[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: 
[email protected]

    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: [email protected]

    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: 
[email protected]

    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: 
[email protected]

    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: [email protected]
    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: 
[email protected]

    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: 
[email protected]

    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