Government-Owned Inventions; Availability for Licensing, 4598-4603 [E8-1232]
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Infectious Diseases, Laboratory of
Infectious Diseases, is seeking
statements of capability or interest from
parties interested in collaborative
research to further develop, evaluate, or
commercialize these vaccines. Please
contact Dr. Brian Murphy at 301–594–
1616 or bm25f@nih.gov for more
information.
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Dengue Tetravalent Vaccine Containing
a Common 30-Nucleotide Deletion in
the 3′-UTR of Dengue Types 1, 2, 3, and
4
Description of Technology: The
invention relates to a dengue virus
tetravalent vaccine containing a
common 30-nucleotide deletion (D30) in
the 3′-untranslated region (UTR) of the
genome of dengue virus serotypes 1, 2,
3, and 4. The previously identified D30
attenuating mutation, created in dengue
virus type 4 (DEN4) by the removal of
30 nucleotides from the 3′-UTR, is also
capable of attenuating a wild-type strain
of dengue virus type 1 (DEN1). Removal
of 30 nucleotides from the DEN1 3′-UTR
in a highly conserved region
homologous to the DEN4 region
encompassing the D30 mutation yielded
a recombinant virus attenuated in
rhesus monkeys to a level similar to
recombinant virus DEN4D30. This
established the transportability of the
D30 mutation and its attenuation
phenotype to a dengue virus type other
than DEN4. The effective transferability
of the D30 mutation establishes the
usefulness of the D30 mutation to
attenuate and improve the safety of
commercializable dengue virus vaccines
of any serotype.
A tetravalent dengue virus vaccine
containing dengue virus types 1, 2, 3,
and 4 each attenuated by the D30
mutation is being developed. The
presence of the D30 attenuating
mutation in each virus component
precludes the reversion to a wild-type
virus by intertypic recombination. In
addition, because of the inherent genetic
stability of deletion mutations, the D30
mutation represents an excellent
alternative for use as a common
mutation shared among each component
of a tetravalent vaccine.
Inventors: Stephen S. Whitehead
(NIAID), Brian R. Murphy (NIAID),
Lewis Markoff (FDA), Barry Falgout
(FDA), Kathryn A. Hanley (NIAID),
Joseph E. Blaney (NIAID).
Patent Status: U.S. Patent Application
No. 10/970,640 filed 21 Oct 2004,
claiming priority to 03 May 2002 (HHS
Reference No. E–089–2002/1–US–02).
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
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Collaborative Research Opportunity:
The National Institute of Allergy and
Infectious Diseases, Laboratory of
Infectious Diseases, is seeking
statements of capability or interest from
parties interested in collaborative
research to further develop, evaluate, or
commercialize these vaccines. Please
contact Dr. Brian Murphy at 301–594–
1616 or bm25f@nih.gov for more
information.
Collaborative Research Opportunity:
The National Institute of Allergy and
Infectious Diseases, Laboratory of
Infectious Diseases, is seeking
statements of capability or interest from
parties interested in collaborative
research to further develop, evaluate, or
commercialize these vaccines. Please
contact Dr. Brian Murphy at 301–594–
1616 or bm25f@nih.gov for more
information.
Development of Mutations Useful for
Attenuating Dengue Viruses and
Chimeric Dengue Viruses
Description of Technology: Although
flaviviruses cause a great deal of human
suffering and economic loss, there is a
shortage of effective vaccines. This
invention relates to dengue virus
mutations that may contribute to the
development of improved dengue
vaccines. Site directed and random
mutagenesis techniques were used to
introduce mutations into the dengue
virus genome and to assemble a
collection of useful mutations for
incorporation in recombinant live
attenuated dengue virus vaccines. The
resulting mutant viruses were screened
for several valuable phenotypes,
including temperature sensitivity in
Vero cells or human liver cells, host cell
restriction in mosquito cells or human
liver cells, host cell adaptation for
improved replication in Vero cells, and
attenuation in mice or in mosquitoes.
The genetic basis for each observed
phenotype was determined by direct
sequence analysis of the genome of the
mutant virus. Mutations identified
through these sequencing efforts have
been further evaluated by reintroduction of the identified mutations,
singly, or in combination, into
recombinant dengue virus and
characterization of the resulting
recombinant virus for phenotypes. In
this manner, a menu of attenuating and
growth promoting mutations was
developed that is useful in fine-tuning
the attenuation and growth
characteristics of dengue virus vaccine
candidates. The mutations promoting
growth in Vero cells have usefulness for
the production of live or inactivated
dengue virus vaccines.
Inventors: Stephen S. Whitehead,
Brian R. Murphy, Kathryn A. Hanley,
Joseph E. Blaney (NIAID).
Patent Status: U.S. Patent No.
7,226,602 issued 05 Jun 2007 (HHS
Reference No. E–120–2001/0–US–04);
U.S. Patent Application No. 11/446,050
filed 02 Jun 2006 (HHS Reference No.
E–120–2001/0–US–10).
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Date: January 10, 2008.
Steven M. Ferguson,
Director, Division of Technology Development
and Transfer, Office of Technology Transfer,
National Institutes of Health.
[FR Doc. E8–1234 Filed 1–24–08; 8:45 am]
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BILLING CODE 4140–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions;
Availability for Licensing
National Institutes of Health,
Public Health Service, HHS.
ACTION: Notice.
AGENCY:
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.
Monoclonal Antibodies Against Dengue
and Other Viruses With Deletion in Fc
Region
Description of Invention: The four
dengue virus (DENV) serotypes (DENV–
1 to DENV–4) are the most important
arthropod-borne flaviviruses in terms of
morbidity and geographic distribution.
Up to 100 million DENV infections
occur every year, mostly in tropical and
subtropical areas where vector
mosquitoes are abundant. Infection with
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any of the DENV serotypes may be
asymptomatic or may lead to classic
dengue fever or more severe dengue
hemorrhagic fever (DHF) and dengue
shock syndrome (DSS), which are
increasingly common in the dengue
endemic areas. Immunity to the same
virus serotype (homotypic immunity) is
life-long, whereas immunity to different
serotypes (heterotypic immunity) lasts
2–3 months so that infection with a
different serotype virus is possible.
DHF/DSS often occurs in patients with
second, heterotypic DENV infections or
in infants with maternally transferred
dengue immunity. Severe dengue is a
major cause of hospitalization, and
fatality rates vary from <1% to 5% in
children.
Antibody-dependent enhancement
(ADE) has been proposed as an
underlying pathogenic mechanism of
DHF/DSS. ADE occurs because
preexisting subneutralizing antibodies
and the infecting DENV form complexes
that bind to Fc receptor-bearing cells,
leading to increased virus uptake and
replication. ADE has been repeatedly
demonstrated in vitro using dengue
immune sera or monoclonal antibodies
and cells of monocytic and recently, B
lymphocytic lineages bearing Fc
receptors. ADE of DENV–2 infection has
also been demonstrated in monkeys
infused with a human dengue immune
serum.
We have identified chimpanzeehuman chimeric IgG1 mAbs capable of
neutralizing or binding to one or more
DENV serotypes. Cross-reactive IgG 1A5
neutralizes DENV–1 and DENV–2 more
efficiently than DENV–3 and DENV–4,
and type-specific IgG 5H2 neutralizes
DENV–4 at a high titer. Analysis of
antigenic variants has localized the IgG
1A5 binding site to the conserved fusion
peptide in E. Thus, IgG 1A5 shares
many characteristics with the crossreactive antibodies detected in
flavivirus infections.
This application claims a variant of an
antibody comprising a polypeptide in
the Fc region, which binds an Fc gamma
receptor (FcgammaR) with lower affinity
than the parent antibody. The variant
polypeptide comprises a deletion of
nine amino acids at the N-terminus of
the CH2 domain in the Fc region.
Introduction of the Fc variant abrogates
the antibody-mediated dengue virus
replication enhancing activity. This
invention has important implications
for the antibody-mediated prevention of
dengue virus infection.
Application: Immunization against
Dengue and/or flaviviruses.
Developmental Status: Antibody
candidates have been synthesized and
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preclinical studies have been
performed.
Inventors: Ana Goncalvez, Robert
Purcell, C.J. Lai (NIAID).
Publication: AP Goncalvez, et al.
Monoclonal antibody-mediated
enhancement of dengue virus infection
in vitro and in vivo and strategies for
prevention Proc Natl Acad Sci USA.
2007 May 29;104(22):9422–9427.
Patent Status: U.S. Provisional
Application No. 60/922,282 filed 04 Apr
2007 (HHS Reference No. E–159–2007/
0–US–01); U.S. Provisional Application
No. 60/927,755 filed 04 May 2007 (HHS
Reference No. E–159–2007/1–US–01);
U.S. Provisional Application No. 60/
928,405 filed 08 May 2007 (HHS
Reference No. E–159–2007/2–US–01).
Licensing Status: Available for
exclusive or non-exclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Monoclonal Antibodies that Neutralize
B. anthracis Protective Antigen (PA),
Lethal Factor (LF) and Edema Factor
(EF)
Description of Invention: Anthrax,
whether resulting from natural or
bioterrorist-associated exposure, is a
constant threat to human health. The
lethality of anthrax is primarily the
result of the effects of anthrax toxin,
which has 3 components: a receptorbinding protein known as ‘‘protective
antigen’’ (PA) and 2 catalytic proteins
known as ‘‘lethal factor’’ (LF) and
‘‘edema factor’’ (EF). Although
production of an efficient anthrax
vaccine is an ultimate goal, the benefits
of vaccination can be expected only if
a large proportion of the population at
risk is immunized. The low incidence of
anthrax suggests that large-scale
vaccination may not be the most
efficient means of controlling this
disease. In contrast, passive
administration of neutralizing human or
chimpanzee monoclonal antibody to a
subject at risk for anthrax or exposed to
anthrax could provide immediate
efficacy for emergency prophylaxis
against or treatment of anthrax.
Four monoclonal antibodies (mAbs)
against PA, three mAbs against LF and
four mAbs specific for EF of anthrax
were isolated from a phage display
library generated from immunized
chimpanzees. Two mAbs recognizing
PA (W1 and W2), two anti-LF mAbs
efficiently neutralized the cytotoxicity
of lethal toxin in a macrophage lysis
assay. One anti-EF mAb efficiently
neutralized edema toxin in cell culture.
All five neutralizing mAbs protected
animals from anthrax toxin challenge.
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Application: Prophylactics or
therapeutics against B. anthracis.
Developmental Status: Preclinical
studies have been performed.
Inventors: Zhaochun Chen, Robert
Purcell, Suzanne Emerson, Stephen
Leppla, Mahtab Moyeri (NIAID).
Publication: Z Chen, et al. Efficient
neutralization of anthrax toxin by
chimpanzee monoclonal antibodies
against protective antigen. J Infect Dis.
2006 Mar 1;193(5):625–633.
Patent Status: U.S. Provisional
Application No. 60/903,022 filed 23 Feb
2007 (HHS Reference No. E–123–2007/
0–US–01); U.S. Patent Application No.
11/793,735 filed 22 Jun 2007 (HHS
Reference No. E–146–2004/0–US–03).
Licensing Status: Available for
exclusive or non-exclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity:
The National Institute of Allergy and
Infectious Diseases, Laboratory of
Infectious Diseases is seeking statements
of capability or interest from parties
interested in collaborative research to
further develop, evaluate, or
commercialize Chimpanzee/human
neutralizing monoclonal antibodies
against anthrax toxins. Please contact
Dr. Robert Purcell at 301–496–5090 for
more information.
Cell-Nanofiber Composite and CellNanofiber Composite Amalgam Based
Engineered Intervertebral Disc
Description of Invention: Diseased or
damaged musculoskeletal tissues are
often replaced by an artificial material,
cadaver tissue or donated, allogenic
tissue. Tissue engineering offers an
attractive alternative whereby a live,
natural tissue is generated from a
construct made up of a patient’s own
cells or an acceptable/compatible cell
source in combination with a
biodegradable scaffold for replacement
of defective tissue.
Degeneration of the intervertebral disc
(IVD) is a common and significant
source of morbidity in our society.
Approximately 8 of 10 adults at some
point in their life will experience an
episode of significant low back pain,
with the majority improving without
any formal treatment. However, for the
subject requiring surgical management
current interventions focus on fusion of
the involved IVD levels, which
eliminates pain but does not attempt to
restore disc function. Approximately
200,000 spinal fusions were performed
in the United States in 2002 to treat pain
associated with lumbar disc
degeneration. Spinal fusion however is
thought to significantly alter the
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biomechanics of the disc and lead to
further degeneration, or adjacent
segment disease. Therefore, in the past
decade there has been mounting interest
in the concept of IVD replacement. The
replacement of the IVD holds
tremendous potential as an alternative
to spinal fusion for the treatment of
degenerative disc disease by offering a
safer alternative to current spinal fusion
practices.
At the present time, several disc
replacement implants are at different
stages of preclinical and clinical testing.
These disc replacement technologies are
designed to address flexion, extension,
and lateral bending motions; however,
they do little to address compressive
forces and their longevity is limited due
to their inability to biointegrate.
Therefore, a cell-based tissue
engineering approach offers the most
promising alternative to replace the
degenerated IVD. Current treatment for
injuries that penetrate subchondral bone
include subchondral drilling, periosteal
tissue grafting, osteochondral
allografting, chondrogenic cell and
transplantation; but are limited due to
suboptimal integration with host
tissues.
The present invention claims tissue
engineered intervertebral discs
comprising a nanofibrous polymer
hydrogel amalgam having cells
dispersed therein, methods of
fabricating tissue engineered
intervertebral discs by culturing a
mixture of stem cells or intervertebral
disc cells and a electrospun nanofibrous
polymer hydrogel amalgam in a suitable
bioreactor, and methods of treatment
comprising implantation of tissue
engineered intervertebral disc into a
subject.
Application: Intervertebral disc bioconstructs and electrospinning methods
for fabrication of the discs.
Developmental Status: Prototype
devices have been fabricated and
preclinical studies have been
performed.
Inventors: Wan-Ju Li, Leon Nesti,
Rocky Tuan (NIAMS)
Patent Status: U.S. Provisional
Application No. 60/847,839 filed 27 Sep
2006 (HHS Reference No. E–309–2006/
0–US–01); U.S. Provisional Application
No. 60/848,284 filed 28 Sep 2006 (HHS
Reference No. E–309–2006/1–US–01)
Licensing Status: Available for
exclusive or non-exclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
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Cell-Nanofiber Composite Based
Engineered Cartilage
Description of Invention: Available for
licensing and commercial development
is a tissue-engineered cartilage derived
from a cellular composite made from a
biodegradable, biocompatible polymeric
nanofibrous matrix having dispersed
chondrocytes or adult mesenchymal
stem cells. More particularly, tissueengineered cartilage can be prepared
where the cartilage has a biodegradable
and biocompatible nanofibrous polymer
matrix prepared by electrospinning and
a plurality of chondrocytes or
mesenchymal stem cells dispersed in
the pores of the matrix. The tissueengineered cartilage possesses
compressive strength properties similar
to natural cartilage.
The electrospinning process is a
simple, economical means to produce
biomaterial matrices or scaffolds of
ultra-fine fibers derived from a variety
of biodegradable polymers (Li WJ, et al.
J. Biomed. Mater. Res. 2002; 60:613–21).
Nanofibrous scaffolds (NFSs) formed by
electrospinning, by virtue of structural
similarity to natural extracellular matrix
(ECM), may represent promising
structures for tissue engineering
applications. Electrospun threedimensional NFSs are characterized by
high porosity with a wide distribution
of pore diameter, high-surface area to
volume ratio and morphological
similarities to natural collagen fibrils (Li
WJ, et al. J. Biomed. Mater. Res. 2002;
60:613–21). These physical
characteristics promote favorable
biological responses of seeded cells in
vitro and in vivo, including enhanced
cell attachment, proliferation,
maintenance of the chondrocytic
phenotype (Li WJ, et al. J. Biomed.
Mater. Res. 2003; 67A: 1105–14), and
support of chondrogenic differentiation
(Li WJ, et al. Biomaterials 2005; 26:599–
609) as well as other connective tissue
linage differentiation (Li WJ, et al.
Biomaterials 2005; 26:5158–5166). The
invention based on cell-nanofiber
composite represents a candidate
engineered tissue for cell-based
approaches to cartilage repair.
Application: Cartilage repair and
methods for making tissue-engineered
cartilage.
Developmental Status:
Electrospinning method is fully
developed and cartilage has been
synthesized.
Inventors: Wan-Ju Li and Rocky Tuan
(NIAMS).
Publications: The invention is further
described in:
1. W-J Li, et al. Engineering
controllable anisotropy in electrospun
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biodegradable nanofibrous scaffolds for
musculoskeletal tissue engineering. J
Biomech. 2007;40(8):1686–1693.
2. W-J Li, et al. Fabrication and
characterization of six electrospun
poly(alpha-hydroxy ester)-based fibrous
scaffolds for tissue engineering
applications. Acta Biomater. 2006
Jul;2(4):377–385.
3. CK Kuo, et al. Cartilage tissue
engineering: its potential and uses. Curr
Opin Rheumatol. 2006 Jan;18(1):64–73.
Review.
4. W-J Li, et al. Multilineage
differentiation of human mesenchymal
stem cells in a three-dimensional
nanofibrous scaffold. Biomaterials. 2005
Sep;26(25):5158–5166.
Patent Status: U.S. Provisional
Application No. 60/690,998 filed 15 Jun
2005 (HHS Reference No. E–116–2005/
0–US–01); PCT Application No. PCT/
US2006/0237477 filed 15 Jun 2006
(HHS Reference No. E–116–2005/0–
PCT–02)
Licensing Status: Available for
exclusive or non-exclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Methods for Preparing Complex
Multivalent Immunogenic Conjugates
Description of Invention: Claimed in
this application are novel methods for
preparing complex multivalent
immunogenic conjugates and conjugate
vaccines. The multivalent conjugates
and conjugate vaccines are synthesized
by conjugating mixtures of more than
one polysaccharide at a desired ratio of
the component polysaccharides to at
least one carrier protein using hydrazide
chemistry. Because of the high
efficiency of hydrazide chemistry in
conjugation, the polysaccharides are
effectively conjugated to the carrier
protein(s) so that the resulting complex
synthesized vaccine conjugate products,
without requiring tedious and
complicated purification procedures
such as chromatography and/or
ammonium sulfate precipitation, are
efficacious in inducing antibodies in
mice against each component
polysaccharide. The methods claimed in
this application simplify the preparation
of multivalent conjugate vaccines by
utilizing simultaneous conjugation
reactions in a single reaction mixture or
batch that includes at least two
immunogenic-distinct polysaccharides.
This single-batch simultaneous reaction
eliminates the need for multiple parallel
synthesis processes for each
polysaccharide vaccine conjugate
component as employed in
conventional methods for making
multivalent conjugate vaccines.
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Application: Cost effective and
efficient manufacturing of conjugate
vaccines.
Inventors: Che-Hung Robert Lee
(CBER/FDA)
Patent Status: PCT Application No.
PCT/US2007/006627 filed 16 Mar 2007
(HHS Reference No. E–085–2005/0–
PCT–02).
Licensing Status: Available for
exclusive or non-exclusive licensing.
The technology is not available for
licensing in the field of use of
multivalent meningitis vaccines.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Bioreactor Device and Method and
System for Fabricating Tissue
Description of Invention: Available for
licensing and commercial development
is a millifluidic bioreactor system for
culturing, testing, and fabricating
natural or engineered cells and tissues.
The system consists of a millifluidic
bioreactor device and methods for
sample culture. Biologic samples that
can be utilized include cells, scaffolds,
tissue explants, and organoids. The
system is microchip controlled and can
be operated in closed-loop, providing
controlled delivery of medium and
biofactors in a sterile temperature
regulated environment under tabletop or
incubator use. Sample perfusion can be
applied periodically or continuously, in
a bidirectional or unidirectional
manner, and medium re-circulated.
Advantages: The device is small in
size, and of conventional culture plate
format.
Provides the ability to grow larger
biologic samples than microfluidic
systems, while utilizing smaller
medium volumes than conventional
bioreactors. The bioreactor culture
chamber is adapted to contain sample
volumes on a milliliter scale (10 [mu]L
to 1 mL, with a preferred size of 100
[mu]L), significantly larger than
chamber volumes in microfluidic
systems (on the order of 1 [mu]L).
Typical microfluidic systems are
designed to culture cells and not larger
tissue samples.
The integrated medium reservoirs and
bioreactor chamber design provide for,
(1) concentration of biofactors produced
by the biologic sample, and (2) the use
of smaller amounts of exogenous
biofactor supplements in the culture
medium. The local medium volume
(within the vicinity of the sample) is
less than twice the sample volume. The
total medium volume utilized is small,
preferably 2 ml, significantly smaller
than conventional bioreactors (typically
using 500–1,000 mL).
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Provides for real-time monitoring of
sample growth and function in response
to stimuli via an optical port and
embedded sensors. The optical port
provides for microscopy and
spectroscopy measurements using
transmitted, reflected, or emitted (e.g.,
fluorescent, chemiluminescent) light.
The embedded sensors provide for
measurement of culture fluid pressure
and sample pH, oxygen tension, and
temperature.
Capable of providing external
stimulation to the biologic sample,
including mechanical forces (e.g. fluid
shear, hydrostatic pressure, matrix
compression, microgravity via
clinorotation), electrical fields (e.g., AC
currents), and biofactors (e.g., growth
factors, cytokines) while monitoring
their effect in real-time via the
embedded sensors, optical port, and
medium sampling port.
Monitoring of biologic sample
response to external stimulation can be
performed non-invasively and nondestructively through the embedded
sensors, optical port, and medium
sampling port. Testing of tissue
mechanical and electrical properties
(e.g., stiffness, permeability, loss
modulus via stress or creep test,
electrical impedance) can be performed
over time without removing the sample
from the bioreactor device.
The bioreactor sample chamber can be
constructed with multiple levels fed via
separate perfusion circuits, facilitating
the growth and production of
multiphasic tissues.
Application: Cartilage repair and
methods for making tissue-engineered
cartilage.
Development Stage: Electrospinning
method is fully developed and cartilage
has been synthesized.
Inventors: Juan M. Taboas (NIAMS),
Rocky S. Tuan (NIAMS), et al.
Patent Status: U.S. Provisional
Application No. 60/701,186 filed 20 Jul
2005 (HHS Reference No. E–042–2005/
0–US–01); PCT Application No. PCT/
US2006/028417 filed 20 Jul 2006, which
published as WO 2007/012071 on 25 Jan
2007 (HHS Reference No. E–042–2005/
0–PCT–02)
Licensing Status: Available for
exclusive or non-exclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Monoclonal Antibodies Against
Orthopoxviruses
Description of Invention: Concerns
that variola (smallpox) virus might be
used as a biological weapon have led to
the recommendation of widespread
vaccination with vaccinia virus. While
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vaccination is generally safe and
effective for prevention of smallpox, it
is well documented that various adverse
reactions in individuals have been
caused by vaccination with existing
licensed vaccines. Vaccinia immune
globulin (VIG) prepared from vaccinated
humans has historically been used to
treat adverse reactions arising from
vaccinia immunization. However, VIG
lots may have different potencies and
carry the potential to transmit other
viral agents.
Chimpanzee Fabs against the B5 and
A33 outer extracellular membrane
proteins of vaccinia virus were isolated
and converted into complete mAbs with
human gamma1 heavy chain constant
regions. The two mAbs displayed high
binding affinities to B5 and A33. The
mAbs inhibited the spread of vaccinia
virus as well as variola virus (the
causative agent of smallpox) in vitro,
protected mice from subsequent
intranasal challenge with virulent
vaccinia virus, protected mice when
administered 2 days after challenge, and
provided significantly greater protection
than that afforded by VIG.
Application: Prophylactics or
therapeutics against orthopoxviruses.
Developmental Status: Preclinical
studies have been performed.
Inventors: Zhaochun Chen, Robert
Purcell, Suzanne Emerson, Patricia Earl,
Bernard Moss (NIAID).
Publications:
1. Z Chen, et al. Chimpanzee/human
mAbs to vaccinia virus B5 protein
neutralize vaccinia and smallpox
viruses and protect mice against
vaccinia virus. Proc Natl Acad Sci USA.
2006 Feb 7;103(6):1882–1887. Epub
2006 Jan 25.
2. Z Chen, et al. Characterization of
chimpanzee/human monoclonal
antibodies to the vaccinia A33
glycoprotein and its variola virus
homolog in vitro and in a vaccinia
mouse protection model. J Virol. 2007
Jun 20; Epub ahead of print, doi
10.1128/JVI.00906–07.
Patent Status: PCT Patent Application
No. PCT/US2006/048832 filed 22 Dec
2006 (HHS Reference No. E–145–2004/
3–PCT–01); PCT Patent Application No.
PCT/US2006/048833 filed 22 Dec 2006
(HHS Reference No. E–145–2004/4–
PCT–01)
Licensing Status: Available for
exclusive or non-exclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity:
The National Institute of Allergy and
Infectious Diseases, Laboratory of
Infectious Diseases, is seeking
statements of capability or interest from
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Federal Register / Vol. 73, No. 17 / Friday, January 25, 2008 / Notices
parties interested in collaborative
research to further develop, evaluate, or
commercialize Chimpanzee/human
neutralizing monoclonal antibodies
against orthopoxviruses. Please contact
Dr. Robert Purcell at 301–496 5090 for
more information.
jlentini on PROD1PC65 with NOTICES
A Method With Increased Yield for
Production of Polysaccharide-Protein
Conjugate Vaccines Using Hydrazide
Chemistry
Description of Invention: Current
methods for synthesis and
manufacturing of polysaccharideprotein conjugate vaccines employ
conjugation reactions with low
efficiency (about twenty percent). This
means that up to eighty percent of the
added activated polysaccharide (PS) is
lost. In addition, inclusion of a
chromatographic process for
purification of the conjugates from
unconjugated PS is required.
The present invention utilizes the
characteristic chemical property of
hydrazide groups on one reactant to
react with aldehyde groups or cyanate
esters on the other reactant with an
improved conjugate yield of at least
sixty percent. With this conjugation
efficiency the leftover unconjugated
protein and polysaccharide would not
need to be removed and thus the
purification process of the conjugate
product can be limited to diafiltration to
remove the by-products of small
molecules. The new conjugation
reaction can be carried out within one
or two days with reactant
concentrations between 1 and 25 mg/mL
at PS/protein ratios from 1:2 to 3:1, at
temperatures between 4 and 40 degrees
Centigrade, and in a pH range of 5.5 to
7.4, optimal conditions varying from PS
to PS.
Application: Cost effective and
efficient manufacturing of conjugate
vaccines.
Inventors: Che-Hung Robert Lee and
Carl E. Frasch (CBER/FDA)
Patent Status: U.S. Patent Application
No. 10/566,899 filed 01 Feb 2006,
claiming priority to 06 Aug 2003 (HHS
Reference No. E–301–2003/0–US–10);
U.S. Patent Application No. 10/566,898
filed 01 Feb 2006, claiming priority to
06 Aug 2003 (HHS Reference No. E–
301–2003/1–US–02); International
rights available.
Licensing Status: Available for nonexclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
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gPGA Conjugates for Eliciting Immune
Responses Directed Against Bacillus
anthracis and Other Bacilli
Description of Invention: This
invention claims immunogenic
conjugates of a poly-g-glutamic acid
(gPGA) of B. anthracis, or of another
bacillus that expresses a gPGA that elicit
a serum antibody response against B.
anthracis, in mammalian hosts to which
the conjugates are administered. The
invention also relates methods which
are useful for eliciting an immunogenic
response in mammals, particularly
humans, including responses which
provide protection against, or reduce the
severity of, infections caused by B.
anthracis. The vaccines claimed in this
application are intended for active
immunization for prevention of B.
anthracis infection, and for preparation
of immune antibodies. The vaccines of
this invention are designed to confer
specific immunity against infection with
B. anthracis, and to induce antibodies
specific to B. anthracis gPGA. The B.
anthracis vaccine is composed of nontoxic bacterial components, suitable for
infants, children of all ages, and adults.
Inventors: Rachel Schneerson
(NICHD), Stephen Leppla (NIAID), John
Robbins (NICHD), Joseph Shiloach
(NIDDK), Joanna Kubler-Kielb (NICHD),
Darrell Liu (NIDCR), Fathy Majadly
(NICHD).
Publication: R Schneerson, et al. Poly
(gamma-D-glutamic acid) protein
conjugates induce IgG antibodies in
mice to the capsule of Bacillus
anthracis: a potential addition to the
anthrax vaccine. Proc Natl Acad Sci
USA. 2003 Jul 22;100(15):8945–50.
Patent Status: U.S. Patent Application
No. 10/559,825 filed 02 Dec 2005,
claiming priority to 05 Jun 2003 (HHS
Reference No. E–343–2002/0–US–04).
Licensing Status: Available for
licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Oligodeoxynucleotide and its Use To
Induce an Immune Response
Description of Invention: This
invention comprises
oligodeoxynucleotides (ODNs) having at
least 10 nucleotides with an
unmethylated central CpG motif that are
immunostimulatory in humans. The
inventors have shown that the various
ODNs of this invention (having different
CpG motifs and backbones) induce
immune responses from human non-B
and B cells. The motif that stimulates
non-B cells induces production and
release of multiple T cell cytokines and
chemokines; specifically, the Th1
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cytokine IFN-gamma, which facilitates
the development of a cytotoxic T cell
response. In contrast, the motif that
stimulates B cells induces production
and release of various cytokines,
including, but not limited to IL–6,
which supports a Th2 antibody
response. The inventors have generated
in vitro and ex vivo data showing the
ODNs of this invention have utility in
precisely regulating the type and
magnitude of the immune response in
human cells. The present invention has
multiple therapeutic uses, including but
not limited to cancer, vaccine adjuvants,
treating autoimmune disorders and
immune system deficiencies, as well as
an anti-infective agent and in
combination with any antisense
therapy.
Inventors: Dennis Klinman (FDA),
Daniela Verthelyi (FDA), Kenji Ishii
(NINDS).
Patent Status: U.S. Patent Application
No. 11/595,211 filed 09 Nov 2006,
claiming priority to 12 Apr 1999 (HHS
Reference No. E–147–1999/0–US–05).
Licensing Status: Available for
licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
A Method of Immunizing Humans
Against Salmonella Typhi Using a
Vi-rEPA Conjugate Vaccine
Description of Invention: This
invention is a method of immunization
against typhoid fever using a conjugate
vaccine comprising the capsular
polysaccharide of Salmonella typhi, Vi,
conjugated through an adipic
dihydrazide linker to nontoxic
recombinant exoprotein A (rEPA) from
Pseudomonas aeruginosa. The three
licensed vaccines against typhoid fever,
attenuated S. typhi Ty21a, killed whole
cell vaccines and Vi polysaccharide,
have limited efficacy, in particular for
children under 5 years of age, which
make an improved vaccine desirable.
It is generally recognized that an
effective vaccine against Salmonella
typhi is one that increases serum antiVi IgG eight-fold six weeks after
immunization. The conjugate vaccine of
the invention increases anti-Vi IgG, 48fold, 252-fold and 400-fold in adults, in
5–14 years-old and 2–4 years-old
children, respectively. Thus this is a
highly effective vaccine suitable for
children and should find utility in
endemic regions and as a traveler’s
vaccine. The route of administration can
also be combined with routine
immunization. In 2–5 years old, the
protection against typhoid fever is 90%
for 4 years. In school age children and
in adults the protection could mount to
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jlentini on PROD1PC65 with NOTICES
completer protection according to the
immunogenicity data.
Application: Immunization against
Salmonella typhi for long term
prevention of typhoid fever in all ages.
Developmental Status: Conjugates
have been synthesized and clinical
studies have been performed. The
synthesis of the conjugates is described
by Kossaczka, et al. in Infect Immun.
1997 June;65(7):2088–2093. Phase III
clinical studies are described by Mai, et
al. in N Engl J Med. 2003 October 2;
349(14):1390–1391. Dosage studies are
described by Canh, et al. in Infect
Immun. 2004 Nov; 72(11):6586–6588.
A safety and immunogenicity study in
infants are under way. The aim is to
administer the conjugate vaccine with
routine infant immunization.
Preliminary results shows the vaccine is
safe in 2 months old infants.
Inventors: Zuzana Kossaczka,
Shousun C. Szu, and John B. Robbins
(NICHD).
Patent Status: U.S. Patent 6,797,275
issued 28 Sep 2004 (HHS Reference No.
E–020–1999/0–US–02); U.S. Patent
Application No. 10/866,343 filed 10 Jun
2004 (HHS Reference No. E–020–1999/
0–US–03); U.S. Patent Application No.
11/726,304 filed 20 Mar 2007 (HHS
Reference No. E–020–1999/0–US–04).
Licensing Status: Available for nonexclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity:
The National Institute of Child Health
and Human Development, Laboratory of
Developmental and Molecular
Immunity, is seeking statements of
capability or interest from parties
interested in collaborative research to
further develop, evaluate, or
commercialize A Method of Immunizing
Humans Against Salmonella Typhi
Using a Vi-rEPA Conjugate Vaccine.
Please contact John D. Hewes, Ph.D., at
301–435–3121 or hewesj@mail.nih.gov
for more information.
Dated: January 10, 2008.
Steven M. Ferguson,
Director, Division of Technology Development
and Transfer, Office of Technology Transfer,
National Institutes of Health.
[FR Doc. E8–1232 Filed 1–24–08; 8:45 am]
BILLING CODE 4140–01–P
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions;
Availability for Licensing
National Institutes of Health,
Public Health Service, HHS.
ACTION: Notice.
AGENCY:
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.
Diagnosis and Treatment of Barrett’s
Esophagus and Associated Esophageal
Adenocarcinoma
Description of Invention: Barrett’s
esophagus is a condition in which the
normal esophageal tissue lining has
been replaced by an abnormal lining of
gastric and intestinal tissue resulting
from chronic gastroesophageal reflux
disease. Patients have an increased risk
of developing esophageal
adenocarcinoma, which is often
detected at later stages and is associated
with poor prognosis. Survival rates are
very low ranging from 10% in Europe to
16% in the United States.
Available for licensing are microRNA
(miRNA) biomarkers that show
differential expression in the
adenocarcinoma diagnosis and Barrett’s
esophagus status, and they can predict
diagnosis and Barrett’s esophagus with
accuracies of 71.4% and 74.7%,
respectively. Thus, these miRNA
biomarkers that may predispose
individuals to Barrett’s esophagus and/
or esophageal adenocarcinoma could
provide a means for earlier detection
and help in better identifying treatment
options.
Applications:
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4603
Method to diagnose and treat Barrett’s
esophagus and esophageal
adenocarcinoma.
miRNA pharmaceutical compositions
to treat Barrett’s esophagus.
Advantages: Early diagnostic that can
more accurately stratify patients for
increased survival rates and appropriate
treatments.
Development Status: The technology
is currently in the pre-clinical stage of
development.
Market: Esophageal cancer is the 8th
most common cancer and 6th most
common cause of cancer worldwide.
Survival rate of esophageal cancer is
10% to 16% in Europe and United
States respectively.
miRNA technologies have an
emerging market, and in 2007, it was
worth an estimated 23 million dollars in
the U.S. and it has a projected annual
growth rate of 100%.
Inventors: Ewy Mathe (NCI), Curtis C.
Harris (NCI), et al.
Patent Status: U.S. Provisional
Application No. 60/979,300 filed 11 Oct
2007 (HHS Reference No. E–008–2008/
0–US–01).
Licensing Status: Available for nonexclusive licensing.
Licensing Contact: Jennifer Wong;
301–435–4633; wongje@mail.nih.gov.
Collaborative Research Opportunity:
The Laboratory of Human
Carcinogenesis at the National Cancer
Institute is seeking statements of
capability or interest from parties
interested in collaborative research to
further develop, evaluate, or
commercialize methods to diagnose and
treat Barrett’s esophagus and esophageal
carcinoma. Please contact John D.
Hewes, Ph.D. at 301–435–3121 or
hewesj@mail.nih.gov for more
information.
Mouse Model for Obesity and Type 2
Diabetes Due to Inactivation of
ANKRD26 Gene
Description of Invention: Obesity and
type II diabetes are major health hazards
both in the United States and
internationally. The incidence of obesity
has been steadily increasing,
underscoring the need to identify and
develop effective treatments. As a result,
there has been a strong effort to create
animal models to help study these
diseases.
NIH inventors have created a new
mouse model for obesity and type II
diabetes. In this model, both copies of
the ANKRD26 gene are inactivated by
the insertion of a marker gene (betagalactosidase) into the open reading
frame of the gene. The resulting
knockout mouse exhibits extreme
obesity, increased organ and body size,
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]]>Agencies
[Federal Register Volume 73, Number 17 (Friday, January 25, 2008)]
[Notices]
[Pages 4598-4603]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-1232]
-----------------------------------------------------------------------
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.
Monoclonal Antibodies Against Dengue and Other Viruses With Deletion in
Fc Region
Description of Invention: The four dengue virus (DENV) serotypes
(DENV-1 to DENV-4) are the most important arthropod-borne flaviviruses
in terms of morbidity and geographic distribution. Up to 100 million
DENV infections occur every year, mostly in tropical and subtropical
areas where vector mosquitoes are abundant. Infection with
[[Page 4599]]
any of the DENV serotypes may be asymptomatic or may lead to classic
dengue fever or more severe dengue hemorrhagic fever (DHF) and dengue
shock syndrome (DSS), which are increasingly common in the dengue
endemic areas. Immunity to the same virus serotype (homotypic immunity)
is life-long, whereas immunity to different serotypes (heterotypic
immunity) lasts 2-3 months so that infection with a different serotype
virus is possible. DHF/DSS often occurs in patients with second,
heterotypic DENV infections or in infants with maternally transferred
dengue immunity. Severe dengue is a major cause of hospitalization, and
fatality rates vary from <1% to 5% in children.
Antibody-dependent enhancement (ADE) has been proposed as an
underlying pathogenic mechanism of DHF/DSS. ADE occurs because
preexisting subneutralizing antibodies and the infecting DENV form
complexes that bind to Fc receptor-bearing cells, leading to increased
virus uptake and replication. ADE has been repeatedly demonstrated in
vitro using dengue immune sera or monoclonal antibodies and cells of
monocytic and recently, B lymphocytic lineages bearing Fc receptors.
ADE of DENV-2 infection has also been demonstrated in monkeys infused
with a human dengue immune serum.
We have identified chimpanzee-human chimeric IgG1 mAbs capable of
neutralizing or binding to one or more DENV serotypes. Cross-reactive
IgG 1A5 neutralizes DENV-1 and DENV-2 more efficiently than DENV-3 and
DENV-4, and type-specific IgG 5H2 neutralizes DENV-4 at a high titer.
Analysis of antigenic variants has localized the IgG 1A5 binding site
to the conserved fusion peptide in E. Thus, IgG 1A5 shares many
characteristics with the cross-reactive antibodies detected in
flavivirus infections.
This application claims a variant of an antibody comprising a
polypeptide in the Fc region, which binds an Fc gamma receptor
(FcgammaR) with lower affinity than the parent antibody. The variant
polypeptide comprises a deletion of nine amino acids at the N-terminus
of the CH2 domain in the Fc region. Introduction of the Fc
variant abrogates the antibody-mediated dengue virus replication
enhancing activity. This invention has important implications for the
antibody-mediated prevention of dengue virus infection.
Application: Immunization against Dengue and/or flaviviruses.
Developmental Status: Antibody candidates have been synthesized and
preclinical studies have been performed.
Inventors: Ana Goncalvez, Robert Purcell, C.J. Lai (NIAID).
Publication: AP Goncalvez, et al. Monoclonal antibody-mediated
enhancement of dengue virus infection in vitro and in vivo and
strategies for prevention Proc Natl Acad Sci USA. 2007 May
29;104(22):9422-9427.
Patent Status: U.S. Provisional Application No. 60/922,282 filed 04
Apr 2007 (HHS Reference No. E-159-2007/0-US-01); U.S. Provisional
Application No. 60/927,755 filed 04 May 2007 (HHS Reference No. E-159-
2007/1-US-01); U.S. Provisional Application No. 60/928,405 filed 08 May
2007 (HHS Reference No. E-159-2007/2-US-01).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Monoclonal Antibodies that Neutralize B. anthracis Protective Antigen
(PA), Lethal Factor (LF) and Edema Factor (EF)
Description of Invention: Anthrax, whether resulting from natural
or bioterrorist-associated exposure, is a constant threat to human
health. The lethality of anthrax is primarily the result of the effects
of anthrax toxin, which has 3 components: a receptor-binding protein
known as ``protective antigen'' (PA) and 2 catalytic proteins known as
``lethal factor'' (LF) and ``edema factor'' (EF). Although production
of an efficient anthrax vaccine is an ultimate goal, the benefits of
vaccination can be expected only if a large proportion of the
population at risk is immunized. The low incidence of anthrax suggests
that large-scale vaccination may not be the most efficient means of
controlling this disease. In contrast, passive administration of
neutralizing human or chimpanzee monoclonal antibody to a subject at
risk for anthrax or exposed to anthrax could provide immediate efficacy
for emergency prophylaxis against or treatment of anthrax.
Four monoclonal antibodies (mAbs) against PA, three mAbs against LF
and four mAbs specific for EF of anthrax were isolated from a phage
display library generated from immunized chimpanzees. Two mAbs
recognizing PA (W1 and W2), two anti-LF mAbs efficiently neutralized
the cytotoxicity of lethal toxin in a macrophage lysis assay. One anti-
EF mAb efficiently neutralized edema toxin in cell culture. All five
neutralizing mAbs protected animals from anthrax toxin challenge.
Application: Prophylactics or therapeutics against B. anthracis.
Developmental Status: Preclinical studies have been performed.
Inventors: Zhaochun Chen, Robert Purcell, Suzanne Emerson, Stephen
Leppla, Mahtab Moyeri (NIAID).
Publication: Z Chen, et al. Efficient neutralization of anthrax
toxin by chimpanzee monoclonal antibodies against protective antigen. J
Infect Dis. 2006 Mar 1;193(5):625-633.
Patent Status: U.S. Provisional Application No. 60/903,022 filed 23
Feb 2007 (HHS Reference No. E-123-2007/0-US-01); U.S. Patent
Application No. 11/793,735 filed 22 Jun 2007 (HHS Reference No. E-146-
2004/0-US-03).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases, Laboratory of Infectious Diseases is
seeking statements of capability or interest from parties interested in
collaborative research to further develop, evaluate, or commercialize
Chimpanzee/human neutralizing monoclonal antibodies against anthrax
toxins. Please contact Dr. Robert Purcell at 301-496-5090 for more
information.
Cell-Nanofiber Composite and Cell-Nanofiber Composite Amalgam Based
Engineered Intervertebral Disc
Description of Invention: Diseased or damaged musculoskeletal
tissues are often replaced by an artificial material, cadaver tissue or
donated, allogenic tissue. Tissue engineering offers an attractive
alternative whereby a live, natural tissue is generated from a
construct made up of a patient's own cells or an acceptable/compatible
cell source in combination with a biodegradable scaffold for
replacement of defective tissue.
Degeneration of the intervertebral disc (IVD) is a common and
significant source of morbidity in our society. Approximately 8 of 10
adults at some point in their life will experience an episode of
significant low back pain, with the majority improving without any
formal treatment. However, for the subject requiring surgical
management current interventions focus on fusion of the involved IVD
levels, which eliminates pain but does not attempt to restore disc
function. Approximately 200,000 spinal fusions were performed in the
United States in 2002 to treat pain associated with lumbar disc
degeneration. Spinal fusion however is thought to significantly alter
the
[[Page 4600]]
biomechanics of the disc and lead to further degeneration, or adjacent
segment disease. Therefore, in the past decade there has been mounting
interest in the concept of IVD replacement. The replacement of the IVD
holds tremendous potential as an alternative to spinal fusion for the
treatment of degenerative disc disease by offering a safer alternative
to current spinal fusion practices.
At the present time, several disc replacement implants are at
different stages of preclinical and clinical testing. These disc
replacement technologies are designed to address flexion, extension,
and lateral bending motions; however, they do little to address
compressive forces and their longevity is limited due to their
inability to biointegrate. Therefore, a cell-based tissue engineering
approach offers the most promising alternative to replace the
degenerated IVD. Current treatment for injuries that penetrate
subchondral bone include subchondral drilling, periosteal tissue
grafting, osteochondral allografting, chondrogenic cell and
transplantation; but are limited due to suboptimal integration with
host tissues.
The present invention claims tissue engineered intervertebral discs
comprising a nanofibrous polymer hydrogel amalgam having cells
dispersed therein, methods of fabricating tissue engineered
intervertebral discs by culturing a mixture of stem cells or
intervertebral disc cells and a electrospun nanofibrous polymer
hydrogel amalgam in a suitable bioreactor, and methods of treatment
comprising implantation of tissue engineered intervertebral disc into a
subject.
Application: Intervertebral disc bio-constructs and electrospinning
methods for fabrication of the discs.
Developmental Status: Prototype devices have been fabricated and
preclinical studies have been performed.
Inventors: Wan-Ju Li, Leon Nesti, Rocky Tuan (NIAMS)
Patent Status: U.S. Provisional Application No. 60/847,839 filed 27
Sep 2006 (HHS Reference No. E-309-2006/0-US-01); U.S. Provisional
Application No. 60/848,284 filed 28 Sep 2006 (HHS Reference No. E-309-
2006/1-US-01)
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Cell-Nanofiber Composite Based Engineered Cartilage
Description of Invention: Available for licensing and commercial
development is a tissue-engineered cartilage derived from a cellular
composite made from a biodegradable, biocompatible polymeric
nanofibrous matrix having dispersed chondrocytes or adult mesenchymal
stem cells. More particularly, tissue-engineered cartilage can be
prepared where the cartilage has a biodegradable and biocompatible
nanofibrous polymer matrix prepared by electrospinning and a plurality
of chondrocytes or mesenchymal stem cells dispersed in the pores of the
matrix. The tissue-engineered cartilage possesses compressive strength
properties similar to natural cartilage.
The electrospinning process is a simple, economical means to
produce biomaterial matrices or scaffolds of ultra-fine fibers derived
from a variety of biodegradable polymers (Li WJ, et al. J. Biomed.
Mater. Res. 2002; 60:613-21). Nanofibrous scaffolds (NFSs) formed by
electrospinning, by virtue of structural similarity to natural
extracellular matrix (ECM), may represent promising structures for
tissue engineering applications. Electrospun three-dimensional NFSs are
characterized by high porosity with a wide distribution of pore
diameter, high-surface area to volume ratio and morphological
similarities to natural collagen fibrils (Li WJ, et al. J. Biomed.
Mater. Res. 2002; 60:613-21). These physical characteristics promote
favorable biological responses of seeded cells in vitro and in vivo,
including enhanced cell attachment, proliferation, maintenance of the
chondrocytic phenotype (Li WJ, et al. J. Biomed. Mater. Res. 2003; 67A:
1105-14), and support of chondrogenic differentiation (Li WJ, et al.
Biomaterials 2005; 26:599-609) as well as other connective tissue
linage differentiation (Li WJ, et al. Biomaterials 2005; 26:5158-5166).
The invention based on cell-nanofiber composite represents a candidate
engineered tissue for cell-based approaches to cartilage repair.
Application: Cartilage repair and methods for making tissue-
engineered cartilage.
Developmental Status: Electrospinning method is fully developed and
cartilage has been synthesized.
Inventors: Wan-Ju Li and Rocky Tuan (NIAMS).
Publications: The invention is further described in:
1. W-J Li, et al. Engineering controllable anisotropy in
electrospun biodegradable nanofibrous scaffolds for musculoskeletal
tissue engineering. J Biomech. 2007;40(8):1686-1693.
2. W-J Li, et al. Fabrication and characterization of six
electrospun poly(alpha-hydroxy ester)-based fibrous scaffolds for
tissue engineering applications. Acta Biomater. 2006 Jul;2(4):377-385.
3. CK Kuo, et al. Cartilage tissue engineering: its potential and
uses. Curr Opin Rheumatol. 2006 Jan;18(1):64-73. Review.
4. W-J Li, et al. Multilineage differentiation of human mesenchymal
stem cells in a three-dimensional nanofibrous scaffold. Biomaterials.
2005 Sep;26(25):5158-5166.
Patent Status: U.S. Provisional Application No. 60/690,998 filed 15
Jun 2005 (HHS Reference No. E-116-2005/0-US-01); PCT Application No.
PCT/US2006/0237477 filed 15 Jun 2006 (HHS Reference No. E-116-2005/0-
PCT-02)
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Methods for Preparing Complex Multivalent Immunogenic Conjugates
Description of Invention: Claimed in this application are novel
methods for preparing complex multivalent immunogenic conjugates and
conjugate vaccines. The multivalent conjugates and conjugate vaccines
are synthesized by conjugating mixtures of more than one polysaccharide
at a desired ratio of the component polysaccharides to at least one
carrier protein using hydrazide chemistry. Because of the high
efficiency of hydrazide chemistry in conjugation, the polysaccharides
are effectively conjugated to the carrier protein(s) so that the
resulting complex synthesized vaccine conjugate products, without
requiring tedious and complicated purification procedures such as
chromatography and/or ammonium sulfate precipitation, are efficacious
in inducing antibodies in mice against each component polysaccharide.
The methods claimed in this application simplify the preparation of
multivalent conjugate vaccines by utilizing simultaneous conjugation
reactions in a single reaction mixture or batch that includes at least
two immunogenic-distinct polysaccharides. This single-batch
simultaneous reaction eliminates the need for multiple parallel
synthesis processes for each polysaccharide vaccine conjugate component
as employed in conventional methods for making multivalent conjugate
vaccines.
[[Page 4601]]
Application: Cost effective and efficient manufacturing of
conjugate vaccines.
Inventors: Che-Hung Robert Lee (CBER/FDA)
Patent Status: PCT Application No. PCT/US2007/006627 filed 16 Mar
2007 (HHS Reference No. E-085-2005/0-PCT-02).
Licensing Status: Available for exclusive or non-exclusive
licensing. The technology is not available for licensing in the field
of use of multivalent meningitis vaccines.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Bioreactor Device and Method and System for Fabricating Tissue
Description of Invention: Available for licensing and commercial
development is a millifluidic bioreactor system for culturing, testing,
and fabricating natural or engineered cells and tissues. The system
consists of a millifluidic bioreactor device and methods for sample
culture. Biologic samples that can be utilized include cells,
scaffolds, tissue explants, and organoids. The system is microchip
controlled and can be operated in closed-loop, providing controlled
delivery of medium and biofactors in a sterile temperature regulated
environment under tabletop or incubator use. Sample perfusion can be
applied periodically or continuously, in a bidirectional or
unidirectional manner, and medium re-circulated.
Advantages: The device is small in size, and of conventional
culture plate format.
Provides the ability to grow larger biologic samples than
microfluidic systems, while utilizing smaller medium volumes than
conventional bioreactors. The bioreactor culture chamber is adapted to
contain sample volumes on a milliliter scale (10 [mu]L to 1 mL, with a
preferred size of 100 [mu]L), significantly larger than chamber volumes
in microfluidic systems (on the order of 1 [mu]L). Typical microfluidic
systems are designed to culture cells and not larger tissue samples.
The integrated medium reservoirs and bioreactor chamber design
provide for, (1) concentration of biofactors produced by the biologic
sample, and (2) the use of smaller amounts of exogenous biofactor
supplements in the culture medium. The local medium volume (within the
vicinity of the sample) is less than twice the sample volume. The total
medium volume utilized is small, preferably 2 ml, significantly smaller
than conventional bioreactors (typically using 500-1,000 mL).
Provides for real-time monitoring of sample growth and function in
response to stimuli via an optical port and embedded sensors. The
optical port provides for microscopy and spectroscopy measurements
using transmitted, reflected, or emitted (e.g., fluorescent,
chemiluminescent) light. The embedded sensors provide for measurement
of culture fluid pressure and sample pH, oxygen tension, and
temperature.
Capable of providing external stimulation to the biologic sample,
including mechanical forces (e.g. fluid shear, hydrostatic pressure,
matrix compression, microgravity via clinorotation), electrical fields
(e.g., AC currents), and biofactors (e.g., growth factors, cytokines)
while monitoring their effect in real-time via the embedded sensors,
optical port, and medium sampling port.
Monitoring of biologic sample response to external stimulation can
be performed non-invasively and non-destructively through the embedded
sensors, optical port, and medium sampling port. Testing of tissue
mechanical and electrical properties (e.g., stiffness, permeability,
loss modulus via stress or creep test, electrical impedance) can be
performed over time without removing the sample from the bioreactor
device.
The bioreactor sample chamber can be constructed with multiple
levels fed via separate perfusion circuits, facilitating the growth and
production of multiphasic tissues.
Application: Cartilage repair and methods for making tissue-
engineered cartilage.
Development Stage: Electrospinning method is fully developed and
cartilage has been synthesized.
Inventors: Juan M. Taboas (NIAMS), Rocky S. Tuan (NIAMS), et al.
Patent Status: U.S. Provisional Application No. 60/701,186 filed 20
Jul 2005 (HHS Reference No. E-042-2005/0-US-01); PCT Application No.
PCT/US2006/028417 filed 20 Jul 2006, which published as WO 2007/012071
on 25 Jan 2007 (HHS Reference No. E-042-2005/0-PCT-02)
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Monoclonal Antibodies Against Orthopoxviruses
Description of Invention: Concerns that variola (smallpox) virus
might be used as a biological weapon have led to the recommendation of
widespread vaccination with vaccinia virus. While vaccination is
generally safe and effective for prevention of smallpox, it is well
documented that various adverse reactions in individuals have been
caused by vaccination with existing licensed vaccines. Vaccinia immune
globulin (VIG) prepared from vaccinated humans has historically been
used to treat adverse reactions arising from vaccinia immunization.
However, VIG lots may have different potencies and carry the potential
to transmit other viral agents.
Chimpanzee Fabs against the B5 and A33 outer extracellular membrane
proteins of vaccinia virus were isolated and converted into complete
mAbs with human gamma1 heavy chain constant regions. The two mAbs
displayed high binding affinities to B5 and A33. The mAbs inhibited the
spread of vaccinia virus as well as variola virus (the causative agent
of smallpox) in vitro, protected mice from subsequent intranasal
challenge with virulent vaccinia virus, protected mice when
administered 2 days after challenge, and provided significantly greater
protection than that afforded by VIG.
Application: Prophylactics or therapeutics against orthopoxviruses.
Developmental Status: Preclinical studies have been performed.
Inventors: Zhaochun Chen, Robert Purcell, Suzanne Emerson, Patricia
Earl, Bernard Moss (NIAID).
Publications:
1. Z Chen, et al. Chimpanzee/human mAbs to vaccinia virus B5
protein neutralize vaccinia and smallpox viruses and protect mice
against vaccinia virus. Proc Natl Acad Sci USA. 2006 Feb 7;103(6):1882-
1887. Epub 2006 Jan 25.
2. Z Chen, et al. Characterization of chimpanzee/human monoclonal
antibodies to the vaccinia A33 glycoprotein and its variola virus
homolog in vitro and in a vaccinia mouse protection model. J Virol.
2007 Jun 20; Epub ahead of print, doi 10.1128/JVI.00906-07.
Patent Status: PCT Patent Application No. PCT/US2006/048832 filed
22 Dec 2006 (HHS Reference No. E-145-2004/3-PCT-01); PCT Patent
Application No. PCT/US2006/048833 filed 22 Dec 2006 (HHS Reference No.
E-145-2004/4-PCT-01)
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is
seeking statements of capability or interest from
[[Page 4602]]
parties interested in collaborative research to further develop,
evaluate, or commercialize Chimpanzee/human neutralizing monoclonal
antibodies against orthopoxviruses. Please contact Dr. Robert Purcell
at 301-496 5090 for more information.
A Method With Increased Yield for Production of Polysaccharide-Protein
Conjugate Vaccines Using Hydrazide Chemistry
Description of Invention: Current methods for synthesis and
manufacturing of polysaccharide-protein conjugate vaccines employ
conjugation reactions with low efficiency (about twenty percent). This
means that up to eighty percent of the added activated polysaccharide
(PS) is lost. In addition, inclusion of a chromatographic process for
purification of the conjugates from unconjugated PS is required.
The present invention utilizes the characteristic chemical property
of hydrazide groups on one reactant to react with aldehyde groups or
cyanate esters on the other reactant with an improved conjugate yield
of at least sixty percent. With this conjugation efficiency the
leftover unconjugated protein and polysaccharide would not need to be
removed and thus the purification process of the conjugate product can
be limited to diafiltration to remove the by-products of small
molecules. The new conjugation reaction can be carried out within one
or two days with reactant concentrations between 1 and 25 mg/mL at PS/
protein ratios from 1:2 to 3:1, at temperatures between 4 and 40
degrees Centigrade, and in a pH range of 5.5 to 7.4, optimal conditions
varying from PS to PS.
Application: Cost effective and efficient manufacturing of
conjugate vaccines.
Inventors: Che-Hung Robert Lee and Carl E. Frasch (CBER/FDA)
Patent Status: U.S. Patent Application No. 10/566,899 filed 01 Feb
2006, claiming priority to 06 Aug 2003 (HHS Reference No. E-301-2003/0-
US-10); U.S. Patent Application No. 10/566,898 filed 01 Feb 2006,
claiming priority to 06 Aug 2003 (HHS Reference No. E-301-2003/1-US-
02); International rights available.
Licensing Status: Available for non-exclusive licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
[gamma]PGA Conjugates for Eliciting Immune Responses Directed Against
Bacillus anthracis and Other Bacilli
Description of Invention: This invention claims immunogenic
conjugates of a poly-[gamma]-glutamic acid ([gamma]PGA) of B.
anthracis, or of another bacillus that expresses a [gamma]PGA that
elicit a serum antibody response against B. anthracis, in mammalian
hosts to which the conjugates are administered. The invention also
relates methods which are useful for eliciting an immunogenic response
in mammals, particularly humans, including responses which provide
protection against, or reduce the severity of, infections caused by B.
anthracis. The vaccines claimed in this application are intended for
active immunization for prevention of B. anthracis infection, and for
preparation of immune antibodies. The vaccines of this invention are
designed to confer specific immunity against infection with B.
anthracis, and to induce antibodies specific to B. anthracis
[gamma]PGA. The B. anthracis vaccine is composed of non-toxic bacterial
components, suitable for infants, children of all ages, and adults.
Inventors: Rachel Schneerson (NICHD), Stephen Leppla (NIAID), John
Robbins (NICHD), Joseph Shiloach (NIDDK), Joanna Kubler-Kielb (NICHD),
Darrell Liu (NIDCR), Fathy Majadly (NICHD).
Publication: R Schneerson, et al. Poly (gamma-D-glutamic acid)
protein conjugates induce IgG antibodies in mice to the capsule of
Bacillus anthracis: a potential addition to the anthrax vaccine. Proc
Natl Acad Sci USA. 2003 Jul 22;100(15):8945-50.
Patent Status: U.S. Patent Application No. 10/559,825 filed 02 Dec
2005, claiming priority to 05 Jun 2003 (HHS Reference No. E-343-2002/0-
US-04).
Licensing Status: Available for licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Oligodeoxynucleotide and its Use To Induce an Immune Response
Description of Invention: This invention comprises
oligodeoxynucleotides (ODNs) having at least 10 nucleotides with an
unmethylated central CpG motif that are immunostimulatory in humans.
The inventors have shown that the various ODNs of this invention
(having different CpG motifs and backbones) induce immune responses
from human non-B and B cells. The motif that stimulates non-B cells
induces production and release of multiple T cell cytokines and
chemokines; specifically, the Th1 cytokine IFN-gamma, which facilitates
the development of a cytotoxic T cell response. In contrast, the motif
that stimulates B cells induces production and release of various
cytokines, including, but not limited to IL-6, which supports a Th2
antibody response. The inventors have generated in vitro and ex vivo
data showing the ODNs of this invention have utility in precisely
regulating the type and magnitude of the immune response in human
cells. The present invention has multiple therapeutic uses, including
but not limited to cancer, vaccine adjuvants, treating autoimmune
disorders and immune system deficiencies, as well as an anti-infective
agent and in combination with any antisense therapy.
Inventors: Dennis Klinman (FDA), Daniela Verthelyi (FDA), Kenji
Ishii (NINDS).
Patent Status: U.S. Patent Application No. 11/595,211 filed 09 Nov
2006, claiming priority to 12 Apr 1999 (HHS Reference No. E-147-1999/0-
US-05).
Licensing Status: Available for licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
A Method of Immunizing Humans Against Salmonella Typhi Using a Vi-rEPA
Conjugate Vaccine
Description of Invention: This invention is a method of
immunization against typhoid fever using a conjugate vaccine comprising
the capsular polysaccharide of Salmonella typhi, Vi, conjugated through
an adipic dihydrazide linker to nontoxic recombinant exoprotein A
(rEPA) from Pseudomonas aeruginosa. The three licensed vaccines against
typhoid fever, attenuated S. typhi Ty21a, killed whole cell vaccines
and Vi polysaccharide, have limited efficacy, in particular for
children under 5 years of age, which make an improved vaccine
desirable.
It is generally recognized that an effective vaccine against
Salmonella typhi is one that increases serum anti-Vi IgG eight-fold six
weeks after immunization. The conjugate vaccine of the invention
increases anti-Vi IgG, 48-fold, 252-fold and 400-fold in adults, in 5-
14 years-old and 2-4 years-old children, respectively. Thus this is a
highly effective vaccine suitable for children and should find utility
in endemic regions and as a traveler's vaccine. The route of
administration can also be combined with routine immunization. In 2-5
years old, the protection against typhoid fever is 90% for 4 years. In
school age children and in adults the protection could mount to
[[Page 4603]]
completer protection according to the immunogenicity data.
Application: Immunization against Salmonella typhi for long term
prevention of typhoid fever in all ages.
Developmental Status: Conjugates have been synthesized and clinical
studies have been performed. The synthesis of the conjugates is
described by Kossaczka, et al. in Infect Immun. 1997 June;65(7):2088-
2093. Phase III clinical studies are described by Mai, et al. in N Engl
J Med. 2003 October 2; 349(14):1390-1391. Dosage studies are described
by Canh, et al. in Infect Immun. 2004 Nov; 72(11):6586-6588.
A safety and immunogenicity study in infants are under way. The aim
is to administer the conjugate vaccine with routine infant
immunization. Preliminary results shows the vaccine is safe in 2 months
old infants.
Inventors: Zuzana Kossaczka, Shousun C. Szu, and John B. Robbins
(NICHD).
Patent Status: U.S. Patent 6,797,275 issued 28 Sep 2004 (HHS
Reference No. E-020-1999/0-US-02); U.S. Patent Application No. 10/
866,343 filed 10 Jun 2004 (HHS Reference No. E-020-1999/0-US-03); U.S.
Patent Application No. 11/726,304 filed 20 Mar 2007 (HHS Reference No.
E-020-1999/0-US-04).
Licensing Status: Available for non-exclusive licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity: The National Institute of Child
Health and Human Development, Laboratory of Developmental and Molecular
Immunity, is seeking statements of capability or interest from parties
interested in collaborative research to further develop, evaluate, or
commercialize A Method of Immunizing Humans Against Salmonella Typhi
Using a Vi-rEPA Conjugate Vaccine. Please contact John D. Hewes, Ph.D.,
at 301-435-3121 or hewesj@mail.nih.gov for more information.
Dated: January 10, 2008.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer, National Institutes of Health.
[FR Doc. E8-1232 Filed 1-24-08; 8:45 am]
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