[Federal Register Volume 70, Number 16 (Wednesday, January 26, 2005)]
[Notices]
[Pages 3716-3718]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-1415]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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SUMMARY: The inventions listed below are owned by an agency of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for companies and may also be available for licensing.

ADDRESSES: Licensing information and copies of the U.S. patent 
applications listed below may be obtained by writing to the indicated 
licensing contact at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-3804; telephone: (301) 496-7057; fax: (301) 402-0220. A 
signed Confidential Disclosure Agreement will be required to receive 
copies of the patent applications.

Treatment of Inappropriate Immune Responses

Drs. He Xu and Allan D. Kirk (NIDDK)
U.S. Provisional Patent Application filed Jun 18, 2004 (DHHS Reference 
No. E-102-2004/0-US-01)
Licensing Contact: Marlene Shinn-Astor; 301/435-4426; 
[email protected].

    Activated human leukocytes play an essential role in counter-
adaptive immune responses such as allograft rejection, autoimmune 
disease, and graft-versus-host disease. Depletion of leukocytes 
involved in these responses by using preparations of leukocytes-
specific antibodies may be therapeutic in preventing and reversing 
these conditions. To date, however, the available monoclonal 
preparations do not have sufficiently broad specificity to limit the 
activity of many types of cells involved in counter-adaptive immunity, 
and the available polyclonal preparations have significant side effects 
caused by their unintended specificity for bystander cells or cells 
with beneficial properties.
    The NIH announces a new treatment for blocking an undesirable 
immune response, wherein polyclonal antibodies are designed to 
preferentially target activated immune cells, rather than resting 
immune cells or blood cells involved in non-immune processes. These 
antibodies have a heightened specificity for activated lymphocytes and 
monocytes and decreased activity for resting or beneficial leukocytes 
and other blood elements.

A Novel Nuclear Receptor Cofactor Modulates Glucocorticoid-Responsive 
Gene Expression

S. Stoney Simons and Yuanzheng He (NIDDK);
U.S. Patent Application No. 60/548, 039 filed 26 Feb 2004 (DHHS 
Reference No. E-056-2004/0-US-01);
Licensing Contact: Susan Carson, (301) 435-5020; [email protected].

    Nuclear receptors are ligand-activated transcription factors that 
regulate a wide range of biological processes and dysfunction of these 
receptors can lead to proliferative, reproductive and metabolic 
diseases, such as cancer, infertility, obesity and diabetes. Nuclear 
receptors are the second largest class of drug targets and the market 
for nuclear receptor targeted drugs is estimated to be almost 15% of 
the $400 billion global pharmaceutical market. Researchers at the 
National Institute of Diabetes and Digestive and Kidney Disease have 
isolated a novel protein termed STAMP (SRC-1 and TIF-2 Associated 
Modulatory Protein) that interacts with the biologically active domains 
of the coactivators TIF-2 and SRC-1 (J. Biol. Chem. (2002) 51, 49256-
66) and present data which support a role for STAMP as an important new 
factor in the glucocorticoid regulatory network. There remains a need 
for novel therapeutics that specifically block or enhance specific 
genes and an emerging therapeutic goal is the discovery of agents that 
modulate co-activators or co-repressors in a tissue specific manner.
    The invention is a novel protein that plays a key role in 
modulating transcriptional properties of glucocorticoid receptor (GR)-
steroid complexes during both gene induction and gene repression, and 
is likely to modulate the transcriptional properties of all the steroid 
receptors including androgen, mineralocorticoid and progesterone 
receptors. The inventors have shown that ectopically expressed STAMP 
protein both modulates the EC50 of glucocorticoid receptor-agonist 
complexes for induced genes and increases glucocorticoid receptor-
repressive activity of suppressed genes in a manner that is inhibited 
by specific siRNAs under physiologically relevant conditions. The 
modulation of STAMP levels at the cell or organism level could possibly 
be used as a therapeutic able to modify inappropriate gene expression 
that occurs in certain diseases or as a result of long-term steroid 
treatment.
    Available for licensing are claims directed to compositions which 
are capable of modulating the GR gene expression in a mammalian cell 
using DNA, siRNA or antibodies and to methods of shifting a steroid 
dose-response curve, where less of the steroid needs to be administered 
because the composition contains the STAMP polypeptide. The novel STAMP 
functional sequence can be used in a composition of matter claim or as 
a target that could be regulated by an antibody or perhaps other 
modulator that would vary the ability of STAMP to either induce or 
repress the activity of glucocorticoid receptors. Diseases that could 
be treated include: hypertension, diabetes, cardiovascular disease, 
osteoporosis, Cushing's Disease as well as any disease requiring 
chronic steroid treatment such as Rheumatoid Arthritis, Asthma, 
inflammatory and auto-immune diseases. The present invention provides a 
broad, flexible IP platform that should be of interest to companies 
which focus on nuclear receptors as drug target and lead discovery 
generators, as well as to companies which have the capability to 
develop STAMP's potential as a therapeutic.
    In addition to licensing, the technology is available for further 
development through collaborative research with the inventors via a 
Cooperative Research and Development Agreement (CRADA).

Generation of Smad3-Null Mice and Smad4-Conditional Mice

Chuxia Deng (NIDDK);
DHHS Reference Nos. E-349-2003/0 and E-350-2003/0--Research Tools;
Licensing Contact: Marlene Shinn-Astor; (301) 435-4426; 
[email protected].

    SMADs are a novel set of mammalian proteins that act downstream of 
TGF-beta family ligands. These proteins can be categorized into three 
distinct functional sets, receptor-activated SMADs (SMADs 1, 2, 3, 5, 
and 8), the common mediator SMAD (SMAD 4), and inhibitory SMADs (SMADs 
6 and 7). SMAD proteins are thought to play a role in vertebrate 
development and tumorigenesis.

[[Page 3717]]

    One of the research tools our NIH inventors have prepared is the 
Smad3-null mice model, created by disrupting exon 8 on the Smad3 gene. 
Symptomatic mice exhibit leukocytosis, with massive inflammation and 
pyogenous abscess formation adjacent to mucosal surfaces. Smad3 plays 
an important role in mediating TGF-beta signals in T lymphocytes and in 
neutrophils, and demonstrate that Smad3 deficiency results in immune 
dysregulation and susceptibility to opportunistic infection, ultimately 
leading to the lethality of the mice between 1 and 8 months. TGF-beta 
signals also play a role in cancer formation in multiple organs and 
tissues. Smad3-null mice could be used to clone downstream target genes 
for TGF-beta signals, which may be used in gene therapy and 
chemoprevention studies.
    Smad4-null mice die around embryonic day 6.5, so the inventors 
prepared the SMAD4-conditional mice model, created by a Smad4 
conditional knockout allele at exon 8 using Cre-mediated recombination. 
PCR analysis determined Cre-mediated recombination in the pancreas but 
not in a number of other organs, indicating that the Smad4 conditional 
allele can be recombined to delete exon 8 in a tissue-specific fashion. 
This knockout mouse could be used to test the function of TGF-beta/
Smad4 signals at all stages of mouse development. Interestingly, 
mutation of human Smad4 has been found in approximately half of all 
pancreatic cancers, 30 percent of colon cancers, and about 10 percent 
in other cancers. The Smad4-conditional mice could be used to study 
pathways that are involved in formation of these tumors or to clone 
downstream target genes that may be used in gene therapy and 
chemoprevention studies.
    Additional information may be found in the following research 
articles: Yang et al., ``Generation of Smad4/Dpc4 conditional knockout 
mice,'' Genesis 2002 Feb; 32(2):80-81, Epub 13 Feb 2002 doi 10.1002/
gene.10029; Yang et al., ``Targeted disruption of SMAD3 results in 
impaired mucosal immunity and diminished T cell responsiveness to TGF-
beta,'' EMBO J. 1999 Mar 1; 18(5):1280-1291, Epub doi: 10.1093/emboj/
18.5.1280.
    In addition to licensing, the technology is available for further 
development through collaborative research with the inventors via a 
Cooperative Research and Development Agreement (CRADA).

Anti-Proliferative Activity of an Unexpected mTOR Kinase Inhibitor

Joel Moss and Arnold Kristof (NHLBI);
U.S. Provisional Patent Application No. 60/528,340 filed 09 Dec 2003 
(DHHS Reference No. E-259-2003/0-US-01); PCT Application filed 09 Dec 
2004 (DHHS Reference No. E-259-2003/0-PCT-02);
Licensing Contact: Susan Carson; 301/435-5020; [email protected].

    The second leading cause of death in the United States is cancer 
and more than one million Americans are diagnosed with cancer each 
year, with this number likely to increase as the population ages. There 
remains a need for effective therapeutics with improved safety 
profiles, and promising results have been obtained from targeting the 
phosphatidylinositol-3-kinase (PI3K) signalling cascade (including 
PI3K, AKT/PKB and mammalian target of rapamycin (mTOR/S6K) kinases) 
which is integral to the regulation of cell growth, protein synthesis 
and apoptosis in response to nutrients and mitogens, and which is 
frequently dysregulated in different cancers and other proliferative 
diseases. In particular, efforts have been directed at inhibiting 
specific kinases in this pathway as effective treatments for cancer, 
restenosis and autoimmune diseases and researchers at the National 
Heart, Lung and Blood Institute have recently shown that one of the 4H-
1-benzopyran-4--one derivatives is unexpectedly an effective mTOR 
inhibitor.
    Proof of concept data is available. This compound has been shown to 
attenuate tumor growth in an in vivo human xenograft PC-3 prostate 
tumor model, without observed toxicity. An improved therapeutic safety 
profile is suggested, as this compound was a weak inhibitor of PI3K. 
Further data indicate that inhibition of cell proliferation occurs 
through both mTOR-dependent and mTOR-independent mechanisms, suggesting 
a novel kinase inhibitor. Additionally, this cytostatic compound is 
shown to have an anti-inflammatory effect in peritoneal macrophages. 
Finally, this compound inhibits primary human smooth muscle cell 
proliferation in vitro, suggesting a possible role in the treatment of 
vascular restenosis.
    This compound may therefore prove to be an effective anti-
proliferative therapeutic. Available for licensing are methods of use 
directed to derivatives of 2-(4-piperazinyl)-substituted 4H-1-
benzopyran-4--one compounds as antiproliferative, immunosuppressive and 
anti-neoplastic agents.
    In addition to licensing, the technology is available for further 
development through collaborative research with the inventors via a 
Cooperative Research and Development Agreement (CRADA contact: Vincent 
Kolesnitchenko; Tel: (301) 402-5579; E-mail: [email protected]).

Methods for Making and Using Mass Tag Standards for Quantitative 
Proteomics

David E. Anderson (NIDDK);
U.S. Provisional Application No. 60/574,612 filed 25 May 2004 (DHHS 
Reference No. E-200-2003/0-US-01);
Licensing Contact: Fatima Sayyid; (301) 435-4521; [email protected].

    There is a growing need for peptide standards for quantitative 
proteomic analysis of gene and cellular functions in cells and tissues. 
Current methods for generating peptide standards for identification and 
absolute quantification of proteins rely almost solely on synthetic 
approaches which require expensive reagents, equipment and rare 
expertise.
    The present invention describes a process for simultaneously 
generating peptide standards of known concentration for several 
proteins of interest within a single easily parallelized experiment. 
This process uses a combination of automated synthetic gene design, 
gene synthesis, cloning, bacterial expression with heavy isotope 
incorporation, generic protein purification, optical quantitation, and 
endoprotease cleavage to make sets of peptides of known concentration. 
Non-modified peptides can be made for a fraction of the cost of 
synthetic approaches. Since the main cost involves the initial 
production of a DNA construct, follow-up preparations of peptides 
(which can use different isotope backgrounds) are even cheaper.

A Method of Treating Inflammatory Bowel Disease (IBD)

Warren Strober, Ivan Fuss, Frank Heller, Richard Blumberg (NIAID); PCT 
Application No. PCT/US2002/018790 filed 14 Jun 2002, which published as 
International Publication No. WO 2004/001655 on 31 Dec 2003 (DHHS 
Reference No. E-131-2002/0-PCT-01)
Licensing Contact: Susan Carson; (301) 435-5020; [email protected].

    Ulcerative colitis (UC) is a chronic inflammatory disease of the 
colorectum and affects approximately 400,000 people in the United 
States (of these, approximately 5 percent develop colon cancer). The 
cause of UC is not known, although an abnormal mucosal T cell, 
responsive to bacterial antigens in the gut microflora, is thought to 
be

[[Page 3718]]

involved. Present treatments for UC include anti-inflammatory therapy 
using aminosalicylates or corticosteroids, as well as immunomodulators 
and diet. However, 25-40 percent of ulcerative colitis patients must 
eventually have their colons removed due to massive bleeding, severe 
illness, rupture of the colon, risk of cancer or due to side effects of 
corticosteroids and novel treatments are still actively being sought. 
NIH scientists and their collaborators have used a mouse model of 
experimental colitis (OC) to show that IL-13, a Th2 cytokine, is a 
significant pathologic factor in OC and that neutralizing IL-13 in 
these animals effectively prevents colitis (Immunity (2002) 17, 629-
638).
    OC is a colitis induced by intrarectal administration of a 
relatively low dose of the haptenating agent oxazolone subsequent to 
skin sensitization with oxazolone. A highly reproducible and chronic 
colonic inflammation is obtained that is histologically similar to 
human ulcerative colitis. Studies show that NKT cells rather than 
conventional CD4+T cells mediate oxazolone colitis and that NKT cells 
are the source of IL-13, and are activated by CD1 expressing intestinal 
epithelial cells. Tissue removed from UC patients were also shown to 
contain increased numbers of nonclassical NKT cells that produce 
markedly increased amounts of IL-13 and that in keeping with epithelial 
damage being a key factor in UC, these NKT cells are cytotoxic for 
epithelial cells (J. Clin. Investigation (2004) 113, 1490-1497).
    With obvious implications for the treatment of human Ulcerative 
Colitis, inflammation in this mouse model has been shown to be 
effectively blocked by neutralizing IL-13 or by inhibiting the 
activation of NK-T cells through CD1. Available for licensing are broad 
claims covering treatments preventing the inflammatory response of 
colitis by modulating IL-13 and NKT cell activity and methods for 
screening for therapeutic compounds effective for colitis.
    In addition to licensing, the technology is available for further 
development through collaborative research with the inventors via a 
Cooperative Research and Development Agreement (CRADA).

    Dated: January 18, 2005.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 05-1415 Filed 1-25-05; 8:45 am]
BILLING CODE 4140-01-P