[Federal Register Volume 64, Number 43 (Friday, March 5, 1999)]
[Notices]
[Pages 10665-10667]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-5419]


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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.

Identification of Polymorphisms of the PCTG-4 Gene

RA Philibert, EI Ginns (NIMH)
Provisional U.S. Patent Application No. 60/083,465 filed 29 Apr 98
Licensing Contact: Leopold J. Luberecki, Jr.; 301/496-7735 ext. 223; e-
mail: [email protected]

    Mental retardation affects approximately 1-3% of the U.S. 
population and results in at least $10 billion in annual treatment 
costs. Mutations in the X-chromosome may cause 30-50% of all cases of 
mental retardation. This technology is directed to the identification 
of an X-linked polymorphism that appears to convey a five-fold increase 
in the relative risk for mental retardation and is markedly enriched in 
individuals suffering from autism. The various polymorphisms will 
likely enable further studies aimed at eliciting the underlying 
mechanisms of these diseases and may provide a model system for the 
development of new drugs. It may also have a role as a prognostic 
indicator.

Combination Therapy with VIP Antagonists

Illana Gozes (Tel Aviv University), Terry W. Moody (NCI), Douglas C. 
Brenneman (NICHD), Mati Fridkin (Weizman Institute of Science), Edgar 
Gelber (Tel Aviv University) and Albert Levy (Tel Aviv University)
Serial No. 60/104,472 filed 16 Oct 98 and Serial No. 60/104,907 filed 
20 Oct 98
Licensing Contact: Dennis Penn; 301/496-7056 ext. 211; e-mail: 
[email protected]

    This invention relates generally to cancer treatment. More 
particularly, the present invention relates to combination therapy 
using a polypeptide which is an antagonist of the vasoactive intestinal 
polypeptide (VIP) and a chemotherapeutic agent, preferably in a 
pharmaceutical composition.
    Vasoactive intestinal polypeptide (VIP) is a widely distributed 
peptide hormone which mediates a variety of physiological responses 
including gastrointestinal secretion, relaxation of gastrointestinal 
vascular and respiratory smooth muscle, lipolysis in adipocytes, 
pituitary hormone secretion, and excitation and hyperthermia after 
injection into the central nervous system. Vasoactive intestinal 
peptide is a 28 amino acid peptide with an amidated C-terminus, the 
peptide results from post translational processing of a hormone 
composed of 170 amino acid residues. The VIP peptide has been shown to 
contain at least two functional regions, a region involved in receptor 
specific binding and a region involved in biological activity (Gozes 
and Brenneman, Molecular Neurobiology, 3:201-236 (1989)).
    Gozes, et al. have developed a VIP antagonist that has proven 
useful for altering the function of the vasoactive intestinal peptide. 
(See, U.S. Patent No. 5,217,953 issued to Gozes, et al. (1993)). This 
VIP antagonist was designed to retain the binding properties of VIP for 
its receptor, but to lack the amino acid sequence necessary for 
biological activity. Studies have shown that this VIP antagonist 
effectively antagonizes VIP-associated activity. It has been reported 
that this VIP antagonist inhibits the growth of VIP receptor bearing 
tumor cells such as, for example, lung tumor cells (i.e., non-small 
cell lung cancer cells). (See, U.S. Patent No. 5,217,953.)
    U.S. Patent No. 5,565,424, which issued to Gozes, et al. on October 
15, 1996, discloses another family of polypeptides which are 
antagonists of the vasoactive intestinal polypeptide. The VIP 
antagonists disclosed therein are 10-1000 times more efficacious, i.e., 
more potent in inhibiting VIP-associated activity than previous VIP 
antagonists. These superactive VIP antagonists were shown to inhibit 
cancer growth in lung and gioblastoma cells. Examples of superactive 
VIP antagonists include amino acid sequences referred to as the 
``norleucine-hybrid VIP antagonist'', the ``stearyl-norleucine-hybrid 
VIP antagonist'' and the ``stearyl-hybrid VIP antagonist''.
    The present invention relates to a pharmaceutical composition 
comprising a vasoactive intestinal polypeptide (VIP) antagonist, a 
chemotherapeutic agent

[[Page 10666]]

(such as platinum coordination compounds, topoisomerase inhibitors, 
antibiotics, antimitotic alkaloids, antimicrotubules, and 
difluoronucleosides) and a pharmaceutically acceptable carrier. Certain 
combinations of a VIP antagonist plus a chemotherapeutic agent resulted 
in a synergistic reduction in the IC50 of 2-7 fold. This synergistic 
affect was observed in a non-small cell lung cancer, breast cancer, 
pancreatic cancer, glioblastoma, ovarian, and prostate cancer cell 
lines.

A Test for Both Sensitivity to and Resistance to Warfarin and Other 
Drugs Metabolized by CYP2C9 and CYP2A6

Frank J. Gonzalez (NCI) and Jeffery R. Idle (University of Newcastle)
Serial No. 08/750,703 filed 07 Apr 97
Licensing Contact: Dennis Penn; 301/496-7056 ext. 211; e-mail: 
[email protected]

    It is well known that genetic polymorphisms in drug metabolizing 
genes give rise to a variety of phenotypes. This information has been 
used to advantage in the past for developing genetic assays that 
predict phenotype and thus predict an individual's ability to 
metabolize a given drug. The information is of particular volume in 
determining the likely side effects and therapeutic failures of various 
drugs.
    Drug metabolism is carried out by the cytochrome P450 family of 
enzymes. For example, the cytochrome P450 isozyme gene, CYP2C9 encodes 
a high affinity hepatic [S]-warfarin 7-hydroxylase which appears to be 
principally responsible for the metabolic clearance of the most potent 
enantiomer of warfarin. Similarly, the cytochrome P450 isozyme gene, 
CYP2A6, encodes a protein that metabolizes nicotine and coumarin and 
activates the tobacco-specific nitrosamine 4-(methyinitrosamino)-1-(3-
pyridyl)-1-butanone) (NNK). The above gene products are also known to 
metabolize other substrates, for example, the CYP2C9 gene product is 
also know to metabolize Tolbutamide, Phenytoin, Ibuprofen, Naproxen, 
Tienilic acid, Diclofenac and Tetrahydrocannabinol. It follows that 
genetic polymorphisms or mutations in either of the two aforementioned 
genes can lead to an impairment in metabolism of at least the 
aforementioned drugs.
    The present invention relates to novel variant alleles incytochrome 
P450 genes, which express ezymes involved in the metabolism of 
particular drugs and/or chemical carcinogens. The present invention 
describes a new mutant or variant CYP2A6 allele wherein the human gene 
is characterized. This variant allele is designated CYP2A6v2 and its 
cDNA and genomic sequence are provided in the present invention. 
Another new gene related to CYP2A6 has been discovered and is 
designated CYP2A13 and its cDNA and genomic sequence are included.
    The objective of this invention is to provide the genetic material, 
a method, and a kit which enable genotyping of the CYP2C9 and CYP2A65 
gene with a view to providing phenotyping information concerning drug 
metabolism for use in screening and evaluating side effects and 
therapeutic failures. In addition, the method may be used to screen 
patients for a predisposition to cancers related to excessive 
nitrosamine activation, which are associated with mutations within the 
CYP2A6 gene locus. Further, the method may be used to screen patients 
for sensitivity to chemical carcinogens, based upon the genotype of the 
CYP2A6 and/or CYP2C9 alleles.

Method for Detecting a Receptor-Ligand Complex Using a Cytochrome 
P450 Reporter Gene

Charles L. Crespi (Gentest), Bruce W. Pennman (Gentest), Frank J. 
Gonzalez (NCI), Harry V. Gelboin (NCI) and Talia Sher (NCI)
Serial No. 08/697,329 filed 22 Aug 96; U.S. Patent 5,726,041 issued 10 
Mar 98
Licensing Contact: Dennis Penn; 301/496-7056 ext. 211; e-mail: 
[email protected]

    The use of reporter genes to measure the relative activity of a 
promoter sequence is well known. This invention is directed to methods 
and compositions for measuring the activity of a promoter sequence in a 
mammalian cell. The methods involve substituting a DNA sequence 
encoding a cytochrome P450 for a known reporter gene (e.g. CAT, 
luciferase) and measuring the relative activity of the expressed 
cytochrome P450 protein. In contrast to the reporter genes of the prior 
art, the claimed invention advantageously provides a method for 
measuring the activity of a promoter sequence in intact mammalian cells 
that contain a P450 catalysis system using real time light 
(fluorescence) measurements. Virtually all mammalian cells contain the 
requisite cytochrome P450 catalysis system. Thus, the invention 
eliminates the labor-intensive aspects (e.g., cell lysis and separation 
of cellular components) that are required to practice other methods for 
measuring the activity of a promoter sequence in a mammalian cell.
    The invention also provides a method for detecting the formation of 
a receptor-ligand complex in a mammalian cell. The cell contains a 
reported cassette for detecting formation of the receptor-ligand 
complex and a cytochrome P450 catalysis system. The reporter cassette 
includes a DNA sequence encoding a cytochrome P450 with a 
polyadenylation signal sequence operatively coupled to a promoter 
sequence that is responsive to (i.e., binds to) a DNA binding element 
present in the receptor-ligand complex. According to one aspect of the 
invention, this method is useful for detecting the activation of 
PPAR by peroxisome proliferators.

Restenosis/Atherosclerosis Diagnosis, Prophylaxis, and Therapy

SE Epstein, T Finkel, EH Speir, Y Zhou, J Zhou, L Erdile, S Pincus 
(NHLBI)
Serial No. 08/796,101 filed 05 Feb 97
Licensing Contact: Manja Blazer; 301/496-7735 ext. 224; e-mail: 
[email protected]

    This technology relates to the compositions and methods for the 
diagnosis, prevention, and therapy of restenosis and atherosclerosis. 
It involves the use of an agent for decreasing viral load, preferably a 
vaccine, against cytomegalovirus (CMV) and p53, including a method for 
providing the therapy and administering the agent. This invention thus 
relates to stimulating an immune response, preferably a cellular immune 
response, directed against CMV and p53 inhibit or prevent restenosis, 
atherosclerosis, and smooth muscle proliferation. Such a response can 
cause cell death and thus inhibition of smooth muscle cell 
proliferation, atherosclerosis, and restenosis. Therefore, the 
technology offers methods for inducing cell death with the purpose of 
inhibiting smooth muscle proliferation as a means of preventing or 
treating restenosis and atherosclerosis.

The Use of Lecithin-Cholesterol Acyltransferase (LCAT) in the 
Treatment of Atherosclerosis

S Santamarina-Fojo, JM Hoeg, B Brewer Jr. (NHLBI)
DHHS Reference No. E-007-96/1 filed 11 Aug 96
Licensing Contact: Manja Blazer; 301/496-7735 ext. 224; e-mail: 
[email protected]

    This technology relates to methods for the preventive and 
therapeutic treatment of atherosclerosis and to diseases relating to a 
deficiency of

[[Page 10667]]

lecithin-cholesterol acyltransferase activity. The plasma protein 
enzyme lecithin-cholesterol acyltransferase (LCAT) catalyzes the 
transfer of fatty acid from the sn-2 position of lecithin to the free 
hydroxyl group of cholesterol. Various mutations of the LCAT gene are 
known. Individuals who are homozygous for a non-functional LCAT mutant 
have classic LCAT deficiency disease, characterized by clouding of the 
cornea, normochromic anemia and glomerulosclerosis. Mutations of the 
LCAT gene that result in some residual LCAT activity lead to Fish Eye 
disease, characterized by opacity of the cornea and 
hypoalphalipoproteinemia. Thus there is a need for compositions and 
methods for the prevention and therapeutic treatment of atherosclerosis 
and conditions associated with LCAT deficiency. This invention 
satisfies this need by providing compositions and methods for 
increasing the serum level of LCAT activity.

    Dated: February 22, 1999.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer.
[FR Doc. 99-5419 Filed 3-4-99; 8:45 am]
BILLING CODE 4140-01-M