[Federal Register Volume 64, Number 108 (Monday, June 7, 1999)]
[Notices]
[Pages 30345-30347]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-14377]
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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, DHHS.
ACTION: Notice.
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SUMMARY: The inventions listed below are owned by agencies 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.
N-Acylphosphoramidites and Their Use in Oligonucleotide Synthesis
Serge Beaucage et al. (FDA)
DHHS Reference No. E-031-98/0 filed 24 Mar 99
Licensing Contact: Charles Maynard; 301/496-7735 ext. 243; e-mail:
cm251n@nih.gov
This technology relates to the synthesis of oligonucleotides, and
intermediates useful in its synthesis. The therapeutic application of
oligonucleotides is based on the selective formation of hybrids between
antisense oligonucleotides and complimentary nucleic acids, such as
messenger RNAs. Such hybrids inhibit gene expression by blocking
protein translation. Successful inhibition of gene expression requires
the antisense oligonucleotide to be nuclease resistant so that it can
be successfully transported through biological membranes and can
hybridize selectively to a target complementary nucleic acid, thereby
actively blocking protein translation.
This present invention of synthesizing polymers has tremendous
synthetic advantages that are unprecedented with respect to the
synthesis of oligonucleotides in that it enables the facile production
of P-chiral oligomeric or polymeric products, with complete control of
stereochemistry with respect to the phosphorous atom.
Identification and Use of High Efficacy Vaccine Antigens
Ronald N. Germain (NIAID), Irena Stefanova (NIAID), Roland Martin
(NINDS), Marco Vergelli (NINDS), Bernhard Hemmer (NINDS)
Serial No. 60/124,064 filed 12 Mar 99
Licensing Contact: Richard U. Rodriguez; 301/496-7056 ext. 287; e-
mail: rr154z@nih.gov
The invention relates to the identification and use of high
efficacy
[[Page 30346]]
antigens or immunogens. Antigen-specific or adaptive immunity in higher
vertebrates is mediated by limphoid effector cells, T and B-
lymphocytes. T-lymphocytes have -receptors (TCR) that
recognize ligands comprised of cell-surface molecules encoded in the
major histocompatibility complex (MHC) bound to short peptide fragments
of protein antigens. These antigen-specific effector T-lymphocytes are
involved in resistance to infections, in anti-tumor immunity and in
autoimmune-diseases. Studies have shown that activation of the TCR by a
peptide-MHC complex triggers an intracellular biochemical signaling
cascade. These studies have also shown that different peptide-MHC
complexes can yield different levels of responses, thus affecting the
effectiveness of an immune response to various disease states. The
inventors provide methods to efficiently identify optimized or
heteroclitic-ligands (superagonists) which would have utility in the
formation of anti-cancer and anti-pathogen vaccines with enhanced
potency compared to the natural self- or foreign peptide ligand. This
is achieved by a ``biochemical fingerprinting'' process that involves
the analysis of various phosphorylation patterns elicited in specific
T-cells by TCR activation using peptide-MHC complexes. These patterns
enable direct identification of how optimal a given ligand is for the
test T-cells. When the initial ligand proves suboptimal by this
technique, improved ligands can be identified by making variants of the
original peptide, and then analyzing the phosphorylation patterns
elicited by these variants until an optimal pattern is achieved. In
this manner, specific peptides can be tested until a ``superagonist''
is isolated and development of this ``superagonist'' as a potential
vaccine can proceed. These methods provide a direct evaluation of the
immunologic ``quality'' of an initial vaccine candidate. Their use
should greatly reduce the number of potential antigen-candidates that
need to be researched and focus important resources on antigen-
candidates with superior potential to succeed.
Polymorphic Human GABAA Receptor Alpha-6 Subunit
Drs. Nakao Iwata, David Goldman, and Mark Shuckit (NIAAA)
DHHS Reference Number E-061-98/0 filed 19 Fed 99
Licensing Contact: Marlene Shinn; 301/496-7056 ext. 285; e-mail:
ms482m@nih.gov
Human heritability studies using twins and adoptees have indicated
that alcoholism is a complex disorder having a genetic component.
Studies of Children of Alcoholics (COA) have determined that there is a
differential decrease in sensitivity to benzodiazepine drugs (BZD) and
ethanol within this specific population.
G-Aminobutryric Acid (GABA) receptors are implicated in various
neurological and psychiatric disorders. There are two major types of
GABA receptors: A, which is associated with a C1- Channel;
and B, which is associated with K+ and Ca2+
channels. Differential expression of individual subunits of the
multimeric protein appears to provide a mechanism for the body to
convey different physiological functions. the subunit
displays benzodiazepine activity and the 6 subunit
has been associated with alcohol related activity. A proline to serine
substitution at amino acid position 385 in the 6
subunit of the GABAA receptor within the COA population has
displayed a statistical correlation to the average smooth pursuit eye
movement after diazepam administration.
The point mutation can be used as a genetic marker to investigate
susceptibility to alcoholism as well as the biochemical and
physiological responses to both pre- and post-treatment with
benzodiazepines. It is also useful in the investigation of psychiatric
disorders such as schizophrenia, affective disorder, or anxiety
disorders in which abnormal function of the GABAergic neuronal system
is implicated.
A Method of Immunizing Humans Against Salmonella Typhi Using a Vi-
rEPA Conjugate Vaccine
Zuzana Kossaczka, Shousun C. Szu and John B. Robbins (NICHD) DHHS
Reference No. E-020-99/0 filed 04 Dec 98 (PCT/US98/25746)
Licensing Contact: Robert Benson; 301/496-7056 ext. 267; e-mail:
rb20m@nih.gov
This invention is a method of immunizing 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. The
synthesis of the conjugates, not including the superior clinical
results, is described in Infection & Immunity 65(7), pp. 2088-2093,
June 1997.
Antagonists Of The E7 Integrin As Therapeutic
Agents For Inflammatory Diseases
Bjorn R. Ludviksson, Warren Strober, Rolf Ehrhardt (NIAID) Serial
No. 60/019,957 filed 25 Nov 98
Licensing Contact: Richard U. Rodriguez; 301/496-7056 ext. 287; e-
mail: rr154z@nih.gov
The disclosed invention relates to a method of treating and/or
preventing the inflammatory response of an autoimmune disease, an
allergic disease, a graft-versus-host disease and a transplantation
rejection. In particular, this treatment or prevention is accomplished
by administering antagonists of the
7 integrin.
7 is expressed on intra-
epithelial lymphocytes (IELs) and on lamina propria (LP) lymphocytes.
7 can be upregulated by TGF-
, and it is speculated to have regulatory functions such as
homing or retention. The pathogensis of chronic intestinal inflammation
may depend on the traffic of lymphocytes from sites of induction to
sites of inflammation. The inventors have shown that chronic intestinal
inflammation can be prevented and reversed in an IL-2 -/- murine model.
Administration of anti-7 prevents
colonic inflammation and reverses pre-existing inflammation. Therefore,
this technology can be used to treat, prevent or reverse inflammatory
conditions as well as providing a method of screening for substances
effective in reducing the inflammatory effects of
7.
Methods And Compositions for HDL Holoparticle Uptake Receptor
Insertion
B Brewer Jr., AT Remaley, S Argraves (NHLBI) DHHS Reference No. E-
204-98/0 filed 15 May 98
Licensing Contact: Charles Maynard; 301/496-7735 ext. 243; e-mail:
cm251n@nih.gov
This technology relates to compositions and methods for a high
density lipoprotein (HDL) holoparticle uptake receptor. This receptor
is used in the identification and development of substances
(therapeutic agents) which modulate the activity and/or expression
[[Page 30347]]
of the receptor, thereby modulating the uptake of HDL by cells
expressing the receptor on the cell surface.
HDL has anti-atherogenic properties and is known to inhibit
oxidation of low density kiporprotein (LDL). Transgenic animals having
elevated levels of HDL are resistant to high cholesterol dieto-induced
atherosclerosis. Therefore, understanding factors which influence
plasma levels of HDL, such as mechanisms of HDL metabolism, is of major
importance.
The present invention makes a significant contribution to the art
by providing an HDL holoparticle uptake receptor comprising a complex
of proteins and screening methods for identifying substances that
modulate the activity and/or expression of the receptor.
Modified HCV Peptide Vaccine
Jay A. Berzofsky (NCI), Pablo Sarobe (NCI), CD Pendleton (NCI),
Stephen M. Feinstone (FDA)
Serila No. 60/-97,446 filed 21 Aug 98
Licensing Contact: J. Peter Kim; 301/496-7056 ext. 264; e-mail:
jk141n@nih.gov
Hepatitis C virus (HCV) is a single stranded RNA virus responsible
for the majority of non-A non-B hepatitis. Hepatitis C virus (HCV) has
a worldwide distribution and is a major cause of liver cirrhosis and
hepatocellular carcinoma in the U.S., Europe, and Japan. For this
reason, development of a vaccine against hepatitis C is of great
importance.
The present invention provides immunogenic peptides of HCV core
protein which elicit an enhanced immune response, methods for making
these pepetides, and methods for using these peotides for a variety of
therapeutic, diagnostic, and prognostic applications, including a
vaccine. More specifically, the present invention provides an isolated
peptide, and isolated HCV core polypeptide, a fragment of an HCV core
polypeptide and nucleic acids which encode the peptides and
polypeptides of this invention. The invention provides a modified HCV
core peptide that is more immunogenic than the corresponding natural
core peptide for eliciting human cytotoxic T lymphocytes.
Conformationally Locked Nucleoside Analogues
Inventors: Victor E. Marquez, Juan B. Rodriguez, Marc C. Nicklaus,
Joseph J. Barchi, Jr., Maqbool A. Siddiqui (NCI)
U.S. Patent Numbers: 5,869,666 (filed March 14, 1997); 5,629,454
(filed September 23, 1994, with priority back to September 24, 1993)
Foreign Filing: PCT/US94/10794 (issued as European Patent Number
0720604 and Australian Patent Number 677441)
Conformationally Locked Nucleoside Analogs As Antiherpetic Agents
Inventors: Victor E. Marquez, Juan B. Rodriguez, Marc C. Nicklaus,
Joseph J. Barchi, Jr., Maqbool A. Siddiqui (NCI)
U.S. Patent Number: 5,840,728 (filed August 7, 1997, with priority
back to August 7, 1996)
Licensing Contact: Peter Soukas; 301/496-7056 ext. 268; e-mail:
[email protected]
The compounds of the present invention represent the first examples
of carbocyclic dedeoxynucleosides that in solution exist locked in a
defined N-geometry (C3'-endo) conformation typical of conventional
nucleosides. These analogues exhibit increased stability due to the
substitution of carbon for oxygen in the ribose ring. The invention
includes 4'-6'-cyclopropane fused carbocyclic dideoxynucleosides, 2'-
deoxynucleosides and ribonucleosides as well as oligonucleotides
derived from these analogues; the preferred embodiment of the invention
is carbocyclic-4'-6'-cyclopropane-fused analogues of dideoxypurines,
dideoxypyrimidines, deoxypurines, deoxypyrimidines, purine
ribonucleosides and pyrimidine ribonucleosides. In addition,
oligonucleotides derived from one or more of the nucleosides in
combination with the naturally occurring nucleosides are within the
scope of the present invention.
The second invention discloses a method for the treatment of herpes
virus infections by the administration of cyclopropanated carbocyclic
2'-deoxynucleosides to an affected individual. This invention is a
method of administration of the compounds described above. The
compounds of this invention are particularly efficacious against herpes
simplex viruses 1 and 2 (HSV-1 and HSV-2), Epstein-Barr Virus (EBV) and
human cytomegalovirus (CMV), although the nucleoside analogues of the
invention may be used to treat any condition caused by a herpes virus.
Specifically, the N-methanocarba-T (Thymidine) analogue has been shown
to exhibit strong activity against HSV-1 and HSV-2, and moderate to
strong activity against EBV. Significantly, the anti-HSV activity of
the Thymidine analogue is stronger than that of Acyclovir (shown in a
plaque reduction assay), a widely used anti-HSV therapeutic.
Furthermore, the Thymidine analogue is also non-toxic against
stationary cells and is potent against rapidly dividing cells. Dosage
amounts for the compounds are similar to those of Acyclovir.
Descriptions of the inventions may be found in Rodriguez et al., J.
Medicinal Chemistry 37:3389 3399 (1994) and Marquez et al., J.
Medicinal Chemistry 39:3739-3747 (1996).
Dated: May 28, 1999.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer.
[FR Doc. 99-14377 Filed 6-4-99; 8:45 am]
BILLING CODE 4140-01-M
