug product for which the original 
505(b)(2) application is submitted, an appropriate patent certification 
or statement under this section with respect to each patent that claims 
the drug substance or drug product or that claims an approved use for 
one such drug product.
    (ii) No relevant patents. If, in the opinion of the applicant and 
to the best of its knowledge, there are no patents described in 
paragraph (i)(1)(i) of this section, a certification in the following 
form:

    In the opinion and to the best knowledge of (name of applicant), 
there are no patents that claim the drug or drugs on which 
investigations that are relied upon in this 505(b)(2) application 
were conducted or that claim a use of such drug or drugs.

    (iii) Method-of-use patent. (A) If information that is submitted 
under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act 
and Sec.  314.53 is for a method-of-use patent, and the labeling for 
the drug product for which the applicant is seeking approval does not 
include an indication or other condition of use that is covered by the 
method-of-use patent, a statement explaining that the method-of-use 
patent does not claim a proposed indication or other condition of use.
    (B) If the labeling of the drug product for which the applicant is 
seeking approval includes an indication or other condition of use that, 
according to the patent information submitted under section 505(b) or 
(c) of the Federal Food, Drug, and Cosmetic Act and Sec.  314.53 or in 
the opinion of the applicant, is claimed by a method-of-use patent, the 
applicant must submit an applicable certification under paragraph 
(i)(1)(i) of this section.
    (2) [Reserved]
    (3) Licensing agreements. If a 505(b)(2) application is submitted 
for a drug or method of using a drug claimed by a patent and the 
applicant has a licensing agreement with the patent owner, the 
applicant must submit a paragraph IV certification as to that patent 
and a statement that the applicant has been granted a patent license. 
If the patent owner consents to approval of the 505(b)(2) application 
(if otherwise eligible for approval) as of a specific date, the 
505(b)(2) application must contain a written statement from the patent 
owner that it has a licensing agreement with the applicant and that it 
consents to approval of the 505(b)(2) application as of a specific 
date.
    (4) Untimely filing of patent information. (i) If a patent 
described in paragraph (i)(1)(i)(A) of this section is issued and the 
holder of the approved NDA for the patented drug does not file with FDA 
the required information on the patent within 30 days of issuance of 
the patent, an applicant who submitted a 505(b)(2) application that, 
before the submission of the patent information, contained an 
appropriate patent certification or statement is not required to submit 
a patent certification or statement to address the patent or patent 
information that is late-listed with respect to the pending 505(b)(2) 
application. Except as provided in Sec.  314.53(f)(1), an NDA holder's 
amendment to the description of the approved method(s) of use claimed 
by the patent will be considered untimely filing of patent information 
unless:
    (A) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of patent 
issuance;
    (B) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of approval of a 
corresponding change to product labeling; or
    (C) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of a decision by 
the U.S. Patent and Trademark Office or by a Federal district court, 
the Court of Appeals for the Federal Circuit, or the U.S. Supreme Court 
that is specific to the patent and alters the construction of a method-
of-use claim(s) of the patent, and the amendment contains a copy of the 
decision.
    (ii) An applicant whose 505(b)(2) application is submitted after 
the NDA holder's untimely filing of patent information or whose 
505(b)(2) application was previously filed but did not contain an 
appropriate patent certification or statement at the time of the patent 
submission must submit a certification under paragraph (i)(1)(i) of 
this section and/or a statement under paragraph (i)(1)(iii) of this 
section as to that patent.
    (5) Disputed patent information. If an applicant disputes the 
accuracy or relevance of patent information submitted to FDA, the 
applicant may seek a confirmation of the correctness of the patent 
information in accordance with the procedures under Sec.  314.53(f). 
Unless the patent information is withdrawn, the applicant must submit 
an appropriate certification or statement for each listed patent.
    (6) Amended certifications. A patent certification or statement 
submitted under paragraphs (i)(1)(i) through (iii) of this section may 
be amended at any time before the approval of the 505(b)(2) 
application. An applicant must submit

[[Page 69641]]

an amended certification as an amendment to a pending 505(b)(2) 
application. If an applicant with a pending 505(b)(2) application 
voluntarily makes a patent certification for an untimely filed patent, 
the applicant may withdraw the patent certification for the untimely 
filed patent. Once an amendment is submitted to change the 
certification, the 505(b)(2) application will no longer be considered 
to contain the prior certification.
    (i) After finding of infringement. An applicant who has submitted a 
paragraph IV certification and is sued for patent infringement must 
submit an amendment to change its certification if a court enters a 
final decision from which no appeal has been or can be taken, or signs 
and enters a settlement order or consent decree in the action that 
includes a finding that the patent is infringed, unless the final 
decision, settlement order, or consent decree also finds the patent to 
be invalid. In its amendment, the applicant must certify under 
paragraph (i)(1)(i)(A)(3) of this section that the patent will expire 
on a specific date or, with respect to a patent claiming a method of 
use, the applicant may instead provide a statement under paragraph 
(i)(1)(iii) of this section if the applicant amends its 505(b)(2) 
application such that the applicant is no longer seeking approval for a 
method of use claimed by the patent. Once an amendment for the change 
has been submitted, the 505(b)(2) application will no longer be 
considered to contain a paragraph IV certification to the patent. If a 
final decision finds the patent to be invalid and infringed, an amended 
certification is not required.
    (ii) After request to remove a patent or patent information from 
the list. If the list reflects that an NDA holder has requested that a 
patent or patent information be removed from the list and no ANDA 
applicant is eligible for 180-day exclusivity based on a paragraph IV 
certification to that patent, the patent or patent information will be 
removed and any applicant with a pending 505(b)(2) application 
(including a tentatively approved 505(b)(2) application) who has made a 
certification with respect to such patent must submit an amendment to 
withdraw its certification. In the amendment, the applicant must state 
the reason for withdrawing the certification or statement (that the 
patent has been removed from the list). If the list reflects that an 
NDA holder has requested that a patent or patent information be removed 
from the list and one or more first applicants are eligible for 180-day 
exclusivity based on a paragraph IV certification to that patent, the 
patent will remain listed until any 180-day exclusivity based on that 
patent has expired or has been extinguished. A 505(b)(2) applicant is 
not required to provide or maintain a certification to a patent or 
patent information that remains listed only for purposes of a first 
applicant's 180-day exclusivity for its ANDA. Once an amendment to 
withdraw the certification has been submitted, the 505(b)(2) 
application will no longer be considered to contain a paragraph IV 
certification to the patent. If removal of a patent from the list 
results in there being no patents listed for the listed drug(s) 
identified in the 505(b)(2) application, the applicant must submit an 
amended certification reflecting that there are no listed patents.
    (iii) Other amendments. (A) Except as provided in paragraphs (i)(4) 
and (i)(6)(iii)(B) of this section:
    (1) An applicant must amend a submitted certification or statement 
if, at any time before the approval of the 505(b)(2) application, the 
applicant learns that the submitted certification or statement is no 
longer accurate; and
    (2) An applicant must submit an appropriate patent certification or 
statement under paragraph (i)(1) of this section if, after submission 
of the 505(b)(2) application, a new patent is issued by the U.S. Patent 
and Trademark Office that, in the opinion of the applicant and to the 
best of its knowledge, claims a listed drug relied upon or that claims 
an approved use for such listed drug for which information is required 
to be filed under section 505(b) and (c) of the Federal Food, Drug, and 
Cosmetic Act and Sec.  314.53.
    (B) An applicant is not required to submit a supplement to change a 
submitted certification when information on an otherwise applicable 
patent is submitted after the approval of the 505(b)(2) application.
    (j) * * *
    (4) * * *
    (iii) * * * If the applicant was the sponsor named in the Form FDA 
1571 for an IND under which the new clinical investigation(s) that is 
essential to the approval of its NDA was conducted, identification of 
the IND by number. If the applicant was not the sponsor of the IND 
under which the clinical investigation(s) was conducted, a 
certification that the applicant or its predecessor in interest 
provided substantial support for the clinical investigation(s) that is 
essential to the approval of its NDA, and information supporting the 
certification. * * *
* * * * *
    (l) * * *
    (2) Review copy. The applicant must submit a review copy of the 
NDA. Each of the technical sections, described in paragraphs (d)(1) 
through (6) of this section, in the review copy is required to be 
separately bound with a copy of the application form required under 
paragraph (a) of this section and a copy of the summary required under 
paragraph (c) of this section.
    (3) Field copy. The applicant must submit a field copy of the NDA 
that contains the technical section described in paragraph (d)(1) of 
this section, a copy of the application form required under paragraph 
(a) of this section, a copy of the summary required under paragraph (c) 
of this section, and a certification that the field copy is a true copy 
of the technical section described in paragraph (d)(1) of this section 
contained in the archival and review copies of the NDA.
* * * * *

0
4. Section 314.52 is revised to read as follows:


Sec.  314.52  Notice of certification of invalidity, unenforceability, 
or noninfringement of a patent.

    (a) Notice of certification. For each patent that claims the listed 
drug or drugs relied upon or that claims a use for such listed drug or 
drugs and for which the 505(b)(2) applicant submits a paragraph IV 
certification, the applicant must send notice of such certification by 
registered or certified mail, return receipt requested, or by a 
designated delivery service, as defined in paragraph (g) of this 
section, to each of the following persons:
    (1) Each owner of the patent that is the subject of the 
certification or the representative designated by the owner to receive 
the notice. The name and address of the patent owner or its 
representative may be obtained from the U.S. Patent and Trademark 
Office; and
    (2) The holder of the approved NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act for each drug product which is 
claimed by the patent or a use of which is claimed by the patent and 
for which the applicant is seeking approval, or, if the NDA holder does 
not reside or maintain a place of business within the United States, 
the NDA holder's attorney, agent, or other authorized official. The 
name and address of the NDA holder or its attorney, agent, or 
authorized official may be obtained by sending a written or electronic 
communication to the Orange Book Staff, Office of Generic Drugs, 7620 
Standish Pl., Rockville, MD 20855, or to the Orange Book Staff at the 
email

[[Page 69642]]

address listed on the Agency's Web site at https://www.fda.gov.
    (3) This paragraph (a) does not apply to a method-of-use patent 
that does not claim a use for which the applicant is seeking approval.
    (4) An applicant may send notice by an alternative method only if 
FDA has agreed in advance that the method will produce an acceptable 
form of documentation.
    (b) Sending the notice. (1) Except as provided under paragraph (d) 
of this section, the applicant must send the notice required by 
paragraph (a) of this section on or after the date of filing described 
in Sec.  314.101(a)(2) or (3), as applicable, but not later than 20 
days after the date of the postmark on the paragraph IV acknowledgment 
letter. The 20-day clock described in this paragraph (b) begins on the 
day after the date of the postmark on the paragraph IV acknowledgment 
letter. When the 20th day falls on Saturday, Sunday, or a Federal 
holiday, the 20th day will be the next day that is not a Saturday, 
Sunday, or Federal holiday.
    (2) Any notice required by paragraph (a) of this section is invalid 
if it is sent before the date of filing described in Sec.  
314.101(a)(2) or, if FDA notifies the applicant that FDA has refused to 
file the 505(b)(2) application, before the date described in Sec.  
314.101(a)(3) on which the 505(b)(2) application is filed. The 
applicant will not have complied with this paragraph (b) until it sends 
valid notice.
    (3) The applicant must submit to FDA an amendment to its 505(b)(2) 
application that includes a statement certifying that the notice has 
been provided to each person identified under paragraph (a) of this 
section and that the notice met the content requirement under paragraph 
(c) of this section. A copy of the notice itself need not be submitted 
to the Agency.
    (c) Content of a notice. In the notice, the applicant must cite 
section 505(b)(3)(D) of the Federal Food, Drug, and Cosmetic Act and 
the notice must include, but is not limited to, the following 
information:
    (1) A statement that a 505(b)(2) application that contains any 
required bioavailability or bioequivalence studies has been submitted 
by the applicant and filed by FDA.
    (2) The NDA number.
    (3) The established name, if any, as defined in section 502(e)(3) 
of the Federal Food, Drug, and Cosmetic Act, of the proposed drug 
product.
    (4) The active ingredient, strength, and dosage form of the 
proposed drug product.
    (5) The patent number and expiration date of each patent on the 
list alleged to be invalid, unenforceable, or not infringed.
    (6) A detailed statement of the factual and legal basis of the 
applicant's opinion that the patent is not valid, unenforceable, or 
will not be infringed. The applicant must include in the detailed 
statement:
    (i) For each claim of a patent alleged not to be infringed, a full 
and detailed explanation of why the claim is not infringed.
    (ii) For each claim of a patent alleged to be invalid or 
unenforceable, a full and detailed explanation of the grounds 
supporting the allegation.
    (7) If the applicant alleges that the patent will not be infringed 
and the applicant seeks to preserve the option to later file a civil 
action for declaratory judgment in accordance with section 505(c)(3)(D) 
of the Federal Food, Drug, and Cosmetic Act, then the notice must be 
accompanied by an offer of confidential access to the 505(b)(2) 
application for the sole and limited purpose of evaluating possible 
infringement of the patent that is the subject of the paragraph IV 
certification.
    (8) If the applicant does not reside or have a place of business in 
the United States, the name and address of an agent in the United 
States authorized to accept service of process for the applicant.
    (d) Amendment or supplement to a 505(b)(2) application. (1) If, 
after the date of filing described in Sec.  314.101(a)(2) or (3), as 
applicable, an applicant submits an amendment or supplement to its 
505(b)(2) application that includes a paragraph IV certification, the 
applicant must send the notice required by paragraph (a) of this 
section at the same time that the amendment or supplement to the 
505(b)(2) application is submitted to FDA, regardless of whether the 
applicant has already given notice with respect to another such 
certification contained in the 505(b)(2) application or in an amendment 
or supplement to the 505(b)(2) application.
    (2) If, before the date of filing described in Sec.  314.101(a)(2) 
or (3), as applicable, an applicant submits a paragraph IV 
certification in an amendment, the applicant must send the notice 
required by paragraph (a) of this section in accordance with the 
procedures in paragraph (b) of this section.
    (3) An applicant that submits an amendment or supplement to seek 
approval of a different strength must provide notice of any paragraph 
IV certification in accordance with paragraph (d)(1) or (2) of this 
section, as applicable.
    (e) Documentation of timely sending and receipt of notice. The 
applicant must amend its 505(b)(2) application to provide documentation 
of the date of receipt of the notice required under paragraph (a) of 
this section by each person provided the notice. The amendment must be 
submitted to FDA within 30 days after the last date on which notice was 
received by a person described in paragraph (a) of this section. The 
applicant's amendment also must include documentation that its notice 
was sent on a date that complies with the timeframe required by 
paragraph (b) or (d) of this section, as applicable. FDA will accept, 
as adequate documentation of the date the notice was sent, a copy of 
the registered mail receipt, certified mail receipt, or receipt from a 
designated delivery service, as defined in paragraph (g) of this 
section. FDA will accept as adequate documentation of the date of 
receipt a return receipt, a signature proof of delivery by a designated 
delivery service, or a letter acknowledging receipt by the person 
provided the notice. An applicant may rely on another form of 
documentation only if FDA has agreed to such documentation in advance. 
A copy of the notice itself need not be submitted to the Agency.
    (f) Forty-five day period after receipt of notice. If the 
requirements of this section are met, the Agency will presume the 
notice to be complete and sufficient and will count the day following 
the date of receipt of the notice by the patent owner or its 
representative and by the approved NDA holder or its attorney, agent, 
or other authorized official as the first day of the 45-day period 
provided for in section 505(c)(3)(C) of the Federal Food, Drug, and 
Cosmetic Act. FDA may, if the applicant amends its 505(b)(2) 
application with a written statement that a later date should be used, 
count from such later date.
    (g) Designated delivery services. (1) For purposes of this section, 
the term ``designated delivery service'' is any delivery service 
provided by a trade or business that the Agency determines:
    (i) Is available to the general public throughout the United 
States;
    (ii) Records electronically to its database, kept in the regular 
course of its business, or marks on the cover in which any item 
referred to in this section is to be delivered, the date on which such 
item was given to such trade or business for delivery; and

[[Page 69643]]

    (iii) Provides overnight or 2-day delivery service throughout the 
United States.
    (2) FDA may periodically issue guidance regarding designated 
delivery services.

0
5. Section 314.53 is revised to read as follows:


Sec.  314.53  Submission of patent information.

    (a) Who must submit patent information. This section applies to any 
applicant who submits to FDA an NDA or an amendment to it under section 
505(b) of the Federal Food, Drug, and Cosmetic Act and Sec.  314.50 or 
a supplement to an approved NDA under Sec.  314.70, except as provided 
in paragraph (d)(2) of this section.
    (b) Patents for which information must be submitted and patents for 
which information must not be submitted--(1) General requirements. An 
applicant described in paragraph (a) of this section must submit to its 
NDA the required information, on the required FDA declaration form, set 
forth in paragraph (c) of this section for each patent that claims the 
drug or a method of using the drug that is the subject of the NDA or 
amendment or supplement to it and with respect to which a claim of 
patent infringement could reasonably be asserted if a person not 
licensed by the owner of the patent engaged in the manufacture, use, or 
sale of the drug product. For purposes of this part, such patents 
consist of drug substance (active ingredient) patents, drug product 
(formulation and composition) patents, and method-of-use patents. For 
patents that claim the drug substance, the applicant must submit 
information only on those patents that claim the drug substance that is 
the subject of the pending or approved NDA or that claim a drug 
substance that is the same as the active ingredient that is the subject 
of the approved or pending NDA. For patents that claim only a polymorph 
that is the same as the active ingredient described in the approved or 
pending NDA, the applicant must certify in the required FDA declaration 
form that the applicant has test data, as set forth in paragraph (b)(2) 
of this section, demonstrating that a drug product containing the 
polymorph will perform the same as the drug product described in the 
NDA. For patents that claim a drug product, the applicant must submit 
information only on those patents that claim the drug product, as is 
defined in Sec.  314.3, that is described in the pending or approved 
NDA. For patents that claim a method of use, the applicant must submit 
information only on those patents that claim indications or other 
conditions of use for which approval is sought or has been granted in 
the NDA. The applicant must separately identify each pending or 
approved method of use and related patent claim(s). For approved NDAs, 
the NDA holder's description of the patented method of use required by 
paragraph (c)(2)(ii)(P)(3) of this section must describe only the 
approved method(s) of use claimed by the patent for which a claim of 
patent infringement could reasonably be asserted if a person not 
licensed by the owner of the patent engaged in the manufacture, use, or 
sale of the drug product. If the method(s) of use claimed by the patent 
does not cover an indication or other approved condition of use in its 
entirety, the applicant must describe only the specific approved method 
of use claimed by the patent for which a claim of patent infringement 
could reasonably be asserted if a person not licensed by the owner of 
the patent engaged in the manufacture, use, or sale of the drug 
product. For approved NDAs, the NDA holder submitting information on 
the method-of-use patent must identify with specificity the section(s) 
and subsection(s) of the approved labeling that describes the method(s) 
of use claimed by the patent submitted. Process patents, patents 
claiming packaging, patents claiming metabolites, and patents claiming 
intermediates are not covered by this section, and information on these 
patents must not be submitted to FDA.
    (2) Test data for submission of patent information for patents that 
claim only a polymorph. The test data, referenced in paragraph (b)(1) 
of this section, must include the following:
    (i) A full description of the polymorphic form of the drug 
substance, including its physical and chemical characteristics and 
stability; the method of synthesis (or isolation) and purification of 
the drug substance; the process controls used during manufacture and 
packaging; and such specifications and analytical methods as are 
necessary to assure the identity, strength, quality, and purity of the 
polymorphic form of the drug substance;
    (ii) The executed batch record for a drug product containing the 
polymorphic form of the drug substance and documentation that the batch 
was manufactured under current good manufacturing practice 
requirements;
    (iii) Demonstration of bioequivalence between the executed batch of 
the drug product that contains the polymorphic form of the drug 
substance and the drug product as described in the NDA;
    (iv) A list of all components used in the manufacture of the drug 
product containing the polymorphic form and a statement of the 
composition of the drug product; a statement of the specifications and 
analytical methods for each component; a description of the 
manufacturing and packaging procedures and in-process controls for the 
drug product; such specifications and analytical methods as are 
necessary to assure the identity, strength, quality, purity, and 
bioavailability of the drug product, including release and stability 
data complying with the approved product specifications to demonstrate 
pharmaceutical equivalence and comparable product stability; and
    (v) Comparative in vitro dissolution testing on 12 dosage units 
each of the executed test batch and the NDA product.
    (c) Reporting requirements--(1) General requirements. An applicant 
described in paragraph (a) of this section must submit the required 
patent information described in paragraph (c)(2) of this section for 
each patent that meets the requirements described in paragraph (b) of 
this section. We will not accept the patent information unless it is 
submitted on the appropriate form, Form FDA 3542 or 3542a, and contains 
the information required in paragraph (c)(2) of this section. These 
forms may be obtained on the Internet at https://www.fda.gov by 
searching for ``forms''.
    (2) Drug substance (active ingredient), drug product (formulation 
or composition), and method-of-use patents--(i) Original declaration. 
For each patent that claims a drug substance (active ingredient), drug 
product (formulation and composition), or method of use, the applicant 
must submit Form FDA 3542a. The following information and verification 
is required, subject to the exceptions listed in paragraph (c)(2)(i)(S) 
of this section:
    (A) NDA number;
    (B) The NDA applicant's name, full address, phone number and, if 
available, fax number and email address;
    (C) Trade name (or proposed trade name) of new drug;
    (D) Active ingredient(s) of new drug;
    (E) Strength(s) of new drug;
    (F) Dosage form(s) and route(s) of administration of new drug, and 
whether the applicant proposes to market the new drug for prescription 
use or over-the-counter use;
    (G) U.S. patent number, issue date, and expiration date of patent 
submitted;
    (H) The patent owner's name, full address, phone number and, if 
available, fax number and email address;
    (I) The name, full address, phone number and, if available, fax 
number and email address of an agent or representative who resides or 
maintains a place of business within the United

[[Page 69644]]

States authorized to receive notice of patent certification under 
section 505(b)(3) and (j)(2)(B) of the Federal Food, Drug, and Cosmetic 
Act and Sec. Sec.  314.52 and 314.95 (if patent owner or NDA applicant 
or holder does not reside or have a place of business within the United 
States);
    (J) Information on whether the patent has been submitted previously 
for the NDA or supplement;
    (K) If the patent has been submitted previously for listing, 
identify all change(s) from the previously submitted patent information 
and specify whether the change is related to the patent or related to 
an FDA action or procedure;
    (L) Information on whether the patent is a product-by-process 
patent in which the product claimed is novel;
    (M) Information on the drug substance (active ingredient) patent, 
including the following:
    (1) Whether the patent claims a drug substance that is an active 
ingredient in the drug product described in the NDA or supplement;
    (2) Whether the patent claims only a polymorph that is the same 
active ingredient that is described in the pending NDA or supplement;
    (3) Whether the applicant has test data, described in paragraph 
(b)(2) of this section, demonstrating that a drug product containing 
only the polymorph will perform the same as the drug product described 
in the NDA or supplement, and a description of the polymorphic form(s) 
claimed by the patent for which such test data exist;
    (4) Whether the patent claims only a metabolite of the active 
ingredient; and
    (5) Whether the patent claims only an intermediate;
    (N) Information on the drug product (composition/formulation) 
patent, including the following:
    (1) Whether the patent claims the drug product for which approval 
is being sought, as defined in Sec.  314.3; and
    (2) Whether the patent claims only an intermediate;
    (O) Information on each method-of-use patent, including the 
following:
    (1) Whether the patent claims one or more methods of using the drug 
product for which approval is being sought and a description of each 
pending method of use and related patent claim of the patent being 
submitted;
    (2) Identification of the specific section(s) and subsection(s) of 
the proposed labeling for the drug product that describes the method of 
use claimed by the patent submitted; and
    (3) An applicant that submits information for a patent that claims 
one or more methods of using the drug product must also submit 
information described in either paragraph (c)(2)(i)(M) or (N) of this 
section, regarding whether that patent also claims either the drug 
substance (active ingredient) or the drug product (composition/
formulation).
    (P) Whether there are no relevant patents that claim the drug 
substance (active ingredient), drug product (formulation or 
composition), or method(s) of use, for which the applicant is seeking 
approval and with respect to which a claim of patent infringement could 
reasonably be asserted if a person not licensed by the owner of the 
patent engaged in the manufacture, use, or sale of the drug product;
    (Q) A signed verification that states:

    The undersigned declares that this is an accurate and complete 
submission of patent information for the NDA, amendment, or 
supplement pending under section 505 of the Federal Food, Drug, and 
Cosmetic Act. This time-sensitive patent information is submitted 
pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR 
314.53 and this submission complies with the requirements of the 
regulation. I verify under penalty of perjury that the foregoing is 
true and correct.

    (R) Information on whether the applicant, patent owner or attorney, 
agent, representative, or other authorized official signed the form; 
the name of the person; and the full address, phone number and, if 
available, the fax number and email address; and
    (S) Exceptions to required submission of patent information:
    (1) If an applicant submits the information described in paragraph 
(c)(2)(i)(M) of this section for a patent that claims the drug 
substance (active ingredient) and meets the requirements for listing on 
that basis, then the applicant is not required to provide the 
information described in paragraph (c)(2)(i)(N) of this section on 
whether that patent also claims the drug product (composition/
formulation);
    (2) If an applicant submits the information described in paragraph 
(c)(2)(i)(N) of this section for a patent that claims the drug product 
(composition/formulation) and meets the requirements for listing on 
that basis, then the applicant is not required to provide the 
information described in paragraph (c)(2)(i)(M) of this section on 
whether that patent also claims the drug substance (active ingredient);
    (3) If the applicant submits a supplement for a change other than 
one of the changes listed under paragraph (d)(2)(i) of this section, 
then the patent information submission requirements of paragraph 
(d)(2)(ii) of this section apply.
    (ii) Submission of patent information upon and after approval. 
Within 30 days after the date of approval of its NDA or supplement, the 
applicant must submit Form FDA 3542 for each patent that claims the 
drug substance (active ingredient), drug product (formulation and 
composition), or approved method of use. FDA will not list or publish 
patent information if it is not provided on this form or if the patent 
declaration does not contain the required information or indicates the 
patent is not eligible for listing. Patent information must also be 
submitted for patents issued after the date of approval of the NDA as 
required in paragraph (c)(2)(ii) of this section. As described in 
paragraph (d)(3) of this section, to be timely filed, patent 
information for patents issued after the date of approval of the NDA 
must be submitted to FDA within 30 days of the date of issuance of the 
patent. If the applicant submits the required patent information within 
the 30 days, but we notify an applicant that a declaration form is 
incomplete or shows that the patent is not eligible for listing, the 
applicant must submit an acceptable declaration form within 15 days of 
FDA notification to be considered timely filed. The following 
information and verification statement is required, subject to the 
exceptions listed in paragraph (c)(2)(ii)(T) of this section:
    (A) NDA number;
    (B) The NDA holder's name, full address, phone number and, if 
available, fax number and email address;
    (C) Trade name of new drug;
    (D) Active ingredient(s) of new drug;
    (E) Strength(s) of new drug;
    (F) Dosage form(s) and route(s) of administration of new drug, and 
whether the new drug is approved for prescription use or over-the-
counter use;
    (G) Approval date of NDA or supplement;
    (H) U.S. patent number, issue date, and expiration date of patent 
submitted;
    (I) The patent owner's name, full address, phone number and, if 
available, fax number and email address;
    (J) The name, full address, phone number and, if available, fax 
number and email address of an agent or representative who resides or 
maintains a place of business within the United States authorized to 
receive notice of patent certification under section 505(b)(3) and 
(j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and Sec. Sec.  
314.52 and 314.95 (if patent owner or NDA applicant or holder does not 
reside or have a place of business within the United States);

[[Page 69645]]

    (K) Information on whether the patent has been submitted previously 
for the NDA or supplement;
    (L) If the patent has been submitted previously for listing, 
identify all change(s) from the previously submitted patent information 
and specify whether the change is related to the patent or related to 
an FDA action or procedure;
    (M) Information on whether the patent is a product-by-process 
patent in which the product claimed is novel;
    (N) Information on the drug substance (active ingredient) patent, 
including the following:
    (1) Whether the patent claims a drug substance that is an active 
ingredient in the drug product described in the approved NDA;
    (2) Whether the patent claims only a polymorph that is the same as 
the active ingredient that is described in the approved NDA;
    (3) Whether the applicant has test data, described in paragraph 
(b)(2) of this section, demonstrating that a drug product containing 
only the polymorph will perform the same as the drug product described 
in the approved NDA and a description of the polymorphic form(s) 
claimed by the patent for which such test data exist;
    (4) Whether the patent claims only a metabolite of the active 
ingredient; and
    (5) Whether the patent claims only an intermediate;
    (O) Information on the drug product (composition/formulation) 
patent, including the following:
    (1) Whether the patent claims the approved drug product as defined 
in Sec.  314.3; and
    (2) Whether the patent claims only an intermediate;
    (P) Information on each method-of-use patent, including the 
following:
    (1) Whether the patent claims one or more approved methods of using 
the approved drug product and a description of each approved method of 
use and related patent claim of the patent being submitted;
    (2) Identification of the specific section(s) and subsection(s) of 
the approved labeling for the drug product that describes the method of 
use claimed by the patent submitted;
    (3) The description of the patented method of use as required for 
publication, which must contain adequate information to assist 
505(b)(2) and ANDA applicants in determining whether a listed method-
of-use patent claims a use for which the 505(b)(2) or ANDA applicant is 
not seeking approval (for example, if the method(s) of use claimed by 
the patent does not cover an indication or other approved condition of 
use in its entirety, then the applicant must describe only the specific 
approved method of use claimed by the patent for which a claim of 
patent infringement could reasonably be asserted if a person not 
licensed by the owner of the patent engaged in the manufacture, use, or 
sale of the drug product); and
    (4) An applicant that submits information for a patent that claims 
one or more methods of using the drug product must also submit 
information described in either paragraph (c)(2)(ii)(N) or (O) of this 
section, regarding whether that patent also claims either the drug 
substance (active ingredient) or the drug product (composition/
formulation).
    (Q) Whether there are no relevant patents that claim the approved 
drug substance (active ingredient), the approved drug product 
(formulation or composition), or approved method(s) of use and with 
respect to which a claim of patent infringement could reasonably be 
asserted if a person not licensed by the owner of the patent engaged in 
the manufacture, use, or sale of the drug product;
    (R) A signed verification that states:

    The undersigned declares that this is an accurate and complete 
submission of patent information for the NDA, amendment, or 
supplement approved under section 505 of the Federal Food, Drug, and 
Cosmetic Act. This time-sensitive patent information or response to 
a request under 21 CFR 314.53(f)(1) is submitted pursuant to 21 CFR 
314.53. I attest that I am familiar with 21 CFR 314.53 and this 
submission complies with the requirements of the regulation. I 
verify under penalty of perjury that the foregoing is true and 
correct.

    (S) Information on whether the applicant, patent owner or attorney, 
agent, representative, or other authorized official signed the form; 
the name of the person; and the full address, phone number and, if 
available, the fax number and email address; and
    (T) Exceptions to required submission of patent information:
    (1) If an applicant submits the information described in paragraph 
(c)(2)(ii)(N) of this section for a patent that claims the drug 
substance (active ingredient) and meets the requirements for listing on 
that basis, then the applicant is not required to provide the 
information described in paragraph (c)(2)(ii)(O) of this section on 
whether that patent also claims the drug product (composition/
formulation).
    (2) If an applicant submits the information described in paragraph 
(c)(2)(ii)(O) of this section for a patent that claims the drug product 
(composition/formulation) and meets the requirements for listing on 
that basis, then the applicant is not required to provide the 
information described in paragraph (c)(2)(ii)(N) of this section on 
whether that patent also claims the drug substance (active ingredient).
    (3) If the applicant submits a supplement for a change other than 
one of the changes listed under paragraph (d)(2)(i) of this section, 
then the patent information submission requirements of paragraph 
(d)(2)(ii) of this section apply.
    (3) No relevant patents. If the applicant believes that there are 
no relevant patents that claim the drug substance (active ingredient), 
drug product (formulation or composition), or the method(s) of use for 
which the applicant has received approval, and with respect to which a 
claim of patent infringement could reasonably be asserted if a person 
not licensed by the owner of the patent engaged in the manufacture, 
use, or sale of the drug product, the applicant will verify this 
information in the appropriate form, Form FDA 3542 or 3542a.
    (4) Authorized signature. The declarations required by this section 
must be signed by the applicant or patent owner, or the applicant's or 
patent owner's attorney, agent (representative), or other authorized 
official.
    (d) When and where to submit patent information--(1) Original NDA. 
An applicant must submit with its original NDA submitted under this 
part, the information described in paragraph (c) of this section on 
each drug substance (active ingredient), drug product (formulation and 
composition), and method-of-use patent issued before the NDA is filed 
with FDA and for which patent information is required to be submitted 
under this section. If a patent is issued after the NDA is filed with 
FDA but before the NDA is approved, the applicant must, within 30 days 
of the date of issuance of the patent, submit the required patent 
information in an amendment to the NDA under Sec.  314.60.
    (2) Supplements. (i) An applicant must submit patent information 
required under paragraph (c) of this section for a patent that claims 
the drug substance, drug product, or method of use for which approval 
is sought in any of the following supplements:
    (A) To add or change the dosage form or route of administration;
    (B) To add or change the strength; or
    (C) To change the drug product from prescription use to over-the-
counter use.
    (ii) If the applicant submits a supplement for a change other than 
one of the changes listed under paragraph (d)(2)(i) of this section 
(for example, to change the formulation, to add a new

[[Page 69646]]

indication or other condition of use, or to make any other patented 
change regarding the drug substance, drug product, or any method of 
use), the following patent information submission requirements apply:
    (A) If existing patents for which information required by paragraph 
(c) of this section has already been submitted to FDA for the product 
approved in the original NDA claim the changed product, the applicant 
is not required to resubmit this patent information pursuant to 
paragraph (c) of this section unless the published description of the 
patented method of use would change upon approval of the supplement, 
and FDA will continue to list this patent information for the product;
    (B) If one or more existing patents for which information has 
already been submitted to FDA no longer claim the changed product, the 
applicant must submit a request under paragraph (f)(2)(iv) of this 
section to remove that patent information from the list at the time of 
approval of the supplement;
    (C) If one or more existing drug substance (active ingredient), 
drug product (formulation and composition), or method-of-use patents 
claim the changed product for which approval is sought in the 
supplement and such patent information has not been submitted to FDA, 
the applicant must submit the patent information required under 
paragraph (c) of this section.
    (3) Newly issued patents. If a patent is issued for a drug 
substance, drug product, or method of use after an NDA is approved, the 
applicant must submit to FDA, as described in paragraph (d)(4) of this 
section, the required patent information within 30 days of the date of 
issuance of the patent. If the required patent information is not 
submitted within 30 days of the issuance of the patent, FDA will list 
the patent, but patent certifications or statements will be governed by 
the provisions regarding untimely filed patent information at 
Sec. Sec.  314.50(i)(4) and (6) and 314.94(a)(12)(vi) and (viii).
    (4) Submission of Forms FDA 3542a and 3542--(i) Patent information 
submitted with the filing of an NDA, amendment, or supplement. The 
applicant must submit patent information required by paragraphs (c)(1) 
and (c)(2)(i) of this section and Sec.  314.50(h) or Sec.  314.70(f) on 
Form FDA 3542a to the Central Document Room, Center for Drug Evaluation 
and Research, Food and Drug Administration, 5901-B Ammendale Rd., 
Beltsville, MD 20705-1266, or to FDA in an electronic format submission 
that complies with Sec.  314.50(l)(5). Form FDA 3542a should not be 
submitted to the Orange Book Staff in the Office of Generic Drugs.
    (ii) Patent information submitted upon and after approval of an NDA 
or supplement. The applicant must submit patent information required by 
paragraphs (c)(1) and (c)(2)(ii) of this section on Form FDA 3542 to 
the Central Document Room, Center for Drug Evaluation and Research, 
Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 
20705-1266, or to FDA in an electronic format submission that complies 
with Sec.  314.50(l)(5). Form FDA 3542 should not be submitted to the 
Orange Book Staff in the Office of Generic Drugs.
    (5) Submission date. Patent information will be considered to be 
submitted to FDA for purposes of paragraph (d)(3) of this section as of 
the earlier of the date the information submitted on Form FDA 3542 is 
date-stamped by the Central Document Room, or officially received by 
FDA in an electronic format submission that complies with Sec.  
314.50(l)(5).
    (6) Identification. Each submission of patent information, except 
information submitted with an original NDA, must bear prominent 
identification as to its contents, i.e., ``Patent Information,'' or, if 
submitted after approval of an NDA, ``Time Sensitive Patent 
Information.''
    (e) Public disclosure of patent information. FDA will publish in 
the list the patent number and expiration date of each patent that is 
required to be, and is, submitted to FDA by an applicant, and for each 
method-of-use patent, the description of the method of use claimed by 
the patent as required by Sec.  314.53(c)(2)(ii)(P)(3). FDA will 
publish such patent information upon approval of the NDA, or, if the 
patent information is submitted by the applicant after approval of an 
NDA as provided under paragraph (d)(2) of this section, as soon as 
possible after the submission to the Agency of the patent information. 
A request for copies of the submitted patent information must be sent 
in writing to the Freedom of Information Staff at the address listed on 
the Agency's Web site at https://www.fda.gov. The submitted patent 
information, and requests to remove a patent or patent information from 
the list, may be subject to public disclosure.
    (f) Correction of patent information errors--(1) Requests by 
persons other than the NDA holder. If any person disputes the accuracy 
or relevance of patent information submitted to the Agency under this 
section and published by FDA in the list, or believes that an NDA 
holder has failed to submit required patent information, that person 
must first notify the Agency in a written or electronic communication 
titled ``314.53(f) Patent Listing Dispute.'' The patent listing dispute 
communication must include a statement of dispute that describes the 
specific grounds for disagreement regarding the accuracy or relevance 
of patent information for FDA to send to the applicable NDA holder. For 
a dispute regarding the accuracy or relevance of patent information 
regarding an approved method of using the drug product, this statement 
of dispute must be only a narrative description (no more than 250 
words) of the person's interpretation of the scope of the patent. This 
statement of dispute must only contain information for which the person 
consents to disclosure because FDA will send the text of the statement 
to the applicable NDA holder without review or redaction. The patent 
listing dispute communication should be directed to the Office of 
Generic Drugs, OGD Document Room, Attention: Orange Book Staff, 7620 
Standish Pl., Rockville, MD 20855, or to the Orange Book Staff at the 
email address listed on the Agency's Web site at https://www.fda.gov.
    (i) Communication with the NDA holder--(A) Drug substance or drug 
product claim. For requests submitted under this paragraph (f)(1) that 
are directed to the accuracy or relevance of submitted patent 
information regarding a drug substance or drug product claim, the 
Agency will send the statement of dispute to the applicable NDA holder. 
The NDA holder must confirm the correctness of the patent information 
and include the signed verification required by paragraph (c)(2)(ii)(R) 
of this section or withdraw or amend the patent information in 
accordance with paragraph (f)(2) of this section within 30 days of the 
date on which the Agency sends the statement of dispute. Unless the NDA 
holder withdraws or amends its patent information in response to the 
patent listing dispute, the Agency will not change the patent 
information in the Orange Book.
    (B) Method-of-use claim. For requests submitted under this 
paragraph (f)(1) that are directed to the accuracy or relevance of 
submitted patent information regarding an approved method of using the 
drug product, FDA will send the statement of dispute to the NDA holder. 
The NDA holder must confirm the correctness of its description of the 
approved method of use claimed by the patent that has been included as 
the ``Use Code'' in the Orange Book, or withdraw or amend the patent 
information in accordance with paragraph (f)(2) of this section, 
provide a narrative description (no more than 250 words) of the NDA 
holder's

[[Page 69647]]

interpretation of the scope of the patent that explains why the 
existing or amended ``Use Code'' describes only the specific approved 
method of use claimed by the patent for which a claim of patent 
infringement could reasonably be asserted if a person not licensed by 
the owner of the patent engaged in the manufacture, use, or sale of the 
drug product, and include the signed verification required by paragraph 
(c)(2)(ii)(R) of this section within 30 days of the date on which the 
Agency sends the statement of dispute. The narrative description must 
only contain information for which the NDA holder consents to 
disclosure because FDA will send the text of the statement to the 
person who submitted the patent listing dispute without review or 
redaction.
    (1) If the NDA holder confirms the correctness of the patent 
information, provides the narrative description required by paragraph 
(f)(1)(i)(B) of this section, and includes the signed verification 
required by paragraph (c)(2)(ii)(R) of this section within 30 days of 
the date on which the Agency sends the statement of dispute, the Agency 
will not change the patent information in the Orange Book.
    (2) If the NDA holder responds to the patent listing dispute with 
amended patent information in accordance with paragraph (f)(2) of this 
section, provides the narrative description required by paragraph 
(f)(1)(i)(B) of this section, and includes the signed verification 
required by paragraph (c)(2)(ii)(R) of this section within 30 days of 
the date on which the Agency sends the statement of dispute, FDA will 
update the Orange Book to reflect the amended patent information.
    (ii) Patent certification or statement during and after patent 
listing dispute. A 505(b)(2) application or ANDA must contain an 
appropriate certification or statement for each listed patent, 
including the disputed patent, during and after the patent listing 
dispute.
    (iii) Information on patent listing disputes. FDA will promptly 
post information on its Web site regarding whether a patent listing 
dispute has been submitted for a published description of a patented 
method of use for a drug product and whether the NDA holder has timely 
responded to the patent listing dispute.
    (2) Requests by the NDA holder--(i) Patents or patent claims that 
no longer meet the statutory requirements for listing. If the NDA 
holder determines that a patent or patent claim no longer meets the 
requirements for listing in section 505(b)(1) or (c)(2) of the Federal 
Food, Drug, and Cosmetic Act (including if there has been a judicial 
finding of invalidity for a listed patent, from which no appeal has 
been or can be taken), the NDA holder is required to promptly notify 
FDA to amend the patent information or withdraw the patent or patent 
information and request that the patent or patent information be 
removed from the list. If the NDA holder is required by court order to 
amend patent information or withdraw a patent from the list, it must 
submit an amendment to its NDA that includes a copy of the order, 
within 14 days of the date the order was entered, to the Central 
Document Room, Center for Drug Evaluation and Research, Food and Drug 
Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. The 
amendment to the NDA must bear the identification described in 
paragraph (d)(6) of this section. FDA will remove a patent or patent 
information from the list if there is no first applicant eligible for 
180-day exclusivity based on a paragraph IV certification to that 
patent or after the 180-day exclusivity period of a first applicant 
based on that patent has expired or has been extinguished.
    (ii) Patent term restoration. If the term of a listed patent is 
extended pursuant to 35 U.S.C. 156(e), the NDA holder must submit on 
Form FDA 3542 a correction to the expiration date of the patent. This 
correction must be submitted within 30 days of receipt of a certificate 
of extension as described in 35 U.S.C. 156(e)(1) or documentation of an 
extension of the term of the patent as described in 35 U.S.C. 
156(e)(2).
    (iii) Submission of corrections or changes to patent information. 
Corrections or changes to previously submitted patent information, 
other than withdrawal of a patent and requests to remove a patent from 
the list, must be submitted on Form FDA 3542 or 3542a, as appropriate, 
in an amendment or supplement to the NDA. The amendment or supplement 
to the NDA must bear the identification described in paragraph (d)(6) 
of this section. We will not accept the corrections or changes unless 
they are submitted on the appropriate forms.
    (iv) Submission of patent withdrawals and requests to remove a 
patent from the list. Withdrawal of a patent and requests to remove a 
patent from the list must be submitted to the same addresses described 
in paragraph (d)(4)(ii) of this section, except that the withdrawal or 
request to remove a patent from the list is not required to be 
submitted on Form FDA 3542 and may be submitted by letter. Withdrawal 
of a patent and a request to remove a patent from the list must contain 
the following information:
    (A) The NDA number to which the request applies;
    (B) Each product(s) approved in the NDA to which the request 
applies; and
    (C) The patent number.

0
6. AmendSec.  314.54 as follows:
0
a. Remove the word ``shall'' and add in its place the word ``must'' in 
paragraph (a)(1) introductory text and paragraphs (a)(1)(i) and (a)(3); 
and
0
b. Revise the section heading, paragraph (a) introductory text, and 
paragraphs (a)(1)(iii), (v), and (vi), (a)(2) and (4), and (b).
    The revisions read as follows:


Sec.  314.54  Procedure for submission of a 505(b)(2) application 
requiring investigations for approval of a new indication for, or other 
change from, a listed drug.

    (a) The Federal Food, Drug, and Cosmetic Act does not permit 
approval of an ANDA for a new indication, nor does it permit approval 
of other changes in a listed drug if investigations, other than 
bioavailability or bioequivalence studies, are essential to the 
approval of the change. Any person seeking approval of a drug product 
that represents a modification of a listed drug (e.g., a new indication 
or new dosage form) and for which investigations, other than 
bioavailability or bioequivalence studies, are essential to the 
approval of the changes may, except as provided in paragraph (b) of 
this section, submit a 505(b)(2) application. This 505(b)(2) 
application need contain only that information needed to support the 
modification(s) of the listed drug.
    (1) * * *
    (iii) Identification of each listed drug for which FDA has made a 
finding of safety and effectiveness and on which finding the applicant 
relies in seeking approval of its proposed drug product by established 
name, if any, proprietary name, dosage form, strength, route of 
administration, name of listed drug's application holder, and listed 
drug's approved NDA number. The listed drug(s) identified as relied 
upon must include a drug product approved in an NDA that:
    (A) Is pharmaceutically equivalent to the drug product for which 
the original 505(b)(2) application is submitted; and
    (B) Was approved before the original 505(b)(2) application was 
submitted.
* * * * *
    (v) Any patent information required under section 505(b)(1) of the 
Federal Food, Drug, and Cosmetic Act with respect to any patent which 
claims the drug for which approval is sought or a method of using such 
drug and to which a claim of patent infringement could

[[Page 69648]]

reasonably be asserted if a person not licensed by the owner of the 
patent engaged in the manufacture, use, or sale of the drug product.
    (vi) Any patent certification or statement required under section 
505(b)(2) of the Federal Food, Drug, and Cosmetic Act with respect to 
any relevant patents that claim the listed drug(s) on which 
investigations relied on by the applicant for approval of the 
application were conducted, or that claim a use for the listed drug(s). 
A 505(b)(2) applicant seeking approval of a drug that is 
pharmaceutically equivalent to a listed drug approved in an NDA 
implicitly relies upon one such pharmaceutically equivalent listed 
drug.
* * * * *
    (2) The applicant must submit a review copy that contains the 
technical sections described in Sec.  314.50(d)(1), except that the 
section described in Sec.  314.50(d)(1)(ii)(c) must contain the 
proposed or actual master production record, including a description of 
the equipment, to be used for the manufacture of a commercial lot of 
the drug product, and Sec.  314.50(d)(3), and the technical sections 
described in Sec.  314.50(d)(2), (d)(4) through (6), and (f) when 
needed to support the modification. Each of the technical sections in 
the review copy is required to be separately bound with a copy of the 
information required under Sec.  314.50(a), (b), and (c) and a copy of 
the proposed labeling.
* * * * *
    (4) The applicant must submit a field copy of the 505(b)(2) 
application that contains the technical section described in Sec.  
314.50(d)(1), a copy of the information required under Sec.  314.50(a) 
and (c), and certification that the field copy is a true copy of the 
technical section described in Sec.  314.50(d)(1) contained in the 
archival and review copies of the 505(b)(2) application.
    (b) A 505(b)(2) application may not be submitted under this section 
for a drug product whose only difference from a listed drug is that:
    (1) The extent to which its active ingredient(s) is absorbed or 
otherwise made available to the site of action is less than that of the 
listed drug; or
    (2) The rate at which its active ingredient(s) is absorbed or 
otherwise made available to the site of action is unintentionally less 
than that of the listed drug.

0
7. Amend Sec.  314.60 as follows:
0
a. Remove the word ``application'' and add in its place ``NDA'' 
wherever it appears;
0
b. Remove the word ``act'' and add in its place ``Federal Food, Drug, 
and Cosmetic Act'' wherever it appears in paragraphs (b)(1) and (4), 
(c)(1)(i), and (c)(2);
0
c. Remove ``505(c)(3)(D)(ii)'' and add in its place 
``505(c)(3)(E)(ii)'' in paragraphs (c)(1)(i) and (c)(2);
0
d. Add paragraph headings in paragraphs (b) and (c);
0
e. Revise the section heading and paragraphs (a), (c)(1)(iii), and (d); 
and
0
f. Add paragraphs (e) and (f).
    The revisions and additions read as follows:


Sec.  314.60  Amendments to an unapproved NDA, supplement, or 
resubmission.

    (a) Submission of NDA. FDA generally assumes that when an original 
NDA, supplement to an approved NDA, or resubmission of an NDA or 
supplement is submitted to the Agency for review, the applicant 
believes that the Agency can approve the NDA, supplement, or 
resubmission as submitted. However, the applicant may submit an 
amendment to an NDA, supplement, or resubmission that has been filed 
under Sec.  314.101 but is not yet approved.
    (b) Submission of major amendment. * * *
    (c) Limitation on certain amendments.
    (1) * * *
    (iii) The applicant has not obtained a right of reference or use to 
the investigation described in paragraph (c)(1)(ii) of this section; 
and
* * * * *
    (d) Field copy. The applicant must submit a field copy of each 
amendment to a section of the NDA described in Sec.  314.50(d)(1). The 
applicant must include in its submission of each such amendment to FDA 
a statement certifying that a field copy of the amendment has been sent 
to the applicant's home FDA district office.
    (e) Different drug. An applicant may not amend a 505(b)(2) 
application to seek approval of a drug that is a different drug from 
the drug in the original submission of the 505(b)(2) application. For 
purposes of this paragraph (e), a drug is a different drug if it has 
been modified to have a different active ingredient, different route of 
administration, different dosage form, or difference in excipients that 
requires either a separate clinical study to establish safety or 
effectiveness or, for topical products, that requires a separate in 
vivo demonstration of bioequivalence. However, notwithstanding the 
limitation described in this paragraph (e), an applicant may amend the 
505(b)(2) application to seek approval of a different strength.
    (f) Patent certification requirements. (1) An amendment to a 
505(b)(2) application is required to contain an appropriate patent 
certification or statement described in Sec.  314.50(i) or a 
recertification for a previously submitted paragraph IV certification 
if approval is sought for any of the following types of amendments:
    (i) To add a new indication or other condition of use;
    (ii) To add a new strength;
    (iii) To make other than minor changes in product formulation; or
    (iv) To change the physical form or crystalline structure of the 
active ingredient.
    (2) If the amendment to the 505(b)(2) application does not contain 
a patent certification or statement, the applicant must verify that the 
proposed change described in the amendment is not one of the types of 
amendments described in paragraph (f)(1) of this section.

0
8. Amend Sec.  314.70 as follows:
0
a. Remove the word ``application'' and add in its place ``NDA'' 
wherever it appears in the paragraph (a) heading and paragraphs 
(a)(1)(i) and (ii), (b)(2)(i) and (viii), (c)(6) introductory text, 
(c)(7), (d)(2)(v) through (vii), (d)(3)(i), and (e);
0
b. Remove the words ``cover letter'' and add in their place the word 
``submission'' in paragraph (a)(6);
0
c. Remove the words ``and its mailing cover'' in paragraph (b)(4);
0
d. Revise the section heading and paragraphs (a)(2) and (f); and
0
e. Add paragraph (h).
    The revisions and addition read as follows:


Sec.  314.70  Supplements and other changes to an approved NDA.

    (a) * * *
    (2) The NDA holder must assess the effects of the change before 
distributing a drug product made with a manufacturing change.
* * * * *
    (f) Patent information. The applicant must comply with the patent 
information requirements under section 505(c)(2) of the Federal Food, 
Drug, and Cosmetic Act and Sec.  314.53.
* * * * *
    (h) Different drug. An applicant may not supplement a 505(b)(2) 
application to seek approval of a drug that is a different drug from 
the drug in the approved 505(b)(2) application. For purposes of this 
paragraph (h), a drug is a different drug if it has been modified to 
have a different active ingredient, different route of administration, 
different dosage form, or difference in excipients that requires either 
a separate clinical study to establish safety or effectiveness or, for 
topical products, that requires a separate in vivo

[[Page 69649]]

demonstration of bioequivalence. However, notwithstanding the 
limitation described in this paragraph (h), an applicant may supplement 
the 505(b)(2) application to seek approval of a different strength.

0
9. Amend Sec.  314.90 by removing the word ``application'' and adding 
in its place ``NDA'' wherever it appears and adding paragraph (c) to 
read as follows:


Sec.  314.90  Waivers.

* * * * *
    (c) If FDA grants the applicant's waiver request with respect to a 
requirement under Sec. Sec.  314.50 through 314.81, the waived 
requirement will not constitute a basis for refusal to approve an NDA 
under Sec.  314.125.

0
10. Amend Sec.  314.93 as follows:
0
a. Remove the words ``abbreviated new drug applications'' and add in 
their place ``ANDAs'' in paragraph (a);
0
b. Remove the words ``abbreviated new drug application'' and add in 
their place ``ANDA'' wherever they appear in paragraphs (b), (c), and 
(e)(3);
0
c. Remove the words ``abbreviated application'' and add in their place 
``ANDA'' in paragraph (b);
0
d. Remove ``201(b)'' and add in its place ``201(p)'' in paragraph 
(d)(3);
0
e. Remove the word ``act'' and add in its place ``Federal Food, Drug, 
and Cosmetic Act'' in paragraphs (d)(3) and (e)(1)(iii)(C);
0
f. Remove the period at the end of paragraph (e)(1)(v) and add in its 
place ``; or'';
0
g. Add paragraph (e)(1)(vi);
0
h. Redesignate paragraph (f) as paragraph (f)(1); and
0
i. Add paragraph (f)(2).
    The revisions and additions read as follows:


Sec.  314.93  Petition to request a change from a listed drug.

* * * * *
    (e) * * *
    (1) * * *
    (vi) A drug product is approved in an NDA for the change described 
in the petition.
* * * * *
    (f) * * *
    (2) If, after approval of a petition and before approval of an ANDA 
submitted pursuant to the approved petition, a drug product is approved 
in an NDA for the change described in the petition, the petition and 
the listed drug identified in the petition can no longer be the basis 
for ANDA submission, irrespective of whether FDA has withdrawn approval 
of the petition. A person seeking approval for such drug product must 
submit a new ANDA that identifies the pharmaceutically equivalent 
reference listed drug as the basis for ANDA submission and comply with 
applicable regulatory requirements.

0
11. Amend Sec.  314.94 as follows:
0
a. Remove the words ``abbreviated application'' and add in their place 
``ANDA'' wherever they appear in paragraphs (a)(1), (a)(5)(ii)(A), 
(a)(6)(ii), (a)(9)(v), (a)(12)(i)(A)(4), (a)(13), (d)(1)(i), (d)(4), 
and (d)(5);
0
b. Remove the words ``abbreviated new drug application'' and add in 
their place ``ANDA'' wherever they appear in paragraph (a) introductory 
text and paragraphs (a)(8)(i) and (b);
0
c. Remove the word ``shall'' and add in its place the word ``must'' 
wherever it appears in paragraph (a) introductory text and paragraphs 
(a)(1), (a)(9)(ii) through (iv), (a)(12)(i)(A)(1) through (3), (a)(13), 
(b), and (d)(5);
0
d. Remove the word ``act'' and add in its place ``Federal Food, Drug, 
and Cosmetic Act'' wherever it appears in paragraphs (a)(5)(ii)(A), 
(a)(7)(ii)(C), and (a)(8)(iv);
0
e. Remove ``Sec.  320.1(g) of this chapter'' and add in its place 
``Sec.  314.3(b)'' in paragraph (a)(7)(i);
0
f. Remove and reserve paragraph (a)(12)(iv); and
0
g. Revise the section heading and the introductory text, paragraph (a) 
heading, paragraph (a)(2), paragraph (a)(3), the first sentence of 
paragraph (a)(7)(ii) introductory text, paragraphs (a)(7)(iii) and 
(a)(9)(i), paragraph (a)(12)(i) heading, paragraph (a)(12)(i)(A) 
introductory text, paragraphs (a)(12)(i)(A)(4), (a)(12)(i)(B), 
(a)(12)(ii) and (iii), (a)(12)(iv) through (viii), paragraph (d) 
heading, paragraph (d)(1) introductory text, and paragraph (d)(2).
    The revisions read as follows:


Sec.  314.94  Content and format of an ANDA.

    ANDAs are required to be submitted in the form and contain the 
information required under this section. Three copies of the ANDA are 
required, an archival copy, a review copy, and a field copy. FDA will 
maintain guidance documents on the format and content of ANDAs to 
assist applicants in their preparation.
    (a) ANDAs. * * *
* * * * *
    (2) Table of contents. The archival copy of the ANDA is required to 
contain a table of contents that shows the volume number and page 
number of the contents of the submission.
    (3) Basis for ANDA submission. An ANDA must refer to a listed drug. 
Ordinarily, that listed drug will be the drug product selected by the 
Agency as the reference standard for conducting bioequivalence testing. 
The ANDA must contain:
    (i) The name of the reference listed drug, including its dosage 
form and strength. For an ANDA based on an approved petition under 
Sec.  10.30 of this chapter and Sec.  314.93, the reference listed drug 
must be the same as the listed drug referenced in the approved 
petition.
    (ii) A statement as to whether, according to the information 
published in the list, the reference listed drug is entitled to a 
period of marketing exclusivity under section 505(j)(5)(F) of the 
Federal Food, Drug, and Cosmetic Act.
    (iii) For an ANDA based on an approved petition under Sec.  10.30 
of this chapter and Sec.  314.93, a reference to the FDA-assigned 
docket number for the petition and a copy of FDA's correspondence 
approving the petition.
* * * * *
    (7) * * *
    (ii) If the ANDA is submitted pursuant to a petition approved under 
Sec.  314.93, the results of any bioavailability or bioequivalence 
testing required by the Agency, or any other information required by 
the Agency to show that the active ingredients of the proposed drug 
product are of the same pharmacological or therapeutic class as those 
in the reference listed drug and that the proposed drug product can be 
expected to have the same therapeutic effect as the reference listed 
drug. * * *
* * * * *
    (iii) For each in vivo or in vitro bioequivalence study contained 
in the ANDA:
    (A) A description of the analytical and statistical methods used in 
each study; and
    (B) With respect to each study involving human subjects, a 
statement that the study either was conducted in compliance with the 
institutional review board regulations in part 56 of this chapter, or 
was not subject to the regulations under Sec.  56.104 or Sec.  56.105 
of this chapter, and that it was conducted in compliance with the 
informed consent regulations in part 50 of this chapter.
* * * * *
    (9) * * *
    (i) The information required under Sec.  314.50(d)(1), except that 
the information required under Sec.  314.50(d)(1)(ii)(c) must contain 
the proposed or actual master production record, including a 
description of the equipment, to be used for the manufacture of a 
commercial lot of the drug product.
* * * * *
    (12) Patent certification--(i) Patents claiming drug substance, 
drug product,

[[Page 69650]]

or method of use. (A) An appropriate patent certification or statement 
with respect to each patent issued by the U.S. Patent and Trademark 
Office that, in the opinion of the applicant and to the best of its 
knowledge, claims the reference listed drug or that claims a use of 
such listed drug for which the applicant is seeking approval under 
section 505(j) of the Federal Food, Drug, and Cosmetic Act and for 
which information is required to be filed under section 505(b) and (c) 
of the Federal Food, Drug, and Cosmetic Act and Sec.  314.53. For each 
such patent, the applicant must provide the patent number and certify, 
in its opinion and to the best of its knowledge, one of the following 
circumstances:
* * * * *
    (4)(i) That the patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for 
which the ANDA is submitted. The applicant must entitle such a 
certification ``Paragraph IV Certification''. This certification must 
be submitted in the following form:

    I, (name of applicant), certify that Patent No. _____ (is 
invalid, unenforceable, or will not be infringed by the manufacture, 
use, or sale of) (name of proposed drug product) for which this ANDA 
is submitted.

    (ii) The certification must be accompanied by a statement that the 
applicant will comply with the requirements under Sec.  314.95(a) with 
respect to providing a notice to each owner of the patent or its 
representative and to the NDA holder (or, if the NDA holder does not 
reside or maintain a place of business within the United States, its 
attorney, agent, or other authorized official) for the listed drug, 
with the requirements under Sec.  314.95(b) with respect to sending the 
notice, and with the requirements under Sec.  314.95(c) with respect to 
the content of the notice.
    (B) If the ANDA refers to a listed drug that is itself a licensed 
generic product of a patented drug first approved under section 505(b) 
of the Federal Food, Drug, and Cosmetic Act, an appropriate patent 
certification or statement under paragraph (a)(12)(i) and/or (iii) of 
this section with respect to each patent that claims the first-approved 
patented drug or that claims a use for such drug.
    (ii) No relevant patents. If, in the opinion of the applicant and 
to the best of its knowledge, there are no patents described in 
paragraph (a)(12)(i) of this section, a certification in the following 
form:

    In the opinion and to the best knowledge of (name of applicant), 
there are no patents that claim the listed drug referred to in this 
ANDA or that claim a use of the listed drug.

    (iii) Method-of-use patent. (A) If patent information is submitted 
under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act 
and Sec.  314.53 for a patent claiming a method of using the listed 
drug, and the labeling for the drug product for which the applicant is 
seeking approval does not include an indication or other condition of 
use that is covered by the method-of-use patent, a statement explaining 
that the method-of-use patent does not claim a proposed indication or 
other condition of use.
    (B) If the labeling of the drug product for which the applicant is 
seeking approval includes an indication or other condition of use that, 
according to the patent information submitted under section 505(b) or 
(c) of the Federal Food, Drug, and Cosmetic Act and Sec.  314.53 or in 
the opinion of the applicant, is claimed by a method-of-use patent, an 
applicable certification under paragraph (a)(12)(i) of this section.
    (iv) [Reserved]
    (v) Licensing agreements. If the ANDA is for a drug or method of 
using a drug claimed by a patent and the applicant has a licensing 
agreement with the patent owner, the applicant must submit a paragraph 
IV certification as to that patent and a statement that the applicant 
has been granted a patent license. If the patent owner consents to 
approval of the ANDA (if otherwise eligible for approval) as of a 
specific date, the ANDA must contain a written statement from the 
patent owner that it has a licensing agreement with the applicant and 
that it consents to approval of the ANDA as of a specific date.
    (vi) Untimely filing of patent information. (A) If a patent on the 
listed drug is issued and the holder of the approved NDA for the listed 
drug does not file with FDA the required information on the patent 
within 30 days of issuance of the patent, an applicant who submitted an 
ANDA for that drug that contained an appropriate patent certification 
or statement before the submission of the patent information is not 
required to submit a patent certification or statement to address the 
patent or patent information that is late-listed with respect to the 
pending ANDA. Except as provided in Sec.  314.53(f)(1), an NDA holder's 
amendment to the description of the approved method(s) of use claimed 
by the patent will be considered untimely filing of patent information 
unless:
    (1) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of patent 
issuance;
    (2) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of approval of a 
corresponding change to product labeling; or
    (3) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of a decision by 
the U.S. Patent and Trademark Office or by a Federal district court, 
the Court of Appeals for the Federal Circuit, or the U.S. Supreme Court 
that is specific to the patent and alters the construction of a method-
of-use claim(s) of the patent, and the amendment contains a copy of the 
decision.
    (B) An applicant whose ANDA is submitted after the NDA holder's 
untimely filing of patent information, or whose pending ANDA was 
previously submitted but did not contain an appropriate patent 
certification or statement at the time of the patent submission, must 
submit a certification under paragraph (a)(12)(i) of this section and/
or a statement under paragraph (a)(12)(iii) of this section as to that 
patent.
    (vii) Disputed patent information. If an applicant disputes the 
accuracy or relevance of patent information submitted to FDA, the 
applicant may seek a confirmation of the correctness of the patent 
information in accordance with the procedures under Sec.  314.53(f). 
Unless the patent information is withdrawn, the applicant must submit 
an appropriate certification or statement for each listed patent.
    (viii) Amended certifications. A patent certification or statement 
submitted under paragraphs (a)(12)(i) through (iii) of this section may 
be amended at any time before the approval of the ANDA. If an applicant 
with a pending ANDA voluntarily makes a patent certification for an 
untimely filed patent, the applicant may withdraw the patent 
certification for the untimely filed patent. An applicant must submit 
an amended certification as an amendment to a pending ANDA. Once an 
amendment is submitted to change a certification, the ANDA will no 
longer be considered to contain the prior certification.
    (A) After finding of infringement. An applicant who has submitted a 
paragraph IV certification and is sued for patent infringement must 
submit an amendment to change its certification if a court enters a 
final decision from which no appeal has been or can be taken, or signs 
and enters a settlement order or consent decree in the action that 
includes a finding that the patent is infringed, unless the final 
decision, settlement order, or consent decree also finds the patent to 
be invalid. In its

[[Page 69651]]

amendment, the applicant must certify under paragraph (a)(12)(i)(A)(3) 
of this section that the patent will expire on a specific date or, with 
respect to a patent claiming a method of use, the applicant may instead 
provide a statement under paragraph (a)(12)(iii) of this section if the 
applicant amends its ANDA such that the applicant is no longer seeking 
approval for a method of use claimed by the patent. Once an amendment 
for the change has been submitted, the ANDA will no longer be 
considered to contain a paragraph IV certification to the patent. If a 
final judgment finds the patent to be invalid and infringed, an amended 
certification is not required.
    (B) After request to remove a patent or patent information from the 
list. If the list reflects that an NDA holder has requested that a 
patent or patent information be removed from the list and no ANDA 
applicant is eligible for 180-day exclusivity based on a paragraph IV 
certification to that patent, the patent or patent information will be 
removed and any applicant with a pending ANDA (including a tentatively 
approved ANDA) who has made a certification with respect to such patent 
must submit an amendment to withdraw its certification. In the 
amendment, the applicant must state the reason for withdrawing the 
certification or statement (that the patent has been removed from the 
list). If the list reflects that an NDA holder has requested that a 
patent or patent information be removed from the list and one or more 
first applicants are eligible for 180-day exclusivity based on a 
paragraph IV certification to that patent, the patent will remain 
listed until any 180-day exclusivity based on that patent has expired 
or has been extinguished. After any applicable 180-day exclusivity has 
expired or has been extinguished, the patent or patent information will 
be removed and any applicant with a pending ANDA (including a 
tentatively approved ANDA) who has made a certification with respect to 
such patent must submit an amendment to withdraw its certification. 
Once an amendment to withdraw the certification has been submitted, the 
ANDA will no longer be considered to contain a paragraph IV 
certification to the patent. If removal of a patent from the list 
results in there being no patents listed for the listed drug identified 
in the ANDA, the applicant must submit an amended certification 
reflecting that there are no relevant patents.
    (C) Other amendments. (1) Except as provided in paragraphs 
(a)(12)(vi) and (a)(12)(viii)(C)(2) of this section:
    (i) An applicant must amend a submitted certification or statement 
if, at any time before the date of approval of the ANDA, the applicant 
learns that the submitted certification or statement is no longer 
accurate; and
    (ii) An applicant must submit an appropriate patent certification 
or statement under paragraph (a)(12)(i) and/or (iii) of this section 
if, after submission of the ANDA, a new patent is issued by the U.S. 
Patent and Trademark Office that, in the opinion of the applicant and 
to the best of its knowledge, claims the reference listed drug or that 
claims an approved use for such reference listed drug and for which 
information is required to be filed under section 505(b) and (c) of the 
Federal Food, Drug, and Cosmetic Act and Sec.  314.53. For a paragraph 
IV certification, the certification must not be submitted earlier than 
the first working day after the day the patent is published in the 
list.
    (2) An applicant is not required to submit a supplement to change a 
submitted certification when information on a patent on the listed drug 
is submitted after the approval of the ANDA.
* * * * *
    (d) Format of an ANDA. (1) The applicant must submit a complete 
archival copy of the ANDA as required under paragraphs (a) and (c) of 
this section. FDA will maintain the archival copy during the review of 
the ANDA to permit individual reviewers to refer to information that is 
not contained in their particular technical sections of the ANDA, to 
give other Agency personnel access to the ANDA for official business, 
and to maintain in one place a complete copy of the ANDA.
* * * * *
    (2) For ANDAs, the applicant must submit a review copy of the ANDA 
that contains two separate sections. One section must contain the 
information described under paragraphs (a)(2) through (6) and (8) and 
(9) of this section and section 505(j)(2)(A)(vii) of the Federal Food, 
Drug, and Cosmetic Act and a copy of the analytical procedures and 
descriptive information needed by FDA's laboratories to perform tests 
on samples of the proposed drug product and to validate the applicant's 
analytical procedures. The other section must contain the information 
described under paragraphs (a)(3), (7), and (8) of this section. Each 
of the sections in the review copy is required to contain a copy of the 
application form described under paragraph (a) of this section.
* * * * *

0
12. Section 314.95 is revised to read as follows:


Sec.  314.95  Notice of certification of invalidity, unenforceability, 
or noninfringement of a patent.

    (a) Notice of certification. For each patent that claims the listed 
drug or that claims a use for such listed drug for which the applicant 
is seeking approval and for which the applicant submits a paragraph IV 
certification, the applicant must send notice of such certification by 
registered or certified mail, return receipt requested, or by a 
designated delivery service, as defined in paragraph (g) of this 
section to each of the following persons:
    (1) Each owner of the patent that is the subject of the 
certification or the representative designated by the owner to receive 
the notice. The name and address of the patent owner or its 
representative may be obtained from the U.S. Patent and Trademark 
Office; and
    (2) The holder of the approved NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act for the listed drug that is 
claimed by the patent and for which the applicant is seeking approval, 
or, if the NDA holder does not reside or maintain a place of business 
within the United States, the NDA holder's attorney, agent, or other 
authorized official. The name and address of the NDA holder or its 
attorney, agent, or authorized official may be obtained by sending a 
written or electronic communication to the Orange Book Staff, Office of 
Generic Drugs, 7620 Standish Pl., Rockville, MD 20855 or to the Orange 
Book Staff at the email address listed on the Agency's Web site at 
https://www.fda.gov.
    (3) This paragraph (a) does not apply to a method-of-use patent 
that does not claim a use for which the applicant is seeking approval.
    (4) An applicant may send notice by an alternative method only if 
FDA has agreed in advance that the method will produce an acceptable 
form of documentation.
    (b) Sending the notice. (1) Except as provided under paragraph (d) 
of this section, the applicant must send the notice required by 
paragraph (a) of this section on or after the date it receives a 
paragraph IV acknowledgment letter from FDA, but not later than 20 days 
after the date of the postmark on the paragraph IV acknowledgment 
letter. The 20-day clock described in this paragraph (b) begins on the 
day after the date of the postmark on the paragraph IV acknowledgment 
letter. When the 20th day falls on Saturday, Sunday, or a Federal 
holiday, the 20th day will be

[[Page 69652]]

the next day that is not a Saturday, Sunday, or Federal holiday.
    (2) Any notice required by paragraph (a) of this section is invalid 
if it is sent before the applicant's receipt of a paragraph IV 
acknowledgment letter, or before the first working day after the day 
the patent is published in the list. The applicant will not have 
complied with this paragraph (b) until it sends valid notice.
    (3) The applicant must submit to FDA an amendment to its ANDA that 
includes a statement certifying that the notice has been provided to 
each person identified under paragraph (a) of this section and that the 
notice met the content requirements under paragraph (c) of this 
section. A copy of the notice itself need not be submitted to the 
Agency.
    (c) Contents of a notice. In the notice, the applicant must cite 
section 505(j)(2)(B)(iv) of the Federal Food, Drug, and Cosmetic Act 
and the notice must include, but is not limited to, the following 
information:
    (1) A statement that FDA has received an ANDA submitted by the 
applicant containing any required bioavailability or bioequivalence 
data or information.
    (2) The ANDA number.
    (3) A statement that the applicant has received the paragraph IV 
acknowledgment letter for the ANDA.
    (4) The established name, if any, as defined in section 502(e)(3) 
of the Federal Food, Drug, and Cosmetic Act, of the proposed drug 
product.
    (5) The active ingredient, strength, and dosage form of the 
proposed drug product.
    (6) The patent number and expiration date of each listed patent for 
the reference listed drug alleged to be invalid, unenforceable, or not 
infringed.
    (7) A detailed statement of the factual and legal basis of the 
applicant's opinion that the patent is not valid, unenforceable, or 
will not be infringed. The applicant must include in the detailed 
statement:
    (i) For each claim of a patent alleged not to be infringed, a full 
and detailed explanation of why the claim is not infringed.
    (ii) For each claim of a patent alleged to be invalid or 
unenforceable, a full and detailed explanation of the grounds 
supporting the allegation.
    (8) If the applicant alleges that the patent will not be infringed 
and the applicant seeks to preserve the option to later file a civil 
action for declaratory judgment in accordance with section 505(j)(5)(C) 
of the Federal Food, Drug, and Cosmetic Act, then the notice must be 
accompanied by an offer of confidential access to the ANDA for the sole 
and limited purpose of evaluating possible infringement of the patent 
that is the subject of the paragraph IV certification.
    (9) If the applicant does not reside or have a place of business in 
the United States, the name and address of an agent in the United 
States authorized to accept service of process for the applicant.
    (d) Amendment or supplement to an ANDA. (1) If, after receipt of a 
paragraph IV acknowledgment letter or acknowledgment letter, an 
applicant submits an amendment or supplement to its ANDA that includes 
a paragraph IV certification, the applicant must send the notice 
required by paragraph (a) of this section at the same time that the 
amendment or supplement to the ANDA is submitted to FDA, regardless of 
whether the applicant has already given notice with respect to another 
such certification contained in the ANDA or in an amendment or 
supplement to the ANDA.
    (2) If, before receipt of a paragraph IV acknowledgment letter, an 
applicant submits an amendment to its ANDA that includes a paragraph IV 
certification, the applicant must send the notice required by paragraph 
(a) of this section in accordance with the procedures in paragraph (b) 
of this section. If an ANDA applicant's notice of its paragraph IV 
certification is timely provided in accordance with paragraph (b) of 
this section and the applicant has not submitted a previous paragraph 
IV certification, FDA will base its determination of whether the 
applicant is a first applicant on the date of submission of the 
amendment containing the paragraph IV certification.
    (3) An applicant that submits an amendment or supplement to seek 
approval of a different strength must provide notice of any paragraph 
IV certification in accordance with paragraph (d)(1) or (2) of this 
section, as applicable.
    (e) Documentation of timely sending and receipt of notice. The 
applicant must amend its ANDA to provide documentation of the date of 
receipt of the notice required under paragraph (a) of this section by 
each person provided the notice. The amendment must be submitted to FDA 
within 30 days after the last date on which notice was received by a 
person described in paragraph (a) of this section. The applicant's 
amendment also must include documentation that its notice was sent on a 
date that complies with the timeframe required by paragraph (b) or (d) 
of this section, as applicable, and a dated printout of the entry for 
the reference listed drug in FDA's ``Approved Drug Products With 
Therapeutic Equivalence Evaluations'' (the list) that includes the 
patent that is the subject of the paragraph IV certification. FDA will 
accept, as adequate documentation of the date the notice was sent, a 
copy of the registered mail receipt, certified mail receipt, or receipt 
from a designated delivery service as defined in paragraph (g) of this 
section. FDA will accept as adequate documentation of the date of 
receipt a return receipt, signature proof of delivery by a designated 
delivery service, or a letter acknowledging receipt by the person 
provided the notice. An applicant may rely on another form of 
documentation only if FDA has agreed to such documentation in advance. 
A copy of the notice itself need not be submitted to the Agency.
    (f) Forty-five day period after receipt of notice. If the 
requirements of this section are met, FDA will presume the notice to be 
complete and sufficient, and it will count the day following the date 
of receipt of the notice by the patent owner or its representative and 
by the approved NDA holder or its attorney, agent, or other authorized 
official as the first day of the 45-day period provided for in section 
505(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act. FDA may, 
if the applicant provides a written statement to FDA that a later date 
should be used, count from such later date.
    (g) Designated delivery services. (1) For purposes of this section, 
the term ``designated delivery service'' means any delivery service 
provided by a trade or business that the Agency determines:
    (i) Is available to the general public throughout the United 
States;
    (ii) Records electronically to its database, kept in the regular 
course of its business, or marks on the cover in which any item 
referred to in this section is to be delivered, the date on which such 
item was given to such trade or business for delivery; and
    (iii) Provides overnight or 2-day delivery service throughout the 
United States.
    (2) FDA may periodically issue guidance regarding designated 
delivery services.

0
13. Amend Sec.  314.96 as follows:
0
a. Revise the section heading;
0
b. Remove the words ``abbreviated new drug application'' and add in 
their place ``ANDA'' in the paragraph (a) heading and the first two 
sentences of paragraph (a)(1);
0
c. Remove ``320.1(g) of this chapter'' and add in its place ``314.3'' 
in paragraph (a)(1);

[[Page 69653]]

0
d. Remove the word ``shall'' and add in its place the word ``must'' 
wherever it appears and remove ``to Sec.  314.94(a)(9)'' and add in its 
place ``under Sec.  314.94(a)(9)'' in paragraph (b);
0
e. Add a heading to paragraph (b); and
0
f. Add paragraphs (c) and (d).
    The revisions and additions read as follows:


Sec.  314.96  Amendments to an unapproved ANDA.

* * * * *
    (b) Field copy. * * *
    (c) Different listed drug. An applicant may not amend an ANDA to 
seek approval of a drug referring to a listed drug that is different 
from the reference listed drug identified in the ANDA. This paragraph 
(c) applies if, at any time before the approval of the ANDA, a 
different listed drug is approved that is the pharmaceutical equivalent 
to the product in the ANDA and is designated as a reference listed 
drug. This paragraph (c) also applies if changes are proposed in an 
amendment to the ANDA such that the proposed product is a 
pharmaceutical equivalent to a different listed drug than the reference 
listed drug identified in the ANDA. A change of the reference listed 
drug must be submitted in a new ANDA. However, notwithstanding the 
limitation described in this paragraph (c), an applicant may amend the 
ANDA to seek approval of a different strength.
    (d)(1) Patent certification requirements. An amendment to an ANDA 
is required to contain an appropriate patent certification or statement 
described in Sec.  314.94(a)(12) or a recertification for a previously 
submitted paragraph IV certification if approval is sought for any of 
the following types of amendments:
    (i) To add a new indication or other condition of use;
    (ii) To add a new strength;
    (iii) To make other than minor changes in product formulation; or
    (iv) To change the physical form or crystalline structure of the 
active ingredient.
    (2) If the amendment to the ANDA does not contain a patent 
certification or statement, the applicant must verify that the proposed 
change described in the amendment is not one of the types of amendments 
described in paragraph (d)(1) of this section.

0
14. Section 314.97 is revised to read as follows:


Sec.  314.97  Supplements and other changes to an approved ANDA.

    (a) General requirements. The applicant must comply with the 
requirements of Sec. Sec.  314.70 and 314.71 regarding the submission 
of supplemental ANDAs and other changes to an approved ANDA.
    (b) Different listed drug. An applicant may not supplement an ANDA 
to seek approval of a drug referring to a listed drug that is different 
from the current reference listed drug identified in the ANDA. This 
paragraph (b) applies if changes are proposed in a supplement to the 
ANDA such that the proposed product is a pharmaceutical equivalent to a 
different listed drug than the reference listed drug identified in the 
ANDA. A change of reference listed drug must be submitted in a new 
ANDA. However, notwithstanding the limitation described in this 
paragraph (b), an applicant may supplement the ANDA to seek approval of 
a different strength.

0
15. Section 314.99 is revised to read as follows:


Sec.  314.99  Other responsibilities of an applicant of an ANDA.

    (a) An applicant must comply with the requirements of Sec.  314.65 
regarding withdrawal by the applicant of an unapproved ANDA and Sec.  
314.72 regarding a change in ownership of an ANDA.
    (b) An applicant may ask FDA to waive under this section any 
requirement that applies to the applicant under Sec. Sec.  314.92 
through 314.99. The applicant must comply with the requirements for a 
waiver under Sec.  314.90. If FDA grants the applicant's waiver request 
with respect to a requirement under Sec. Sec.  314.92 through 314.99, 
the waived requirement will not constitute a basis for refusal to 
approve an ANDA under Sec.  314.127.

0
16. Section 314.101 is revised to read as follows:


Sec.  314.101  Filing an NDA and receiving an ANDA.

    (a) Filing an NDA. (1) Within 60 days after FDA receives an NDA, 
the Agency will determine whether the NDA may be filed. The filing of 
an NDA means that FDA has made a threshold determination that the NDA 
is sufficiently complete to permit a substantive review.
    (2) If FDA finds that none of the reasons in paragraphs (d) and (e) 
of this section for refusing to file the NDA apply, the Agency will 
file the NDA and notify the applicant in writing. In the case of a 
505(b)(2) application that contains a paragraph IV certification, the 
applicant will be notified via a paragraph IV acknowledgment letter. 
The date of filing will be the date 60 days after the date FDA received 
the NDA. The date of filing begins the 180-day period described in 
section 505(c) of the Federal Food, Drug, and Cosmetic Act. This 180-
day period is called the ``filing clock.''
    (3) If FDA refuses to file the NDA, the Agency will notify the 
applicant in writing and state the reason under paragraph (d) or (e) of 
this section for the refusal. If FDA refuses to file the NDA under 
paragraph (d) of this section, the applicant may request in writing 
within 30 days of the date of the Agency's notification an informal 
conference with the Agency about whether the Agency should file the 
NDA. If, following the informal conference, the applicant requests that 
FDA file the NDA (with or without amendments to correct the 
deficiencies), the Agency will file the NDA over protest under 
paragraph (a)(2) of this section, notify the applicant in writing, and 
review it as filed. If the NDA is filed over protest, the date of 
filing will be the date 60 days after the date the applicant requested 
the informal conference. The applicant need not resubmit a copy of an 
NDA that is filed over protest. If FDA refuses to file the NDA under 
paragraph (e) of this section, the applicant may amend the NDA and 
resubmit it, and the Agency will make a determination under this 
section whether it may be filed.
    (b)(1) Receiving an ANDA. An ANDA will be evaluated after it is 
submitted to determine whether the ANDA may be received. Receipt of an 
ANDA means that FDA has made a threshold determination that the 
abbreviated application is substantially complete.
    (2) If FDA finds that none of the reasons in paragraphs (d) and (e) 
of this section for considering the ANDA not to have been received 
applies, the ANDA is substantially complete and the Agency will receive 
the ANDA and notify the applicant in writing. If FDA determines, upon 
evaluation, that an ANDA was substantially complete as of the date it 
was submitted to FDA, FDA will consider the ANDA to have been received 
as of the date of submission. In the case of an ANDA that contains a 
paragraph IV certification, the applicant will be notified via a 
paragraph IV acknowledgment letter.
    (3) If FDA considers the ANDA not to have been received under 
paragraph (d) or (e) of this section, FDA will notify the applicant of 
the refuse-to-receive decision. The applicant may then:
    (i) Withdraw the ANDA under Sec.  314.99; or
    (ii) Correct the deficiencies and resubmit the ANDA; or
    (iii) Take no action, in which case FDA may consider the ANDA 
withdrawn after 1 year.

[[Page 69654]]

    (c) [Reserved]
    (d) NDA or ANDA deficiencies. FDA may refuse to file an NDA or may 
not consider an ANDA to be received if any of the following applies:
    (1) The NDA or ANDA does not contain a completed application form.
    (2) The NDA or ANDA is not submitted in the form required under 
Sec.  314.50 or Sec.  314.94.
    (3) The NDA or ANDA is incomplete because it does not on its face 
contain information required under section 505(b) or section 505(j) of 
the Federal Food, Drug, and Cosmetic Act and Sec.  314.50 or Sec.  
314.94. In determining whether an ANDA is incomplete on its face, FDA 
will consider the nature (e.g., major or minor) of the deficiencies, 
including the number of deficiencies in the ANDA.
    (4) The applicant fails to submit a complete environmental 
assessment, which addresses each of the items specified in the 
applicable format under Sec.  25.40 of this chapter or fails to provide 
sufficient information to establish that the requested action is 
subject to categorical exclusion under Sec.  25.30 or Sec.  25.31 of 
this chapter.
    (5) The NDA or ANDA does not contain an accurate and complete 
English translation of each part of the NDA or ANDA that is not in 
English.
    (6) The NDA or ANDA does not contain a statement for each 
nonclinical laboratory study that the study was conducted in compliance 
with the requirements set forth in part 58 of this chapter, or, for 
each study not conducted in compliance with part 58 of this chapter, a 
brief statement of the reason for the noncompliance.
    (7) The NDA or ANDA does not contain a statement for each clinical 
study that the study was conducted in compliance with the institutional 
review board regulations in part 56 of this chapter, or was not subject 
to those regulations, and that it was conducted in compliance with the 
informed consent regulations in part 50 of this chapter, or, if the 
study was subject to but was not conducted in compliance with those 
regulations, the NDA or ANDA does not contain a brief statement of the 
reason for the noncompliance.
    (8) The drug product that is the subject of the submission is 
already covered by an approved NDA or ANDA and the applicant of the 
submission:
    (i) Has an approved NDA or ANDA for the same drug product; or
    (ii) Is merely a distributor and/or repackager of the already 
approved drug product.
    (9) The NDA is submitted as a 505(b)(2) application for a drug that 
is a duplicate of a listed drug and is eligible for approval under 
section 505(j) of the Federal Food, Drug, and Cosmetic Act.
    (e) Regulatory deficiencies. The Agency will refuse to file an NDA 
or will consider an ANDA not to have been received if any of the 
following applies:
    (1) The drug product is subject to licensing by FDA under the 
Public Health Service Act (42 U.S.C. 201 et seq.) and subchapter F of 
this chapter.
    (2) Submission of a 505(b)(2) application or an ANDA is not 
permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), 
505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 505E(a) of the Federal 
Food, Drug, and Cosmetic Act.
    (f) Outcome of FDA review. (1) Within 180 days after the date of 
filing, plus the period of time the review period was extended (if 
any), FDA will either:
    (i) Approve the NDA; or
    (ii) Issue a notice of opportunity for a hearing if the applicant 
asked FDA to provide it an opportunity for a hearing on an NDA in 
response to a complete response letter.
    (2) Within 180 days after the date of receipt, plus the period of 
time the review clock was extended (if any), FDA will either approve or 
disapprove the ANDA. If FDA disapproves the ANDA, FDA will issue a 
notice of opportunity for hearing if the applicant asked FDA to provide 
it an opportunity for a hearing on an ANDA in response to a complete 
response letter.
    (3) This paragraph (f) does not apply to NDAs or ANDAs that have 
been withdrawn from FDA review by the applicant.

0
17. Section 314.105 is revised to read as follows:


Sec.  314.105  Approval of an NDA and an ANDA.

    (a) FDA will approve an NDA and send the applicant an approval 
letter if none of the reasons in Sec.  314.125 for refusing to approve 
the NDA applies. FDA will issue a tentative approval letter if an NDA 
otherwise meets the requirements for approval under the Federal Food, 
Drug, and Cosmetic Act, but cannot be approved because there is a 7-
year period of orphan exclusivity for the listed drug under section 527 
of the Federal Food, Drug, and Cosmetic Act and Sec.  316.31 of this 
chapter, or if a 505(b)(2) application otherwise meets the requirements 
for approval under the Federal Food, Drug, and Cosmetic Act, but cannot 
be approved until the conditions in Sec.  314.107(b)(3) are met; 
because there is a period of exclusivity for the listed drug under 
Sec.  314.108; because there is a period of pediatric exclusivity for 
the listed drug under section 505A of the Federal Food, Drug, and 
Cosmetic Act; or because there is a period of exclusivity for the 
listed drug under section 505E of the Federal Food, Drug, and Cosmetic 
Act. A drug product that is granted tentative approval is not an 
approved drug and will not be approved until FDA issues an approval 
after any necessary additional review of the NDA. FDA's tentative 
approval of a drug product is based on information available to FDA at 
the time of the tentative approval letter (i.e., information in the 
505(b)(2) application and the status of current good manufacturing 
practices of the facilities used in the manufacturing and testing of 
the drug product) and is therefore subject to change on the basis of 
new information that may come to FDA's attention. A new drug product 
may not be marketed until the date of approval.
    (b) FDA will approve an NDA and issue the applicant an approval 
letter on the basis of draft labeling if the only deficiencies in the 
NDA concern editorial or similar minor deficiencies in the draft 
labeling. Such approval will be conditioned upon the applicant 
incorporating the specified labeling changes exactly as directed, and 
upon the applicant submitting to FDA a copy of the final printed 
labeling prior to marketing.
    (c) FDA will approve an NDA after it determines that the drug meets 
the statutory standards for safety and effectiveness, manufacturing and 
controls, and labeling, and an ANDA after it determines that the drug 
meets the statutory standards for manufacturing and controls, labeling, 
and, where applicable, bioequivalence. While the statutory standards 
apply to all drugs, the many kinds of drugs that are subject to the 
statutory standards and the wide range of uses for those drugs demand 
flexibility in applying the standards. Thus FDA is required to exercise 
its scientific judgment to determine the kind and quantity of data and 
information an applicant is required to provide for a particular drug 
to meet the statutory standards. FDA makes its views on drug products 
and classes of drugs available through guidance documents, 
recommendations, and other statements of policy.
    (d) FDA will approve an ANDA and send the applicant an approval 
letter if none of the reasons in Sec.  314.127 for refusing to approve 
the ANDA applies. FDA will issue a tentative approval letter if an ANDA 
otherwise meets the requirements for approval under the Federal Food, 
Drug, and Cosmetic Act, but cannot be approved because there is a 7-
year period of orphan exclusivity for the listed drug under section 527 
of the

[[Page 69655]]

Federal Food, Drug, and Cosmetic Act and Sec.  316.31 of this chapter, 
or cannot be approved until the conditions in Sec.  314.107(b)(3) or 
(c) are met; because there is a period of exclusivity for the listed 
drug under Sec.  314.108; because there is a period of pediatric 
exclusivity for the listed drug under section 505A of the Federal Food, 
Drug, and Cosmetic Act; or because there is a period of exclusivity for 
the listed drug under section 505E of the Federal Food, Drug, and 
Cosmetic Act. A drug product that is granted tentative approval is not 
an approved drug and will not be approved until FDA issues an approval 
after any necessary additional review of the ANDA. FDA's tentative 
approval of a drug product is based on information available to FDA at 
the time of the tentative approval letter (i.e., information in the 
ANDA and the status of current good manufacturing practices of the 
facilities used in the manufacturing and testing of the drug product) 
and is therefore subject to change on the basis of new information that 
may come to FDA's attention. A new drug product may not be marketed 
until the date of approval.

0
18. Section 314.107 is revised to read as follows:


Sec.  314.107  Date of approval of a 505(b)(2) application or ANDA.

    (a) General. A drug product may be introduced or delivered for 
introduction into interstate commerce when the 505(b)(2) application or 
ANDA for the drug product is approved. A 505(b)(2) application or ANDA 
for a drug product is approved on the date FDA issues an approval 
letter under Sec.  314.105 for the 505(b)(2) application or ANDA.
    (b) Effect of patent(s) on the listed drug. As described in 
paragraphs (b)(1) and (2) of this section, the status of patents listed 
for the listed drug(s) relied upon or reference listed drug, as 
applicable, must be considered in determining the first possible date 
on which a 505(b)(2) application or ANDA can be approved. The criteria 
in paragraphs (b)(1) and (2) of this section will be used to determine, 
for each relevant patent, the date that patent will no longer prevent 
approval. The first possible date on which the 505(b)(2) application or 
ANDA can be approved will be calculated for each patent, and the 
505(b)(2) application or ANDA may be approved on the last applicable 
date.
    (1) Timing of approval based on patent certification or statement. 
If none of the reasons in Sec.  314.125 or Sec.  314.127, as 
applicable, for refusing to approve the 505(b)(2) application or ANDA 
applies, and none of the reasons in paragraph (d) of this section for 
delaying approval applies, the 505(b)(2) application or ANDA may be 
approved as follows:
    (i) Immediately, if the applicant certifies under Sec.  314.50(i) 
or Sec.  314.94(a)(12) that:
    (A) The applicant is aware of a relevant patent but the patent 
information required under section 505(b) or (c) of the Federal Food, 
Drug, and Cosmetic Act has not been submitted to FDA; or
    (B) The relevant patent has expired; or
    (C) The relevant patent is invalid, unenforceable, or will not be 
infringed, except as provided in paragraphs (b)(3) and (c) of this 
section, and the 45-day period provided for in section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act has expired; 
or
    (D) There are no relevant patents.
    (ii) Immediately, if the applicant submits an appropriate statement 
under Sec.  314.50(i) or Sec.  314.94(a)(12) explaining that a method-
of-use patent does not claim an indication or other condition of use 
for which the applicant is seeking approval, except that if the 
applicant also submits a paragraph IV certification to the patent, then 
the 505(b)(2) application or ANDA may be approved as provided in 
paragraph (b)(1)(i)(C) of this section.
    (iii) On the date specified, if the applicant certifies under Sec.  
314.50(i) or Sec.  314.94(a)(12) that the relevant patent will expire 
on a specified date.
    (2) Patent information filed after submission of 505(b)(2) 
application or ANDA. If the holder of the approved NDA for the listed 
drug submits patent information required under Sec.  314.53 after the 
date on which the 505(b)(2) application or ANDA was submitted to FDA, 
the 505(b)(2) applicant or ANDA applicant must comply with the 
requirements of Sec.  314.50(i)(4) and (6) and Sec.  314.94(a)(12)(vi) 
and (viii) regarding submission of an appropriate patent certification 
or statement. If the applicant submits an amendment certifying under 
Sec.  314.50(i)(1)(i)(A)(4) or Sec.  314.94(a)(12)(i)(A)(4) that the 
relevant patent is invalid, unenforceable, or will not be infringed, 
and complies with the requirements of Sec.  314.52 or Sec.  314.95, the 
505(b)(2) application or ANDA may be approved immediately upon 
submission of documentation of receipt of notice of paragraph IV 
certification under Sec.  314.52(e) or Sec.  314.95(e). The 45-day 
period provided for in section 505(c)(3)(C) and (j)(5)(B)(iii) of the 
Federal Food, Drug, and Cosmetic Act does not apply in these 
circumstances.
    (3) Disposition of patent litigation--(i) Approval upon expiration 
of 30-month period or 7\1/2\ years from date of listed drug approval. 
(A) Except as provided in paragraphs (b)(3)(ii) through (viii) of this 
section, if, with respect to patents for which required information was 
submitted under Sec.  314.53 before the date on which the 505(b)(2) 
application or ANDA was submitted to FDA (excluding an amendment or 
supplement to the 505(b)(2) application or ANDA), the applicant 
certifies under Sec.  314.50(i) or Sec.  314.94(a)(12) that the 
relevant patent is invalid, unenforceable, or will not be infringed, 
and the patent owner or its representative or the exclusive patent 
licensee brings suit for patent infringement within 45 days of receipt 
of the notice of certification from the applicant under Sec.  314.52 or 
Sec.  314.95, the 505(b)(2) application or ANDA may be approved 30 
months after the later of the date of the receipt of the notice of 
certification by any owner of the listed patent or by the NDA holder 
(or its representative(s)) unless the court has extended or reduced the 
period because of a failure of either the plaintiff or defendant to 
cooperate reasonably in expediting the action; or
    (B) If the patented drug product qualifies for 5 years of exclusive 
marketing under Sec.  314.108(b)(2) and the patent owner or its 
representative or the exclusive patent licensee brings suit for patent 
infringement during the 1-year period beginning 4 years after the date 
of approval of the patented drug and within 45 days of receipt of the 
notice of certification from the applicant under Sec.  314.52 or Sec.  
314.95, the 505(b)(2) application or ANDA may be approved at the 
expiration of the 7\1/2\ years from the date of approval of the NDA for 
the patented drug product.
    (ii) Federal district court decision of invalidity, 
unenforceability, or non-infringement. If before the expiration of the 
30-month period, or 7\1/2\ years where applicable, the district court 
decides that the patent is invalid, unenforceable, or not infringed 
(including any substantive determination that there is no cause of 
action for patent infringement or invalidity), the 505(b)(2) 
application or ANDA may be approved on:
    (A) The date on which the court enters judgment reflecting the 
decision; or
    (B) The date of a settlement order or consent decree signed and 
entered by the court stating that the patent that is the subject of the 
certification is invalid, unenforceable, or not infringed.
    (iii) Appeal of Federal district court judgment of infringement. If 
before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the district court decides that the patent has been

[[Page 69656]]

infringed, and if the judgment of the district court is appealed, the 
505(b)(2) application or ANDA may be approved on:
    (A) The date on which the mandate is issued by the court of appeals 
entering judgment that the patent is invalid, unenforceable, or not 
infringed (including any substantive determination that there is no 
cause of action for patent infringement or invalidity); or
    (B) The date of a settlement order or consent decree signed and 
entered by the court of appeals stating that the patent that is the 
subject of the certification is invalid, unenforceable, or not 
infringed.
    (iv) Affirmation or non-appeal of Federal district court judgment 
of infringement. If before the expiration of the 30-month period, or 
7\1/2\ years where applicable, the district court decides that the 
patent has been infringed, and if the judgment of the district court is 
not appealed or is affirmed, the 505(b)(2) application or ANDA may be 
approved no earlier than the date specified by the district court in an 
order under 35 U.S.C. 271(e)(4)(A).
    (v) Grant of preliminary injunction by Federal district court. If 
before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the district court grants a preliminary injunction 
prohibiting the applicant from engaging in the commercial manufacture 
or sale of the drug product until the court decides the issues of 
patent validity and infringement, and if the court later decides that:
    (A) The patent is invalid, unenforceable, or not infringed, the 
505(b)(2) application or ANDA may be approved as provided in paragraph 
(b)(3)(ii) of this section; or
    (B) The patent is infringed, the 505(b)(2) application or ANDA may 
be approved as provided in paragraph (b)(3)(iii) or (iv) of this 
section, whichever is applicable.
    (vi) Written consent to approval by patent owner or exclusive 
patent licensee. If before the expiration of the 30-month period, or 
7\1/2\ years where applicable, the patent owner or the exclusive patent 
licensee (or their representatives) agrees in writing that the 
505(b)(2) application or ANDA may be approved any time on or after the 
date of the consent, approval may be granted on or after that date.
    (vii) Court order terminating 30-month or 7\1/2\-year period. If 
before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the court enters an order requiring the 30-month or 7\1/2\-
year period to be terminated, the 505(b)(2) application or ANDA may be 
approved in accordance with the court's order.
    (viii) Court order of dismissal without a finding of infringement. 
If before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the court(s) enter(s) an order of dismissal, with or 
without prejudice, without a finding of infringement in each pending 
suit for patent infringement brought within 45 days of receipt of the 
notice of paragraph IV certification sent by the 505(b)(2) or ANDA 
applicant, the 505(b)(2) application or ANDA may be approved on or 
after the date of the order.
    (4) Tentative approval. FDA will issue a tentative approval letter 
when tentative approval is appropriate in accordance with this section. 
In order for a 505(b)(2) application or ANDA to be approved under 
paragraph (b)(3) of this section, the applicant must receive an 
approval letter from the Agency. Tentative approval of an NDA or ANDA 
does not constitute ``approval'' of an NDA or ANDA and cannot, absent 
an approval letter from the Agency, result in an approval under 
paragraph (b)(3) of this section.
    (c) Timing of approval of subsequent ANDA. (1) If an ANDA contains 
a paragraph IV certification for a relevant patent and the ANDA is not 
that of a first applicant, the ANDA is regarded as the ANDA of a 
subsequent applicant. The ANDA of a subsequent applicant will not be 
approved during the period when any first applicant is eligible for 
180-day exclusivity or during the 180-day exclusivity period of a first 
applicant. Any applicable 180-day exclusivity period cannot extend 
beyond the expiration of the patent upon which the 180-day exclusivity 
period was based.
    (2) A first applicant must submit correspondence to its ANDA 
notifying FDA within 30 days of the date of its first commercial 
marketing of its drug product or the reference listed drug. If an 
applicant does not notify FDA, as required in this paragraph (c)(2), of 
this date, the date of first commercial marketing will be deemed to be 
the date of the drug product's approval.
    (3) If FDA concludes that a first applicant is not actively 
pursuing approval of its ANDA, FDA may immediately approve an ANDA(s) 
of a subsequent applicant(s) if the ANDA(s) is otherwise eligible for 
approval.
    (d) Delay due to exclusivity. The Agency will also delay the 
approval of a 505(b)(2) application or ANDA if delay is required by the 
exclusivity provisions in Sec.  314.108; section 527 of the Federal 
Food, Drug, and Cosmetic Act and Sec.  316.31 of this chapter; section 
505A of the Federal Food, Drug, and Cosmetic Act; or section 505E of 
the Federal Food, Drug, and Cosmetic Act. When the approval of a 
505(b)(2) application or ANDA is delayed under this section and Sec.  
314.108; section 527 of the Federal Food, Drug, and Cosmetic Act and 
Sec.  316.31 of this chapter; section 505A of the Federal Food, Drug, 
and Cosmetic Act; or section 505E of the Federal Food, Drug, and 
Cosmetic Act, the 505(b)(2) application or ANDA will be approved on the 
latest of the days specified under this section and Sec.  314.108; 
section 527 of the Federal Food, Drug, and Cosmetic Act and Sec.  
316.31 of this chapter; section 505A of the Federal Food, Drug, and 
Cosmetic Act; or section 505E of the Federal Food, Drug, and Cosmetic 
Act, as applicable.
    (e) Notification of court actions or written consent to approval. 
(1) The applicant must submit the following information to FDA, as 
applicable:
    (i) A copy of any judgment by the court (district court or mandate 
of the court of appeals) or settlement order or consent decree signed 
and entered by the court (district court or court of appeals) finding a 
patent described in paragraph (b)(3) of this section invalid, 
unenforceable, or not infringed, or finding the patent valid and 
infringed;
    (ii) Written notification of whether or not any action by the court 
described in paragraph (e)(1)(i) of this section has been appealed 
within the time permitted for an appeal;
    (iii) A copy of any order entered by the court terminating the 30-
month or 7\1/2\-year period as described in paragraph (b)(3)(i), (ii), 
(vii), or (viii) of this section;
    (iv) A copy of any written consent to approval by the patent owner 
or exclusive patent licensee described in paragraph (b)(3)(vi) of this 
section;
    (v) A copy of any preliminary injunction described in paragraph 
(b)(3)(v) of this section, and a copy of any subsequent court order 
lifting the injunction; and
    (vi) A copy of any court order pursuant to 35 U.S.C. 271(e)(4)(A) 
ordering that a 505(b)(2) application or ANDA may be approved no 
earlier than the date specified (irrespective of whether the injunction 
relates to a patent described in paragraph (b)(3) of this section).
    (2) All information required by paragraph (e)(1) of this section 
must be sent to the applicant's NDA or ANDA, as appropriate, within 14 
days of the date of entry by the court, the date of appeal or 
expiration of the time for appeal, or the date of written consent to 
approval, as applicable.

[[Page 69657]]

    (f) Forty-five day period after receipt of notice of paragraph IV 
certification--(1) Computation of 45-day time clock. The 45-day clock 
described in paragraph (b)(3) of this section as to each recipient 
required to receive notice of paragraph IV certification under Sec.  
314.52 or Sec.  314.95 begins on the day after the date of receipt of 
the applicant's notice of paragraph IV certification by the recipient. 
When the 45th day falls on Saturday, Sunday, or a Federal holiday, the 
45th day will be the next day that is not a Saturday, Sunday, or a 
Federal holiday.
    (2) Notification of filing of legal action. (i) The 505(b)(2) or 
ANDA applicant must notify FDA in writing within 14 days of the filing 
of any legal action filed within 45 days of receipt of the notice of 
paragraph IV certification by any recipient. A 505(b)(2) applicant must 
send the notification to its NDA. An ANDA applicant must send the 
notification to its ANDA. The notification to FDA of the legal action 
must include:
    (A) The 505(b)(2) application or ANDA number.
    (B) The name of the 505(b)(2) or ANDA applicant.
    (C) The established name of the drug product or, if no established 
name exists, the name(s) of the active ingredient(s), the drug 
product's strength, and dosage form.
    (D) A statement that an action for patent infringement, identified 
by court, case number, and the patent number(s) of the patent(s) at 
issue in the action, has been filed in an appropriate court on a 
specified date.
    (ii) A patent owner or NDA holder (or its representative(s)) may 
also notify FDA of the filing of any legal action for patent 
infringement. The notice should contain the information and be sent to 
the offices or divisions described in paragraph (f)(2)(i) of this 
section.
    (iii) If the 505(b)(2) or ANDA applicant, the patent owner(s), the 
NDA holder, or its representative(s) does not notify FDA in writing 
before the expiration of the 45-day time period or the completion of 
the Agency's review of the 505(b)(2) application or ANDA, whichever 
occurs later, that a legal action for patent infringement was filed 
within 45 days of receipt of the notice of paragraph IV certification, 
the 505(b)(2) application or ANDA may be approved upon expiration of 
the 45-day period (if the 505(b)(2) or ANDA applicant confirms that a 
legal action for patent infringement has not been filed) or upon 
completion of the Agency's review of the 505(b)(2) application or ANDA, 
whichever is later.
    (3) Waiver. If the patent owner or NDA holder who is an exclusive 
patent licensee (or its representative(s)) waives its opportunity to 
file a legal action for patent infringement within 45 days of a receipt 
of the notice of certification and the patent owner or NDA holder who 
is an exclusive patent licensee (or its representative(s)) submits to 
FDA a valid waiver before the 45 days elapse, the 505(b)(2) application 
or ANDA may be approved upon completion of the Agency's review of the 
NDA or ANDA. FDA will only accept a waiver in the following form:

    (Name of patent owner or NDA holder who is an exclusive patent 
licensee or its representative(s)) has received notice from (name of 
applicant) under (section 505(b)(3) or 505(j)(2)(B) of the Federal 
Food, Drug, and Cosmetic Act) and does not intend to file an action 
for patent infringement against (name of applicant) concerning the 
drug (name of drug) before (date on which 45 days elapse). (Name of 
patent owner or NDA holder who is an exclusive patent licensee) 
waives the opportunity provided by (section 505(c)(3)(C) or 
505(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act) and 
does not object to FDA's approval of (name of applicant)'s 
(505(b)(2) application or ANDA) for (name of drug) with an approval 
date on or after the date of this submission.

    (g) Conversion of approval to tentative approval. If FDA issues an 
approval letter in error or a court enters an order requiring, in the 
case of an already approved 505(b)(2) application or ANDA, that the 
date of approval be delayed, FDA will convert the approval to a 
tentative approval if appropriate.

0
19. Amend Sec.  314.108 as follows:
0
a. In paragraph (a):
0
i. Revise the introductory text and the definitions of ``Approved under 
section 505(b)'', ``Essential to approval'', and ``New chemical 
entity'';
0
ii. Remove the definitions of ``Active moiety'', ``Date of approval'', 
and ``FDA''; and
0
iii. Add in alphabetical order the definition of ``Bioavailability 
study''; and
0
b. Revise the paragraph (b) heading and paragraphs (b)(2) through (5).
    The revisions and addition read as follows:


Sec.  314.108  New drug product exclusivity.

    (a) Definitions. The definitions in Sec.  314.3 and the following 
definitions of terms apply to this section:
    Approved under section 505(b) means an NDA submitted under section 
505(b) and approved on or after October 10, 1962, or an application 
that was ``deemed approved'' under section 107(c)(2) of Public Law 87-
781.
    Bioavailability study means a study to determine the 
bioavailability or the pharmacokinetics of a drug.
* * * * *
    Essential to approval means, with regard to an investigation, that 
there are no other data available that could support approval of the 
NDA.
    New chemical entity means a drug that contains no active moiety 
that has been approved by FDA in any other NDA submitted under section 
505(b) of the Federal Food, Drug, and Cosmetic Act.
* * * * *
    (b) Submission of and timing of approval of a 505(b)(2) application 
or ANDA. * * *
    (2) If a drug product that contains a new chemical entity was 
approved after September 24, 1984, in an NDA submitted under section 
505(b) of the Federal Food, Drug, and Cosmetic Act, no person may 
submit a 505(b)(2) application or ANDA under section 505(j) of the 
Federal Food, Drug, and Cosmetic Act for a drug product that contains 
the same active moiety as in the new chemical entity for a period of 5 
years from the date of approval of the first approved NDA, except that 
the 505(b)(2) application or ANDA may be submitted after 4 years if it 
contains a certification of patent invalidity or noninfringement 
described in Sec.  314.50(i)(1)(i)(A)(4) or Sec.  
314.94(a)(12)(i)(A)(4).
    (3) The approval of a 505(b)(2) application or ANDA described in 
paragraph (b)(2) of this section will occur as provided in Sec.  
314.107(b)(1) or (2), unless the owner of a patent that claims the 
drug, the patent owner's representative, or exclusive licensee brings 
suit for patent infringement against the applicant during the 1-year 
period beginning 48 months after the date of approval of the NDA for 
the new chemical entity and within 45 days after receipt of the notice 
described at Sec.  314.52 or Sec.  314.95, in which case, approval of 
the 505(b)(2) application or ANDA will occur as provided in Sec.  
314.107(b)(3).
    (4) If an NDA:
    (i) Was submitted under section 505(b) of the Federal Food, Drug, 
and Cosmetic Act;
    (ii) Was approved after September 24, 1984;
    (iii) Was for a drug product that contains an active moiety that 
has been previously approved in another NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act; and
    (iv) Contained reports of new clinical investigations (other than 
bioavailability studies) conducted or sponsored by the

[[Page 69658]]

applicant that were essential to approval of the application, for a 
period of 3 years after the date of approval of the application, the 
Agency will not approve a 505(b)(2) application or an ANDA for the 
conditions of approval of the NDA, or an ANDA submitted pursuant to an 
approved petition under section 505(j)(2)(C) of the Federal Food, Drug, 
and Cosmetic Act that relies on the information supporting the 
conditions of approval of an original NDA.
    (5) If a supplemental NDA:
    (i) Was approved after September 24, 1984; and
    (ii) Contained reports of new clinical investigations (other than 
bioavailability studies) that were conducted or sponsored by the 
applicant that were essential to approval of the supplemental NDA, for 
a period of 3 years after the date of approval of the supplemental 
application, the Agency will not approve a 505(b)(2) application or an 
ANDA for a change, or an ANDA submitted pursuant to an approved 
petition under section 505(j)(2)(C) of the Federal Food, Drug, and 
Cosmetic Act that relies on the information supporting a change 
approved in the supplemental NDA.

0
20. Amend Sec.  314.125 as follows:
0
a. Remove the word ``application'' and add in its place ``NDA'' 
wherever it appears in paragraphs (a) introductory text, (a)(2), 
(b)(7), (9), (10), and (12), and (b)(14) through (18);
0
b. Remove the word ``act'' and add in its place ``Federal Food, Drug, 
and Cosmetic Act'' in paragraphs (a) introductory text and (b)(2), 
(11), and (18);
0
c. Revise the section heading and paragraph (b) introductory text; and
0
d. Add paragraph (b)(19).
    The revisions and addition read as follows:


Sec.  314.125  Refusal to approve an NDA.

* * * * *
    (b) FDA may refuse to approve an NDA for any of the following 
reasons, unless the requirement has been waived under Sec.  314.90:
* * * * *
    (19) The 505(b)(2) application failed to contain a patent 
certification or statement with respect to each listed patent for a 
drug product approved in an NDA that:
    (i) Is pharmaceutically equivalent to the drug product for which 
the original 505(b)(2) application is submitted; and
    (ii) Was approved before the original 505(b)(2) application was 
submitted.
* * * * *

0
21. Amend Sec.  314.127 as follows:
0
a. Remove the words ``abbreviated application'' and ``abbreviated new 
drug application'' wherever they appear and add in their place ``ANDA'' 
in paragraphs (a) introductory text, (a)(3) through (7), (a)(8)(ii)(A) 
introductory text, (a)(9) and (10), and (b);
0
b. Remove the word ``act'' wherever it appears and add in its place 
``Federal Food, Drug, and Cosmetic Act'' in paragraphs 
(a)(3)(iii)(A)(2) and (a)(12);
0
c. Remove ``officer of employee'' and add in its place ``officer or 
employee'' in paragraph (b);
0
d. Revise the section heading and paragraphs (a) introductory text, 
(a)(2), (a)(8)(i) introductory text, and (a)(8)(ii)(B) and (C); and
0
e. Add paragraph (a)(14).
    The revisions and addition read as follows:


Sec.  314.127  Refusal to approve an ANDA.

    (a) FDA will refuse to approve an ANDA for a new drug under section 
505(j) of the Federal Food, Drug, and Cosmetic Act for any of the 
following reasons, unless the requirement has been waived under Sec.  
314.99:
* * * * *
    (2) Information submitted with the ANDA is insufficient to show 
that each of the proposed conditions of use has been previously 
approved for the listed drug referred to in the ANDA.
* * * * *
    (8)(i) Information submitted in the ANDA or any other information 
available to FDA shows that:
* * * * *
    (ii) * * *
    (B) FDA will consider an inactive ingredient in, or the composition 
of, a drug product intended for parenteral use to be unsafe and will 
refuse to approve the ANDA unless it contains the same inactive 
ingredients, other than preservatives, buffers, and antioxidants, in 
the same concentration as the listed drug, and, if it differs from the 
listed drug in a preservative, buffer, or antioxidant, the ANDA 
contains sufficient information to demonstrate that the difference does 
not affect the safety or efficacy of the drug product.
    (C) FDA will consider an inactive ingredient in, or the composition 
of, a drug product intended for ophthalmic or otic use unsafe and will 
refuse to approve the ANDA unless it contains the same inactive 
ingredients, other than preservatives, buffers, substances to adjust 
tonicity, or thickening agents, in the same concentration as the listed 
drug, and if it differs from the listed drug in a preservative, buffer, 
substance to adjust tonicity, or thickening agent, the ANDA contains 
sufficient information to demonstrate that the difference does not 
affect the safety or efficacy of the drug product and the labeling does 
not claim any therapeutic advantage over or difference from the listed 
drug.
* * * * *
    (14) For an ANDA submitted pursuant to an approved petition under 
Sec.  10.30 of this chapter and Sec.  314.93, an NDA subsequently has 
been approved for the change described in the approved petition.
* * * * *

PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS

0
22. The authority citation for part 320 continues to read as follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 371.


0
23. Section 320.1 is revised to read as follows:


Sec.  320.1  Definitions.

    The definitions contained in Sec.  314.3 of this chapter apply to 
those terms when used in this part.

0
24. Amend Sec.  320.23 as follows:
0
a. Revise the last sentence in paragraph (a)(1);
0
b. Remove the word ``shall'' and add in its place the word ``must'' in 
paragraph (a)(2);
0
c. Redesignate paragraph (b) as paragraph (b)(1); and
0
d. Add paragraph (b)(2).
    The revisions and additions read as follows:


Sec.  320.23  Basis for measuring in vivo bioavailability or 
demonstrating bioequivalence.

    (a)(1) * * * For drug products that are not intended to be absorbed 
into the bloodstream, bioavailability may be assessed by scientifically 
valid measurements intended to reflect the rate and extent to which the 
active ingredient or active moiety becomes available at the site of 
action.
* * * * *
    (b) * * *
    (2) For drug products that are not intended to be absorbed into the 
bloodstream, bioequivalence may be demonstrated by scientifically valid 
methods that are expected to detect a significant difference between 
the drug and the listed drug in safety and therapeutic effect.

    Dated: September 15, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-22690 Filed 10-5-16; 8:45 am]
BILLING CODE 4164-01-P