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[Federal Register Volume 73, Number 174 (Monday, September 8, 2008)]
[Notices]
[Pages 52054-52057]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-20651]

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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.

Over-Expression and Mutation of a Tyrosine Kinase Receptor FGFR4 in 
Tumors

    Description of Technology: Rhabdomyosarcoma (RMS) is the most 
common type of pediatric soft tissue sarcoma. Most children (>70%) with 
the disease die at higher stage (metastatic disease).
    Researchers at NIH have identified mutations in fibroblast growth 
factor receptor 4 (FGFR4) that are associated with RMS tumors. It is 
proposed that individuals with FGFR4 mutations may have an increased 
risk for tumor metastasis. The identified FGFR4 variants can be used to 
identify individuals who may benefit most from treatment with an FGFR4 
inhibitor as an adjuvant to standard anticancer therapeutics to 
decrease the risk of tumor metastasis.
    Available for licensing are methods for identifying candidates for 
treatment with an inhibitor of FGFR4 by determining the presence of at 
least one FGFR4 variant, kits for identifying said candidates, and 
methods for identifying compounds that induce tumor cell death or that 
inhibit tumor growth or metastasis.
    Applications:
     Potential new method for treatment of Rhabdomyosarcomas 
(RMS).
     Potential new method to prepare kits to diagnose 
activating mutations in FGFR4.
     These mutations can be used in laboratory settings to 
screen thousands of compounds for more specific FGFR4 gene inhibitors.
     FGFR4 is also a potential target for lung and breast 
cancer.
     FGFR4 monoclonal can be developed to target RMS tumors.
    Market:
     In the United States, approximately 12,000 new cases of 
cancer are diagnosed in children each year. Childhood cancer remains 
the leading disease-related cause of death in children and adolescents 
in North America, with about 2,300 deaths each year.
     Rhabdomyosarcoma accounts for about 3 percent of childhood 
cancers. In the U.S., about 350 children are diagnosed with 
Rhabdomyosarcoma each year.
    Development Status: Early-stage of development.
    Inventors: Javed Khan et al. (NCI).

[[Page 52055]]

    Patent Status: U.S. Provisional Application No. 61/044,875 filed 14 
Apr 2008 (HHS Reference No. E-175-2008/0-US-01).
    Licensing Status: Available for exclusive and non-exclusive 
licensing.
    Licensing Contact: Betty B. Tong, Ph.D.; 301-594-6565; 
[email protected].
    Collaborative Research Opportunity: The National Cancer Institute, 
Pediatric Oncology Branch, is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize Over-expression and Mutation of a 
Tyrosine Kinase Receptor FGFR4 in Tumors. Please contact John D. Hewes, 
Ph.D. at 301-435-3121 or [email protected] for more information.

Small Molecule Inhibitors of c-Met

    Description of Technology: Aberrant c Met signaling is documented 
in a wide variety of malignancies and occurs via several mechanisms 
including amplification of c-Met (increased gene copy number), point 
mutations in the gene encoding c-Met, receptor over-expression, and 
ligand dependent autocrine/paracrine receptor activation. This 
application describes novel small molecule inhibitors of c-Met 
signaling. The small molecules selectively bind to c-Met and have an 
IC50 in the micromolar range. The small molecules belong to two 
different families. One family of small molecules reduces the level of 
c Met expression via receptor down-regulation and blocks ATP binding. 
The other family of small molecules block ATP binding without inducing 
receptor down-regulation. Evidence suggests that the second family of 
compounds bind to both active and inactive conformations of c-Met.
    Applications: Therapy for cancers associated with aberrant c-Met 
signaling, for example bladder, breast, cervical, colorectal, 
endometrial, esophageal, gastric, head and neck, kidney, liver, lung, 
nasopharyngeal, ovarian, pancreatic, prostate and thyroid cancers, as 
well as cholangiocarconoma, osteosarcoma, rhabdomyosarcoma, synovial 
sarcoma, Kaposi's sarcoma, leiomyosarcomas and MFH/fibrosarcoma. In 
addition to these malignancies, aberrant c Met signaling is associated 
with hematological malignancies such as acute myelogenous leukemia, 
adult T cell leukemia, chronic myeloid leukemia, lymphomas and multiple 
myeloma as well as other tumors like melanoma, mesothelioma, Wilms' 
tumor, glioblastomata and astrocytomas.
    Market: Although the percentage of cancers associated with aberrant 
c Met signaling is not yet well established, the wide variety of 
cancers associated with aberrant c Met signaling are indicative of a 
potentially large market for these compounds. For example, worldwide 
over 1 million persons per year are diagnosed with colorectal cancer 
and it is the most common gastrointestinal cancer in industrialized 
countries. In one study of colorectal cancer 69% of the patients had at 
least a two-fold elevation of cMet mRNA and 48% of the patients had at 
least a ten fold elevation of c Met mRNA. In a study of breast cancer, 
22% of patients with invasive ductal breast tumor specimens exhibited 
strong expression of c Met and patients exhibiting c Met expression had 
only a 52% 5 year survival rate compared with an 89% 5 year survival 
rate in patients with normal c Met levels.
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Inventors: Donald P. Bottaro, Terrence Burke, Jr., et al. (NCI).
    Patent Status: U.S. Provisional Application No. 61/041,523 filed 01 
Apr 2008 (HHS Reference No. E-332-2007/0-US-01).
    Publications: The patent application has not been published. There 
are no journal articles available related to this work.
    Licensing Status: Available for licensing on an exclusive or non-
exclusive basis.
    Licensing Contact: Susan S. Rucker; 301-435-4478; 
[email protected].
    Collaborative Research Opportunity: The National Cancer Institute, 
Urologic Oncology Branch, is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize small molecule inhibitors of the 
HGF/c-Met signaling pathway. Please contact John D. Hewes, Ph.D. at 
301-435-3121 or [email protected] for more information.

Quantitative Immunoassays for Measurement of Topoisomerase I as a 
Pharmacodynamic Marker for the Effect of Anti-Cancer Drugs

    Description of Technology: Topoisomerase I (TopoI) is an enzyme 
that catalyses DNA unwinding which is necessary for many cellular 
functions. Recent data from the Fluorouracil, Oxaliplatin, CPT-11: Use 
and Sequencing (FOCUS) trial demonstrates that nuclear staining of 
TopoI correlates with chemotherapy efficacy [J Clin Oncol (2008) 26, 
2690-8]. This enzyme covalently binds with the DNA substrate and 
introduces a single strand break. Some anti-cancer drugs, including 
those in clinical trials target this cleavage site and prevent re-
ligation of the unwound DNA, trapping the TopoI/DNA covalent complex. 
TopoI trapped by Topo I inhibitor compounds such as Topotecan is 
degraded by the ubiquitin/proteosome pathway. This change in 
intracellular TopoI levels makes total TopoI and the TopoI/DNA covalent 
complex potential pharmacodynamic biomarkers for monitoring TopoI 
inhibiting agents, used in cancer therapy.
    The technology involves a validated, enzyme linked immunosorbent 
assay (ELISA) with a chemiluminescence readout, using commercially 
available antibodies to quantitate total TopoI from cell and tumor 
extracts.
    This technology has been used in a high throughput assay for 
measurement of estrogen and estrogen metabolites in serum. A similar 
ELISA assay has also been used in NCI Phase 0 and Phase I clinical 
trials of a PARP inhibitor
    Applications:
     Anti-cancer drug testing.
     Patient selection for anti-cancer drug treatment.
    Advantages:
     Simple, quantitative, sensitive (LLQ ~40pg/well LLOD= (LOD 
220 pg/ml as formulated), range 200 pg/ml to 50ng/ml).
     Uses commercially available antibodies.
     Excludes the use of radioisotopes.
     Validated Assay.
     SOP available.
     In vitro data support use in anti-cancer drug treated 
melanoma cell lines.
     Mouse model data support use in anti-cancer drug treated 
melanoma and colon cancer xenografts.
    Developmental Status: ELISA was developed in support of Phase I 
clinical trial on experimental TopoI inhibiting drugs.
    Publication: Thomas D. Pfister, Ralph E. Parchment, Joseph 
Tomaszewski, James Doroshow and Robert J. Kinders. ``Development of a 
quantitative immunoassay for measurement of topoisomerase I covalent 
complex as a pharmacodynamic marker for the effect of anti-cancer 
drugs.'' AACR Annual Meeting, Los Angeles, CA April 14-18, 2007.
    Inventors: Thomas D. Pfister and Robert J. Kinders (SAIC/NCI).
    Patent Status: HHS Reference No. E-100-2007/0--Research Tool. 
Patent protection is not being pursued for this technology.
    Licensing Status: Available for non-exclusive licensing of 
biological material.

[[Page 52056]]

    Licensing Contact: John Stansberry, Ph.D.; 301-435-5236; 
[email protected].
    Collaborative Research Opportunity: The National Cancer Institute's 
Laboratory of Human Toxicology and Pharmacology is seeking statements 
of capability or interest from parties interested in collaborative 
research to further develop, evaluate, or commercialize Quantitative 
Immunoassays for Measurement of Topoisomerase I as a Pharmacodynamic 
Marker for the Effect of Anti-Cancer Drugs. Please contact John D. 
Hewes, Ph.D. at 301-435-3121 or [email protected] for more 
information.

New Tumor Endothelial Markers: Genes That Distinguish Physiological and 
Pathological Angiogenesis

    Description of Technology: Angiogenesis, the formation of new blood 
vessels, is associated with normal physiological processes such as 
wound healing, ovulation or menstruation as well as with many diseases. 
Presently, it is thought to be required for the progressive growth of 
solid tumors and age-related macular degeneration. Lack of disease-
specific endothelial markers has hindered the development of cancer 
therapies targeted against angiogenesis.
    This invention describes specific markers that can be used to 
identify tumor angiogenesis, separate from normal physiological 
angiogenesis. Several markers have been identified which may serve as 
potential targets for tumor vessels by using comparative gene 
expression analysis on various normal and tumor endothelial cells. 
Furthermore, the invention describes several organ-specific endothelial 
markers that can aid in the selective delivery of molecular medicine to 
specific sites. For example, brain endothelial markers (BEMs) and liver 
endothelial markers (LEMs) described herein could potentially be used 
to direct molecular medicine specifically to these tissues.
    The novel tumor endothelial markers (TEMs) described in this 
invention also have potential diagnostic ability. These markers can be 
used to distinguish between normal and tumor tissues. Some of the 
secreted TEMs can serve as surrogate markers in the determination of 
the optimum biological dose (OBD) for the current anti-angiogenic drugs 
in clinical trials.
    Applications and Modality:
     Novel therapeutic targets associated with tumor vessels.
     New agents can be developed against these novel targets.
     Novel endothelial markers that distinguish pathological 
angiogenesis from normal physiological angiogenesis.
     Surrogate tumor endothelial markers that can be used to 
determine optimal biological dose (OBD) of anti-angiogenic drugs.
    Market:
     Sales of the first FDA approved anti-angiogenic drug 
AvastinTM has reached $600 million.
     Another promising anti-angiogenic molecule, 
ThalidomideTM, has been approved as an anti-cancer agent and 
for other use in Europe and Australia.
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Inventors: Brad St. Croix and Steven Seaman (NCI).
    Relevant Publication: A Nanda and B St. Croix. Tumor endothelial 
markers: new targets for cancer therapy. Curr Opin Oncol. 2004 
Jan;16(1):44-49.
    Patent Status:
     U.S. Provisional Application No. 60/858,068 filed 09 Nov 
2006 (HHS Reference No. E-285-2006/0-US-01).
     U.S. Provisional Application No. 60/879,457 filed 08 Jan 
2007 (HHS Reference No. E-285-2006/1-US-01).
     PCT Application No. PCT/US2007/072395 filed 28 Jun 2007, 
which published as WO 2008/057632 on 15 May 2008 (HHS Reference No. E-
285-2006/2-PCT-01).
    Licensing Status: Available for exclusive and non-exclusive 
licensing.
    Licensing Contact: Adaku Nwachukwu, J.D.; 301-435-5560; 
[email protected].
    Collaborative Research Opportunity: The NIH National Cancer 
Institute, Tumor Angiogenesis Section, is seeking statements of 
capability or interest from parties interested in collaborative 
research to further develop, evaluate, or commercialize specific 
biomarkers that can be used to identify tumor angiogenesis. Please 
contact John D. Hewes, PhD at 301/435-3121 or [email protected] for 
more information.

Methods of Treating and Preventing Renal Cancer Using a Dimethane 
Sulfonate Compound

    Description of Technology: Currently only a few small molecule 
inhibitors are effective in patients with renal cell carcinoma. 
Approximately 30,000 patients per year are diagnosed with this disease 
but many of them are untreatable because of intrinsic drug resistance, 
and efficient drug transport and detoxification mechanisms. This 
invention described and claimed in the patent application describes a 
series of dimethane sulfonate compounds based on NSC 281612 that are 
suitable for the treatment of renal cancer. Compositions comprising a 
pharmaceutically-acceptable carrier and a compound, or a salt suitable 
for use in the treatment or prevention of renal cancer are also 
described. The anti-tumor activity of NSC 281612 has been established 
in vivo against human renal tumor xenografts in mice. Suitable dosing 
and administration schedules for treatment of renal tumors have also 
been determined in this study.
    Applications: For treatment or prevention of renal cancer.
    Development Status: The technology is currently in the pre-clinical 
stage of development. Phase I clinical trials will begin this fall.
    Inventors: Susan D. Mertins, Susan E. Bates, David G. Covell, 
Geoffrey W. Patton, Melinda G. Hollingshead, B. Rao Vishnuvajjala 
(NCI).
    Patent Status: U.S. Patent Application No. 12/083,583 filed 14 Apr 
2008, claiming priority to 14 Oct 2005 (HHS Reference No. E-249-2005/0-
US-04).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Adaku Nwachukwu, J.D.; 301-435-5560; 
[email protected].
    Collaborative Research Opportunity: The National Cancer Institute, 
Screening Technologies Branch, is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize biomarker assays for clinical 
utility (potential molecular targets have been identified). Please 
contact John D. Hewes, Ph.D. at 301-435-3121 or [email protected] for 
more information.

2-Amino-O\4\-Substituted Pteridines: Improved Chemotherapy Adjuvants

    Description of Technology: O\6\-Benzylguanine derivatives, some 
O\6\-benzylpyrimidines, and related compounds are known to be 
inactivators of the human DNA repair protein O\6\-alkylguanine-DNA 
alkyltransferase (alkyltransferase). This repair protein is the primary 
source of resistance many tumor cells develop when exposed to 
chemotherapeutic agents that modify the O\6\-position of DNA guanine 
residues. Therefore, inactivation of this protein can bring about a 
significant improvement in the therapeutic effectiveness of these 
chemotherapy drugs. The prototype inactivator O\6\-benzylguanine is 
currently in clinical trials in the United States as an adjuvant in 
combination with the chloroethylating agent 1, 3-bis (2-chloroethyl)-1-
nitrosourea (BCNU) and the methylating agent temozolomide. A

[[Page 52057]]

similar alkyltransferase inactivator, O\6\-(4-bromothenyl) guanine is 
in clinical trials in the UK.
    This technology is directed to the discovery of a new class of 
potent alkyltransferase inactivators, 2-amino-O\4\-benzylpteridine 
derivatives targeted for use in cancer treatment in combination with 
chemotherapeutic agents such as 1, 3-bis (2-chloroethyl)-1-nitrosurea 
(BCNU) or temozolomide. The derivatives of the present invention 
inactivate the O\6\-alkylguanine-DNA-alkyltransferase repair protein 
and thus enhance activity of such chemotherapeutic agents. Some of the 
derivatives are water soluble and possess tumor cell selectivity in 
particular by inactivating alkyltransferase in tumor cells that 
overexpress folic acid receptors. The 2-amino-O\4\-benzylpteridine 
derivatives represent a promising new class of alkyltransferase 
inactivator with representatives that may be great candidates as 
chemotherapy adjuvants.
    Applications and Modality:
     New small molecules as alkyltransferase inactivators based 
on 2-amino-O\4\-benzylpteridine compounds.
     Promising candidates as chemotherapy adjuvants for the 
treatment of cancer.
     Therapeutic application for drug resistant tumors where 
acquired resistance is caused by O\6\-alkylguanine-DNA 
alkyltransferase.
    Market:
     600,000 deaths from cancer related diseases estimated in 
2006.
     This technology involving small molecule therapeutics for 
the treatment of several cancers has a potential market of several 
billion U.S. dollars.
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Inventors: Robert C. Moschel (NCI) et al.
    Publication: ME Nelson, NA Loktionova, AE Pegg, RC Moschel. 2-
amino-O\4\-benzylpteridine derivatives: Potent inactivators of O\6\-
alkylguanine-DNA alkyltransferase. J Med Chem. 2004 Jul 15;47(15):3887-
3891.
    Patent Status:
     U.S. Patent Application No. 10/585,566 filed 29 Aug 2006, 
claiming priority to 06 Jan 2004 (HHS Reference No. E-274-2003/0-US-
03).
     Foreign equivalents
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Adaku Nwachukwu, J.D.; 301-435-5560; 
[email protected].

    Dated: August 26, 2008.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E8-20651 Filed 9-5-08; 8:45 am]
BILLING CODE 4140-01-P
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