Government-Owned Inventions; Availability for Licensing, 12761-12764 [2010-5764]
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wwoods2 on DSK1DXX6B1PROD with NOTICES_PART 1
Federal Register / Vol. 75, No. 51 / Wednesday, March 17, 2010 / Notices
that refers to that listed drug may be
approved. FDA may not approve an
ANDA that references a listed drug that
the agency has determined was
withdrawn for reasons of safety or
effectiveness (§ 314.127(a)(11)).
CERNEVIT–12 (multivitamins for
infusion) is the subject of NDA 20–924,
held by Baxter Health Corp. (Baxter).
FDA approved the NDA on April 6,
1999, as an application under section
505(b)(2) of the act (21 U.S.C. 355(b)(2)),
relying in part upon literature and the
agency’s prior findings of safety and
efficacy for a listed parenteral
multivitamin drug product. CERNEVIT–
12 (multivitamins for infusion) is
indicated as a daily multivitamin
maintenance dosage for adults and
children age 11 years and older
receiving parenteral nutrition, and for
situations in which administration by
the intravenous route is required.
Adult parenteral multivitamin drug
products were reviewed for efficacy
under the Drug Efficacy Study
Implementation (DESI) program. Under
this program, implemented in response
to the 1962 amendments to the act
requiring demonstration of effectiveness
(The Kefauver-Harris Amendments,
Public Law No. 87–781 (1962)), the
National Academy of Sciences-National
Research Council (NAS-NRC) undertook
a study of some 4,000 drug formulations
for the express purpose of assessing the
efficacy of the products. Upon
consideration of the findings and
recommendations of the NAS-NRC, FDA
set forth in the Federal Register its
conclusions and assessment of whether
and under what circumstances a drug
product is considered ‘‘effective’’ for use
as required by the act.
In the initial DESI notice of July 27,
1972, addressing parenteral
multivitamin preparations, FDA
announced its conclusion that
parenteral multivitamin preparations as
then formulated lacked substantial
evidence of effectiveness because they
did not contain certain essential
vitamins, or they contained certain
vitamins in doses that were too high or
too low (37 FR 15027, July 27, 1972).
Because of the critical medical
importance of these preparations and
the lack of alternative drug products,
FDA notified manufacturers and
distributors of parenteral multivitamin
products in December 1972 that the
agency would allow these products to
remain on the market pending the
development and testing of new
formulations and the resolution of
complex technical and medical issues
(37 FR 26623, December 14, 1972).
On September 17, 1984, FDA
announced the parenteral multivitamin
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formulations the agency had determined
to be effective and the conditions for
marketing those products (49 FR 36446,
September 17, 1984). The agency
subsequently modified the conditions
for marketing an effective adult
parenteral multivitamin drug product in
2000 (65 FR 21200, April 20, 2000). In
that ‘‘upgrade’’ notice, FDA announced
several changes to the product
formulation including increases in the
dosage amounts of Vitamins B1, B6, C,
and folic acid, and amended portions of
the ‘‘Conditions for Marketing and
Approval’’ for parenteral multivitamin
products set forth in the September 17,
1984, notice to reflect the changes (Id.
at 21201).
In the Federal Register of August 18,
2003, FDA announced that it was
withdrawing approval of NDA 20–924
in response to Baxter’s withdrawal
request dated December 18, 2002 (68 FR
49481, August 18, 2003). As a result,
CERNEVIT–12 (multivitamins for
infusion) was moved to the
‘‘Discontinued Drug Product List’’
section of the Orange Book.
Strides Arcolab Limited submitted a
citizen petition under § 314.161(b) of
the regulations (Docket No. FDA–2009–
P–0318) requesting that FDA determine
whether the NDA for CERNEVIT–12
(multivitamins for infusion) had been
withdrawn from sale for reasons of
safety or effectiveness. After considering
the citizen petition and reviewing
agency records, FDA has determined
that CERNEVIT–12 (multivitamins for
infusion) was withdrawn from sale for
reasons of safety or effectiveness.
Specifically, we have carefully
reviewed our files for records
concerning the withdrawal of
CERNEVIT–12 (multivitamins for
infusion), including the NDA file for
this product. We also have
independently evaluated relevant
literature and data for possible
postmarketing adverse event reports.
Agency records did not contain any
clinical reviews describing safety issues
associated with CERNEVIT–12
(multivitamins for infusion), and
postmarketing safety reports did not
raise any safety concerns.
FDA has determined, however, that
CERNEVIT–12 (multivitamins for
infusion) was not reformulated to
comply with the April 20, 2000, Federal
Register upgrade notice before it was
withdrawn from the market. As
described in that notice, adult
parenteral multivitamin drug products
must contain higher doses of Vitamins
B1, B6, C, and folic acid than the dosages
contained in CERNEVIT–12
(multivitamins for infusion) (65 FR
21201).
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Because CERNEVIT–12
(multivitamins for infusion) is not in
compliance with current FDA standards
for adult parenteral multivitamin drug
products, the agency has determined
under § 314.161 that CERNEVIT–12
(multivitamins for infusion) was
withdrawn from sale for reasons of
safety or efficacy. (57 FR 17950 at
17956, April 28, 1992) (‘‘if the NDA or
ANDA holder fails to comply with [the
DESI upgrade] notice, the NDA or
ANDA product is not considered to be
approved for effectiveness and cannot
be a listed drug’’). The Discontinued
Drug Product List delineates, among
other items, products that have been
discontinued from marketing for reasons
other than safety or effectiveness.
Therefore, CERNEVIT–12
(multivitamins for infusion) will be
removed from the Discontinued Drug
Product List section of the Orange Book
(§ 314.162(a)(2)). In addition, FDA will
not accept or approve ANDAs that refer
to CERNEVIT–12 (multivitamins for
infusion) (21 CFR 314.127(a)(11)).
Dated: March 11, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010–5748 Filed 3–16–10; 8:45 am]
BILLING CODE 4160–01–S
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions;
Availability for Licensing
AGENCY: National Institutes of Health,
Public Health Service, HHS.
ACTION: Notice.
SUMMARY: The inventions listed below
are owned by an agency of the U.S.
Government and are available for
licensing in the U.S. in accordance with
35 U.S.C. 207 to achieve expeditious
commercialization of results of
Federally-funded research and
development. Foreign patent
applications are filed on selected
inventions to extend market coverage
for companies and may also be available
for licensing.
ADDRESSES: Licensing information and
copies of the U.S. patent applications
listed below may be obtained by writing
to the indicated licensing contact at the
Office of Technology Transfer, National
Institutes of Health, 6011 Executive
Boulevard, Suite 325, Rockville,
Maryland 20852–3804; telephone: 301/
496–7057; fax: 301/402–0220. A signed
Confidential Disclosure Agreement will
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Federal Register / Vol. 75, No. 51 / Wednesday, March 17, 2010 / Notices
Defensin-Based Therapeutics for the
Treatment of Pulmonary Disease
Caspase Inhibitors Useful for the Study
of Autoimmune or Inflammatory
Diseases
Description of Invention: Novel and
potent caspase 1 inhibitors are available
for licensing. In particular, this
technology discloses potent and
selective caspase 1 inhibitors that target
the active site of the enzyme. Caspase 1
is known to play a pro-inflammatory
role in numerous autoimmune and
inflammatory diseases and therefore
represents an excellent target for
treatment of a broad range of diseases,
including but not limited to
Huntington’s, amyotrophic lateral
sclerosis, ischemia, rheumatoid
arthritis, osteoarthritis, inflammatory
bowel disease, and sepsis. Not
surprisingly this enormous potential has
resulted in at least three caspase 1
inhibitors entering clinical trials (VX–
740, IDN–6556, and VX–765) in recent
years.
wwoods2 on DSK1DXX6B1PROD with NOTICES_PART 1
be required to receive copies of the
patent applications.
Description of Invention: Investigators
at the National Heart, Lung and Blood
Institute have developed modified
defensins that are resistant to
degradation, have improved
characteristics compared to unmodified
defensins, and are promising candidates
for pulmonary disease therapeutics.
Defensins are small cationic peptides
that defend the lung against pathogenic
microorganisms and play an important
role in innate immunity. However,
during lung inflammation, defensin
concentrations can reach levels that are
cytotoxic for airway epithelial cells.
Therefore, the development of methods
to produce modified defensins that
exhibit reduced cytotoxicity, while
retaining the ability to stimulate the
innate immune response, would be of
potential therapeutic benefit for
pulmonary diseases.
The inventors have previously shown
that a defensin, human neutrophil
peptide 1 (HNP–1), is elevated in
samples from the lungs of patients with
inflammatory lung disease, and that the
HNP–1 in these samples is ADPribosylated at one or both of two
arginine residues within the protein. In
vitro studies by the inventors show that
ADP-ribosyl-HNP–1 has reduced
cytotoxic activity compared to HNP–1,
while retaining its T cell chemotactic
properties and ability to promote
neutrophil recruitment, and thus ADPribosyl-HNP–1 may play an important
role as a regulator of the inflammatory
response. These properties would also
be useful for treatment of pulmonary
inflammation and lung diseases.
However, ADP-ribosylated HNP–1 and
other defensins are degraded rapidly in
vivo due to the susceptibility of the
ADP-ribose moiety to attack by
hydrolases and pyrophosphatases,
which limits their therapeutic potential.
The inventors have recently
discovered that the ADP-ribosylated
arginine residues in HNP–1 can be
converted to ornithine through a nonenzymatic process that results in a
peptide with an altered pharmacological
profile. The investigators have also
successfully generated ornithinesubstituted ADP-ribosyl HNP–1 and
ornithine-HNP–1 in vitro, which are
currently being characterized. Thus,
ornithine-substituted ADP-ribosyl HNP–
1 and ornithine-HNP–1 may be
promising candidates for the
development of therapeutics to treat
pulmonary disease, and the strategy of
replacing ADP-ribosylated residues with
ornithine to enhance stability and
Applications
• Potential therapeutic for a broad
range of autoimmune diseases.
• Potential therapeutic for a broad
range of inflammatory diseases.
Development Status: Early stage.
Market: The market size is potentially
very large. For instance, rheumatoid
arthritis alone affects 1% of the
population, or about 2.5–3 million
Americans. Further, it is estimated that
osteoarthritis affects at least 16 million
people in America.
Inventors: Craig J. Thomas and
Matthew B. Boxer (NHGRI).
Publication: Boxer MB, Quinn AM,
Shen M, Jadhav A, Leister W, Simeonov
A, Auld DS, Thomas CJ. A highly potent
and selective caspase 1 inhibitor that
utilizes a key 3-cyanopropanoic acid
moiety. Chem Med Chem., accepted.
Patent Status: U.S. Provisional
Application No. 61/299,790 filed 29 Jan
2010 (HHS Reference No. E–308–2009/
0–US–01).
Licensing Status: Available for
licensing.
Licensing Contact: Steve Standley,
PhD; 301–435–4074; sstand@od.nih.gov.
Collaborative Research Opportunity:
The NIH Chemical Genomics Center is
seeking statements of capability or
interest from parties interested in
collaborative research to further
develop, evaluate, or commercialize
appropriate lead compounds described
in U.S. Provisional Application No. 61/
299,790. Please contact Dr. Craig J.
Thomas via e-mail
(craigt@nhgri.nih.gov) for more
information.
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therapeutic efficacy may also be
extended to other defensins
Through an earlier, related invention,
the inventors have also demonstrated
that recombinant proteins wherein
tryptophan or phenylalanine residues
substitute for ADP-ribosylarginine have
a similar stabilizing impact on
polypeptides, making them more
suitable as therapeutic agents.
The inventors also hypothesize that it
would be possible to develop a
treatment that increases levels of an
ADP-ribosylated therapeutic protein,
such as HNP–1, in the lung via
inhalation administration of the
therapeutic protein in conjunction with
nicotinamide adenine dinucleotide
(NAD), which is required for ADPribosylation. This could represent a
unique therapeutic strategy for treating
pulmonary disease.
Applications: Development of
defensin-based therapeutics that
enhance the immune response in
pulmonary disease patients, without
damaging the epithelial cells lining the
airway.
Advantages
Modified defensins are less cytotoxic,
while retaining ability to stimulate
innate immunity.
Ornithine-substituted defensins are
resistant to enzymatic degradation,
making them more promising as drug
candidates.
Development Status: In vitro studies,
as well as analysis of patient samples,
have been performed.
Inventors: Joel Moss et al. (NHLBI).
Relevant Publication: Stevens LA,
Levine RL, Gochuico BR, Moss J. ADPribosylation of human defensin HNP–1
results in the replacement of the
modified arginine with the noncoded
amino acid ornithine. Proc Natl Acad
Sci U S A. 2009 Nov 24;106(47):19796–
19800. [PubMed: 19897717.]
Patent Status: U.S. Provisional
Application No. 61/241,311 filed
September 10, 2009 (HHS Reference No.
E–243–2009/0–US–01).
Related Technologies
• HHS Reference No. E–080–2002/0,
‘‘Modified Defensins and Their Use.’’
• HHS Reference No. E–160–2002/0,
‘‘Tryptophan as a Functional
Replacement for ADP-ribose-arginine in
Recombinant Proteins.’’
Licensing Status: Available for
licensing.
Licensing Contact: Tara Kirby, PhD;
301–435–4426; tarak@mail.nih.gov.
Collaborative Research Opportunity:
The National Heart, Lung and Blood
Institute Translational Medicine Branch
is seeking statements of capability or
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Federal Register / Vol. 75, No. 51 / Wednesday, March 17, 2010 / Notices
interest from parties interested in
collaborative research to further
develop, evaluate, or commercialize
defensin-based therapeutic agents to
treat pulmonary diseases. Please contact
Brian W. Bailey, PhD at 301–494–4094
or bbailey@mail.nih.gov for more
information.
wwoods2 on DSK1DXX6B1PROD with NOTICES_PART 1
HTLV–II Vector and Methods of Use
Description of Invention: The
invention hereby offered for licensing is
in the field of vaccines and vaccine
vectors. More specifically the invention
provides compositions and methods of
use of HTLV–II viral vector. The vector
comprises at least a portion of the
HTLV–II genome encoding the gag, pro,
and pol genes and lacking all or a
portion of the pX region. A heterologous
gene is inserted within the deletion of
the pX region. The gene of interest may
encode all or a portion of a protein that
corresponds to a viral protein of a
foreign virus. The viral vectors thus
constructed are useful for inducing
immune response to the viral protein
from the foreign virus. In particular the
invention claims vaccines against HIV
and SIV.
Applications: The technology can be
used for DNA-based vaccines.
Advantages
• Vaccines based on HTLV–II vectors
have exhibited the capability to eliciting
T cell response effectively. In particular
they induce specific CD4+ and CD8+ T
cell response. Antibody response to the
HTLV–II vector is almost undetectable.
The vector is infectious, but highly
attenuated, with respect to the wild type
HTLV–II. Desirably, the HTLV–II viral
vector induces antibodies that can
participate in Antibody-Dependent-CellMediated Cytotoxicity (ADCC), a
mechanism that enhances its
effectiveness.
• Most of the T-cell vaccines
developed for HIV are based on
microbial vectors that have limited
replication capacity and do not persist
in the host. Such vaccines do not
protect macaques from SIV infection
and their ability to protect against high
virus load is merely transient
(approximately six months). They are
perceived to elicit too ‘‘small T-cell
responses’’ that expand ‘‘too late’’. In
addition, few of these vectors target
mucosal sites, the first portal of HIV
entry. In contrast, an HTLV II based
vaccine is anticipated to infect
macaques and replicate at very low level
in lymphoid tissue and particularly in
the gut which may enable them to
maintain sufficient level of effectors
CD8 memory cells to decrease early
seeding of the virus, and sufficient level
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of central memory cells in lymph nodes
that may limit the broadcasting of the
virus at distal sites. These features make
an HTLV–II based vaccine for HIV an
excellent unique candidate to target
mucosal tissues and provide long lasting
mucosal immunity to HIV. In addition,
the HTLV II infects dendritic cells both
in vivo and in vitro, and the HTLV II
infected dendritic cells have a mature
phenotype, suggesting that HIV antigens
expressed within dendritic cells could
be effectively presented to the immune
system.
• HTLV II is a human retrovirus with
no clear disease associations neither in
healthy nor in HIV infected individuals
• HTLV shares many biological and
molecular characteristics of HIV,
including routes of transmission, a Tcell tropism and gut tropism.
• Based on the above, it is believed
that HIV vaccines based on HTLV II
vector will exhibit superiority compared
to other vaccines in development.
Development Status: At the present
only in vitro as well as animal
(macaques) data that demonstrate the
proof of concept are available. The data
indicates that an HTLV II based vaccine
could replicate in the appropriate body
compartment and confer immunity in
humans. The inventors continue to
work on the development of this
approach.
Market: In spite of major global efforts
of more than 25 years in developing a
vaccine against HIV/AIDS, such a
vaccine is still not in existence but yet
very much needed for the fight against
the global epidemic of HIV/AIDS. The
market for HIV/AIDS drugs is currently
at the level of approximately $6 billion
a year and is expected to grow to $13
billion by the year 2015. Should an
effective vaccine be developed the
market for such a vaccine may exceed
this level. The instant technology may
offer superiority to existence approaches
in the area of HIV vaccines and thus a
huge commercial opportunity for
pharmaceutical/vaccine enterprises as
well as a major contribution for global
public health.
Inventors: Genoveffa Franchini et al.
(NCI).
Publications: Paper in preparation.
Patent Status: PCT Application No.
PCT/US2009/051138 filed 20 Jul 2009,
which published as WO 2010/009465
on 21 Jan 2010 (HHS Reference No. E–
269–2008/1–PCT–01).
Related Technologies: RhCMV SIV
vaccine (Picker et al.)
Licensing Status: Available for
licensing.
Licensing Contact: Susan Ano, PhD;
301–435–5515; anos@mail.nih.gov.
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Collaborative Research Opportunity:
The National Cancer Institute, Animal
Models & Retroviral Vaccine Section, is
seeking statements of capability or
interest from parties interested in
collaborative research to further
develop, evaluate, or commercialize
HTLV–II vectored HIV vaccines. Please
contact John D. Hewes, PhD at 301–435–
3121 or hewesj@mail.nih.gov for more
information.
Prevention and Treatment of Cancer
With Kinase Inhibitors Targeting the
PH Domain of AKT
Description of Invention: Activation of
the PI3K/Akt signaling pathway has
been implicated in the development of
cancer. Akt, a kinase that is central to
this pathway, is found at elevated levels
in many tumors and is associated with
a poor disease prognosis. Further
research has validated Akt as a
therapeutic target for the development
of anti-cancer drugs. Most efforts of drug
development targeting Akt have focused
on inhibitors of the ATP-binding
domain which have the drawback that
they interfere with other physiologically
important kinases. This is reflected in
that no Akt inhibitors have been
clinically approved. However,
investigators at the National Institutes of
Health (NIH) and Georgetown
University (GU) have developed an
alternative strategy that improves Akt
specificity by targeting the unique
pleckstrin homology (PH) domain of
Akt.
Scientists at NIH and GU have
discovered several lipid-based
inhibitors of Akt called
phosphatidylinositol ether lipid
analogues (PIAs) that target the
pleckstrin homology (PH) domain of
Akt. These PIAs, which are analogues of
the products of phosphatidylinositol 3kinase (PI3K), inhibit Akt within
minutes and selectively kill cancer cells
that contain high levels of Akt
activation. The mechanism of action of
these compounds has been intensively
studied providing much insight into
how PIAs inhibit the growth of cancer
cells. In addition, several molecular
targets have been identified that highly
correlate with cancer cell sensitivity to
PIA that potentially could serve as
clinical biomarkers predictive of
responsiveness to PIAs. U.S. and
Australian patents issued for this
invention have composition and method
of use claims.
Applications
• Treating or preventing development
of cancer or preventing progression of
premalignant lesions to cancer.
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• Used as single agents or in
combination with other anti-cancer
treatments like chemotherapy,
biological therapy, or radiation.
Advantages: Targeting the PH domain
improves specificity against Akt kinase
in comparison to inhibitors of the ATP
domain which typically are unspecific.
Inventors: Phillip A. Dennis (NCI) et
al.
wwoods2 on DSK1DXX6B1PROD with NOTICES_PART 1
Relevant Publications
1. Memmott RM, Gills JJ,
Hollingshead M, Powers MC, Chen Z,
Kemp B, Kozikowski A, Dennis PA.
Phosphatidylinositol ether lipid
analogues induce AMP-activated
protein kinase-dependent death in
LKB1-mutant non small cell lung cancer
cells. Cancer Res. 2008 Jan
15;68(2):580–588. [PubMed: 18199555.]
2. Gills JJ, Castillo SS, Zhang C,
Petukhov PA, Memmott RM,
Hollingshead M, Warfel N, Han J,
Kozikowski AP, Dennis PA.
Phosphatidylinositol ether lipid
analogues that inhibit AKT also
independently activate the stress kinase,
p38alpha, through MKK3/6independent and -dependent
mechanisms. J Biol Chem. 2007 Sep
14;282(37):27020–27029. [PubMed:
17631503.]
3. Gills JJ, Holbeck S, Hollingshead M,
Hewitt SM, Kozikowski AP, Dennis PA.
Spectrum of activity and molecular
correlates of response to
phosphatidylinositol ether lipid
analogues, novel lipid-based inhibitors
of Akt. Mol Cancer Ther. 2006
Mar;5(3):713–722. [PubMed: 16546986.]
´
4. Caron RW, Yacoub A, Li M, Zhu X,
Mitchell C, Hong Y, Hawkins W,
Sasazuki T, Shirasawa S, Kozikowski
AP, Dennis PA, Hagan MP, Grant S,
Dent P. Activated forms of H–RAS and
K–RAS differentially regulate membrane
association of PI3K, PDK–1, and AKT
and the effect of therapeutic kinase
inhibitors on cell survival. Mol Cancer
Ther. 2005 Feb;4(2):257–270. [PubMed:
15713897.]
5. Castillo SS, Brognard J, Petukhov
PA, Zhang C, Tsurutani J, Granville CA,
Li M, Jung M, West KA, Gills JG,
Kozikowski AP, Dennis PA. Preferential
inhibition of Akt and killing of Aktdependent cancer cells by rationally
designed phosphatidylinositol ether
lipid analogues. Cancer Res. 2004 Apr
15;64(8):2782–2792. [PubMed:
15087394.]
6. Kozikowski AP, Sun H, Brognard J,
Dennis PA. Novel PI analogues
selectively block activation of the prosurvival serine/threonine kinase Akt. J
Am Chem Soc. 2003 Feb 5;125(5):1144–
1145. [PubMed: 12553797.]
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Patent Status: U.S. Patent No.
7,378,403 issued 27 May 2008 (HHS
Reference No. E–245–2002/0–US–03),
and related international filings.
Licensing Status: Available for
licensing.
Licensing Contact: Surekha Vathyam,
PhD; 301–435–4076;
vathyams@mail.nih.gov.
Dated: March 10, 2010.
Richard U. Rodriguez,
Director, Division of Technology Development
and Transfer, Office of Technology Transfer,
National Institutes of Health.
[FR Doc. 2010–5764 Filed 3–16–10; 8:45 am]
BILLING CODE 4140–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions;
Availability for Licensing
AGENCY: National Institutes of Health,
Public Health Service, HHS.
ACTION: Notice.
SUMMARY: The inventions listed below
are owned by an agency of the U.S.
Government and are available for
licensing in the U.S. in accordance with
35 U.S.C. 207 to achieve expeditious
commercialization of results of
federally-funded research and
development. Foreign patent
applications are filed on selected
inventions to extend market coverage
for companies and may also be available
for licensing.
ADDRESSES: Licensing information and
copies of the U.S. patent applications
listed below may be obtained by writing
to the indicated licensing contact at the
Office of Technology Transfer, National
Institutes of Health, 6011 Executive
Boulevard, Suite 325, Rockville,
Maryland 20852–3804; telephone: 301/
496–7057; fax: 301/402–0220. A signed
Confidential Disclosure Agreement will
be required to receive copies of the
patent applications.
Spontaneously Transformed Mouse
Epithelial Cancer Cell Lines Serving as
Mouse Models: A New Model for
Cancer Research
Description of Invention: Investigators
at the NIH have created a collection of
45 mouse epithelial cancer cell lines
derived from six organs: Bladder, cervix,
colon, lung, kidney, and mammary
glands. These cells lines were obtained
from spontaneously transformed
primary cell cultures without genetic,
viral or chemical manipulation so they
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can serve as mouse models for studying
the natural process of oncogenesis.
The cell lines were characterized
cytogenetically during their
transformation from normal to
spontaneously immortalization and
were found to recapitulate many of the
changes observed in human cancer cells
such as the deregulation of oncogenes
(Myc, Mdm2) and tumor suppressor
genes (Cdnk4a/Ink4a/p16, Rb).
Carcinomas that arise from the
epithelial cells lining organs lead to the
most common cancers in humans.
However, research on cellular
transformation has largely relied on
fibroblast cells which are not of
epithelial origin and therefore, may not
reflect the changes that lead to epithelial
oncogenesis. The availability of these
mouse epithelial cancer cell lines
should allow for a more accurate
analysis of this process.
Applications: These cell lines serve as
‘‘ideal’’ murine tumor models as they
show evidence of progression,
permitting analysis of the genetic and
biological changes observed in the
equivalent human carcinomas and
associated with tumor progression.
Their tumor histology is comparable to
human cancers.
The cell lines have unique properties
that make them suitable for study of the
following:
• Unlimited replicative potential.
• Exhibit tumorigenic potential and
EMT (Epithelial Mesencymal
Transition).
• Exhibit high degree of chromosome
instability (chromosome
rearrangements, amplifications) in
regions orthologous to those altered in
human cancers.
• Use in mapping mouse genes
homologous to human cancer genes and
for the study of the effects of
deregulation of cancer associated genes,
through silencing or overexpression.
• For use in gene expression studies
of tumor progression, comparing
profiles to human cancers involving the
same tissue types.
• Use as experimental controls in the
analysis of oncogene signaling
pathways.
• Use in the studying telomerase
pathway regulation (200-fold expression
difference between cell lines).
• Use of mouse as model of epithelial
carcinomas and specifically cancers of
the bladder, cervix, colon, lung,
mammarys and kidney cancers.
• These mouse models serve as
vehicles to test the efficacy of new
therapies, targeting specific targets
associated with the transformation of six
different mouse epithelial tissues.
E:\FR\FM\17MRN1.SGM
17MRN1
]]>Agencies
[Federal Register Volume 75, Number 51 (Wednesday, March 17, 2010)]
[Notices]
[Pages 12761-12764]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2010-5764]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions; Availability for Licensing
AGENCY: National Institutes of Health, Public Health Service, HHS.
ACTION: Notice.
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SUMMARY: The inventions listed below are owned by an agency of the U.S.
Government and are available for licensing in the U.S. in accordance
with 35 U.S.C. 207 to achieve expeditious commercialization of results
of Federally-funded research and development. Foreign patent
applications are filed on selected inventions to extend market coverage
for companies and may also be available for licensing.
ADDRESSES: Licensing information and copies of the U.S. patent
applications listed below may be obtained by writing to the indicated
licensing contact at the Office of Technology Transfer, National
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville,
Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A
signed Confidential Disclosure Agreement will
[[Page 12762]]
be required to receive copies of the patent applications.
Caspase Inhibitors Useful for the Study of Autoimmune or Inflammatory
Diseases
Description of Invention: Novel and potent caspase 1 inhibitors are
available for licensing. In particular, this technology discloses
potent and selective caspase 1 inhibitors that target the active site
of the enzyme. Caspase 1 is known to play a pro-inflammatory role in
numerous autoimmune and inflammatory diseases and therefore represents
an excellent target for treatment of a broad range of diseases,
including but not limited to Huntington's, amyotrophic lateral
sclerosis, ischemia, rheumatoid arthritis, osteoarthritis, inflammatory
bowel disease, and sepsis. Not surprisingly this enormous potential has
resulted in at least three caspase 1 inhibitors entering clinical
trials (VX-740, IDN-6556, and VX-765) in recent years.
Applications
Potential therapeutic for a broad range of autoimmune
diseases.
Potential therapeutic for a broad range of inflammatory
diseases.
Development Status: Early stage.
Market: The market size is potentially very large. For instance,
rheumatoid arthritis alone affects 1% of the population, or about 2.5-3
million Americans. Further, it is estimated that osteoarthritis affects
at least 16 million people in America.
Inventors: Craig J. Thomas and Matthew B. Boxer (NHGRI).
Publication: Boxer MB, Quinn AM, Shen M, Jadhav A, Leister W,
Simeonov A, Auld DS, Thomas CJ. A highly potent and selective caspase 1
inhibitor that utilizes a key 3-cyanopropanoic acid moiety. Chem Med
Chem., accepted.
Patent Status: U.S. Provisional Application No. 61/299,790 filed 29
Jan 2010 (HHS Reference No. E-308-2009/0-US-01).
Licensing Status: Available for licensing.
Licensing Contact: Steve Standley, PhD; 301-435-4074;
sstand@od.nih.gov.
Collaborative Research Opportunity: The NIH Chemical Genomics
Center is seeking statements of capability or interest from parties
interested in collaborative research to further develop, evaluate, or
commercialize appropriate lead compounds described in U.S. Provisional
Application No. 61/299,790. Please contact Dr. Craig J. Thomas via e-
mail (craigt@nhgri.nih.gov) for more information.
Defensin-Based Therapeutics for the Treatment of Pulmonary Disease
Description of Invention: Investigators at the National Heart, Lung
and Blood Institute have developed modified defensins that are
resistant to degradation, have improved characteristics compared to
unmodified defensins, and are promising candidates for pulmonary
disease therapeutics.
Defensins are small cationic peptides that defend the lung against
pathogenic microorganisms and play an important role in innate
immunity. However, during lung inflammation, defensin concentrations
can reach levels that are cytotoxic for airway epithelial cells.
Therefore, the development of methods to produce modified defensins
that exhibit reduced cytotoxicity, while retaining the ability to
stimulate the innate immune response, would be of potential therapeutic
benefit for pulmonary diseases.
The inventors have previously shown that a defensin, human
neutrophil peptide 1 (HNP-1), is elevated in samples from the lungs of
patients with inflammatory lung disease, and that the HNP-1 in these
samples is ADP-ribosylated at one or both of two arginine residues
within the protein. In vitro studies by the inventors show that ADP-
ribosyl-HNP-1 has reduced cytotoxic activity compared to HNP-1, while
retaining its T cell chemotactic properties and ability to promote
neutrophil recruitment, and thus ADP-ribosyl-HNP-1 may play an
important role as a regulator of the inflammatory response. These
properties would also be useful for treatment of pulmonary inflammation
and lung diseases. However, ADP-ribosylated HNP-1 and other defensins
are degraded rapidly in vivo due to the susceptibility of the ADP-
ribose moiety to attack by hydrolases and pyrophosphatases, which
limits their therapeutic potential.
The inventors have recently discovered that the ADP-ribosylated
arginine residues in HNP-1 can be converted to ornithine through a non-
enzymatic process that results in a peptide with an altered
pharmacological profile. The investigators have also successfully
generated ornithine-substituted ADP-ribosyl HNP-1 and ornithine-HNP-1
in vitro, which are currently being characterized. Thus, ornithine-
substituted ADP-ribosyl HNP-1 and ornithine-HNP-1 may be promising
candidates for the development of therapeutics to treat pulmonary
disease, and the strategy of replacing ADP-ribosylated residues with
ornithine to enhance stability and therapeutic efficacy may also be
extended to other defensins
Through an earlier, related invention, the inventors have also
demonstrated that recombinant proteins wherein tryptophan or
phenylalanine residues substitute for ADP-ribosylarginine have a
similar stabilizing impact on polypeptides, making them more suitable
as therapeutic agents.
The inventors also hypothesize that it would be possible to develop
a treatment that increases levels of an ADP-ribosylated therapeutic
protein, such as HNP-1, in the lung via inhalation administration of
the therapeutic protein in conjunction with nicotinamide adenine
dinucleotide (NAD), which is required for ADP-ribosylation. This could
represent a unique therapeutic strategy for treating pulmonary disease.
Applications: Development of defensin-based therapeutics that
enhance the immune response in pulmonary disease patients, without
damaging the epithelial cells lining the airway.
Advantages
Modified defensins are less cytotoxic, while retaining ability to
stimulate innate immunity.
Ornithine-substituted defensins are resistant to enzymatic
degradation, making them more promising as drug candidates.
Development Status: In vitro studies, as well as analysis of
patient samples, have been performed.
Inventors: Joel Moss et al. (NHLBI).
Relevant Publication: Stevens LA, Levine RL, Gochuico BR, Moss J.
ADP-ribosylation of human defensin HNP-1 results in the replacement of
the modified arginine with the noncoded amino acid ornithine. Proc Natl
Acad Sci U S A. 2009 Nov 24;106(47):19796-19800. [PubMed: 19897717.]
Patent Status: U.S. Provisional Application No. 61/241,311 filed
September 10, 2009 (HHS Reference No. E-243-2009/0-US-01).
Related Technologies
HHS Reference No. E-080-2002/0, ``Modified Defensins and
Their Use.''
HHS Reference No. E-160-2002/0, ``Tryptophan as a
Functional Replacement for ADP-ribose-arginine in Recombinant
Proteins.''
Licensing Status: Available for licensing.
Licensing Contact: Tara Kirby, PhD; 301-435-4426;
tarak@mail.nih.gov.
Collaborative Research Opportunity: The National Heart, Lung and
Blood Institute Translational Medicine Branch is seeking statements of
capability or
[[Page 12763]]
interest from parties interested in collaborative research to further
develop, evaluate, or commercialize defensin-based therapeutic agents
to treat pulmonary diseases. Please contact Brian W. Bailey, PhD at
301-494-4094 or bbailey@mail.nih.gov for more information.
HTLV-II Vector and Methods of Use
Description of Invention: The invention hereby offered for
licensing is in the field of vaccines and vaccine vectors. More
specifically the invention provides compositions and methods of use of
HTLV-II viral vector. The vector comprises at least a portion of the
HTLV-II genome encoding the gag, pro, and pol genes and lacking all or
a portion of the pX region. A heterologous gene is inserted within the
deletion of the pX region. The gene of interest may encode all or a
portion of a protein that corresponds to a viral protein of a foreign
virus. The viral vectors thus constructed are useful for inducing
immune response to the viral protein from the foreign virus. In
particular the invention claims vaccines against HIV and SIV.
Applications: The technology can be used for DNA-based vaccines.
Advantages
Vaccines based on HTLV-II vectors have exhibited the
capability to eliciting T cell response effectively. In particular they
induce specific CD4+ and CD8+ T cell response. Antibody response to the
HTLV-II vector is almost undetectable. The vector is infectious, but
highly attenuated, with respect to the wild type HTLV-II. Desirably,
the HTLV-II viral vector induces antibodies that can participate in
Antibody-Dependent-Cell-Mediated Cytotoxicity (ADCC), a mechanism that
enhances its effectiveness.
Most of the T-cell vaccines developed for HIV are based on
microbial vectors that have limited replication capacity and do not
persist in the host. Such vaccines do not protect macaques from SIV
infection and their ability to protect against high virus load is
merely transient (approximately six months). They are perceived to
elicit too ``small T-cell responses'' that expand ``too late''. In
addition, few of these vectors target mucosal sites, the first portal
of HIV entry. In contrast, an HTLV II based vaccine is anticipated to
infect macaques and replicate at very low level in lymphoid tissue and
particularly in the gut which may enable them to maintain sufficient
level of effectors CD8 memory cells to decrease early seeding of the
virus, and sufficient level of central memory cells in lymph nodes that
may limit the broadcasting of the virus at distal sites. These features
make an HTLV-II based vaccine for HIV an excellent unique candidate to
target mucosal tissues and provide long lasting mucosal immunity to
HIV. In addition, the HTLV II infects dendritic cells both in vivo and
in vitro, and the HTLV II infected dendritic cells have a mature
phenotype, suggesting that HIV antigens expressed within dendritic
cells could be effectively presented to the immune system.
HTLV II is a human retrovirus with no clear disease
associations neither in healthy nor in HIV infected individuals
HTLV shares many biological and molecular characteristics
of HIV, including routes of transmission, a T-cell tropism and gut
tropism.
Based on the above, it is believed that HIV vaccines based
on HTLV II vector will exhibit superiority compared to other vaccines
in development.
Development Status: At the present only in vitro as well as animal
(macaques) data that demonstrate the proof of concept are available.
The data indicates that an HTLV II based vaccine could replicate in the
appropriate body compartment and confer immunity in humans. The
inventors continue to work on the development of this approach.
Market: In spite of major global efforts of more than 25 years in
developing a vaccine against HIV/AIDS, such a vaccine is still not in
existence but yet very much needed for the fight against the global
epidemic of HIV/AIDS. The market for HIV/AIDS drugs is currently at the
level of approximately $6 billion a year and is expected to grow to $13
billion by the year 2015. Should an effective vaccine be developed the
market for such a vaccine may exceed this level. The instant technology
may offer superiority to existence approaches in the area of HIV
vaccines and thus a huge commercial opportunity for pharmaceutical/
vaccine enterprises as well as a major contribution for global public
health.
Inventors: Genoveffa Franchini et al. (NCI).
Publications: Paper in preparation.
Patent Status: PCT Application No. PCT/US2009/051138 filed 20 Jul
2009, which published as WO 2010/009465 on 21 Jan 2010 (HHS Reference
No. E-269-2008/1-PCT-01).
Related Technologies: RhCMV SIV vaccine (Picker et al.)
Licensing Status: Available for licensing.
Licensing Contact: Susan Ano, PhD; 301-435-5515; anos@mail.nih.gov.
Collaborative Research Opportunity: The National Cancer Institute,
Animal Models & Retroviral Vaccine Section, is seeking statements of
capability or interest from parties interested in collaborative
research to further develop, evaluate, or commercialize HTLV-II
vectored HIV vaccines. Please contact John D. Hewes, PhD at 301-435-
3121 or hewesj@mail.nih.gov for more information.
Prevention and Treatment of Cancer With Kinase Inhibitors Targeting the
PH Domain of AKT
Description of Invention: Activation of the PI3K/Akt signaling
pathway has been implicated in the development of cancer. Akt, a kinase
that is central to this pathway, is found at elevated levels in many
tumors and is associated with a poor disease prognosis. Further
research has validated Akt as a therapeutic target for the development
of anti-cancer drugs. Most efforts of drug development targeting Akt
have focused on inhibitors of the ATP-binding domain which have the
drawback that they interfere with other physiologically important
kinases. This is reflected in that no Akt inhibitors have been
clinically approved. However, investigators at the National Institutes
of Health (NIH) and Georgetown University (GU) have developed an
alternative strategy that improves Akt specificity by targeting the
unique pleckstrin homology (PH) domain of Akt.
Scientists at NIH and GU have discovered several lipid-based
inhibitors of Akt called phosphatidylinositol ether lipid analogues
(PIAs) that target the pleckstrin homology (PH) domain of Akt. These
PIAs, which are analogues of the products of phosphatidylinositol 3-
kinase (PI3K), inhibit Akt within minutes and selectively kill cancer
cells that contain high levels of Akt activation. The mechanism of
action of these compounds has been intensively studied providing much
insight into how PIAs inhibit the growth of cancer cells. In addition,
several molecular targets have been identified that highly correlate
with cancer cell sensitivity to PIA that potentially could serve as
clinical biomarkers predictive of responsiveness to PIAs. U.S. and
Australian patents issued for this invention have composition and
method of use claims.
Applications
Treating or preventing development of cancer or preventing
progression of premalignant lesions to cancer.
[[Page 12764]]
Used as single agents or in combination with other anti-
cancer treatments like chemotherapy, biological therapy, or radiation.
Advantages: Targeting the PH domain improves specificity against
Akt kinase in comparison to inhibitors of the ATP domain which
typically are unspecific.
Inventors: Phillip A. Dennis (NCI) et al.
Relevant Publications
1. Memmott RM, Gills JJ, Hollingshead M, Powers MC, Chen Z, Kemp B,
Kozikowski A, Dennis PA. Phosphatidylinositol ether lipid analogues
induce AMP-activated protein kinase-dependent death in LKB1-mutant non
small cell lung cancer cells. Cancer Res. 2008 Jan 15;68(2):580-588.
[PubMed: 18199555.]
2. Gills JJ, Castillo SS, Zhang C, Petukhov PA, Memmott RM,
Hollingshead M, Warfel N, Han J, Kozikowski AP, Dennis PA.
Phosphatidylinositol ether lipid analogues that inhibit AKT also
independently activate the stress kinase, p38alpha, through MKK3/6-
independent and -dependent mechanisms. J Biol Chem. 2007 Sep
14;282(37):27020-27029. [PubMed: 17631503.]
3. Gills JJ, Holbeck S, Hollingshead M, Hewitt SM, Kozikowski AP,
Dennis PA. Spectrum of activity and molecular correlates of response to
phosphatidylinositol ether lipid analogues, novel lipid-based
inhibitors of Akt. Mol Cancer Ther. 2006 Mar;5(3):713-722. [PubMed:
16546986.]
4. Car[oacute]n RW, Yacoub A, Li M, Zhu X, Mitchell C, Hong Y,
Hawkins W, Sasazuki T, Shirasawa S, Kozikowski AP, Dennis PA, Hagan MP,
Grant S, Dent P. Activated forms of H-RAS and K-RAS differentially
regulate membrane association of PI3K, PDK-1, and AKT and the effect of
therapeutic kinase inhibitors on cell survival. Mol Cancer Ther. 2005
Feb;4(2):257-270. [PubMed: 15713897.]
5. Castillo SS, Brognard J, Petukhov PA, Zhang C, Tsurutani J,
Granville CA, Li M, Jung M, West KA, Gills JG, Kozikowski AP, Dennis
PA. Preferential inhibition of Akt and killing of Akt-dependent cancer
cells by rationally designed phosphatidylinositol ether lipid
analogues. Cancer Res. 2004 Apr 15;64(8):2782-2792. [PubMed: 15087394.]
6. Kozikowski AP, Sun H, Brognard J, Dennis PA. Novel PI analogues
selectively block activation of the pro-survival serine/threonine
kinase Akt. J Am Chem Soc. 2003 Feb 5;125(5):1144-1145. [PubMed:
12553797.]
Patent Status: U.S. Patent No. 7,378,403 issued 27 May 2008 (HHS
Reference No. E-245-2002/0-US-03), and related international filings.
Licensing Status: Available for licensing.
Licensing Contact: Surekha Vathyam, PhD; 301-435-4076;
vathyams@mail.nih.gov.
Dated: March 10, 2010.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer, National Institutes of Health.
[FR Doc. 2010-5764 Filed 3-16-10; 8:45 am]
BILLING CODE 4140-01-P
