[Federal Register Volume 72, Number 8 (Friday, January 12, 2007)]
[Notices]
[Pages 1547-1548]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-349]



[[Page 1547]]

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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.

Macrocyclic Grb2 SH2 Domain-Binding Inhibitors: New Anti-Cancer and 
Anti-Angiogenic Therapeutic Agents

    Description of Technology: Growth factor receptor bound 2 (Grb2) 
SH2 domain is involved in signaling events leading to a variety of 
proliferative diseases including erb-2 dependent breast cancers and c-
met dependent renal cancers. Inhibiting the Grb2 SH2 domain binding has 
great potential therapeutic utility in the treatment of certain 
cancers.
    This technology discloses the design and synthesis of new 
macrocyclic inhibitors of Grb2 SH2 domain binding. More specifically, a 
simple synthetic approach using upper achiral junctions has been 
utilized that does not require complex stereoselective synthesis. These 
new series of compounds have synthetic advantage over similar 
macrocyclic compounds and retain good binding affinity towards Grb2 SH2 
domain.
    Applications and Modality: (1) New macrocyclic inhibitors of Grb2 
SH2 domain binding; (2) New compounds have good binding affinity for 
Grb2 SH2 domain and can be potential anti-cancer and anti-angiogenic 
agents; (3) Utilization of simple achiral upper ring junctions that do 
not require complex stereoselective synthesis; (4) New compounds have 
synthetic advantage over more structurally complex inhibitors.
    Market: (1) In 2006, receptor tyrosine kinase inhibitor drug sales 
were estimated at more than $1B dollars; (2) In 2006, cancer drug sales 
were estimated to be $25 billion.
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Inventors: Terrence R. Burke Jr. and Fa Liu (NCI)
    Relevant Publications:
    1. F Liu et al. Utilization of achiral alkenyl amines for the 
preparation of high affinity Grb2 SH2 domain-binding macrocycles by 
ring-closing metathesis. Org. Biomol. Chem. 2007;5:367-372.
    2. N Atabey et al. Potent blockade of hepatocyte growth factor-
stimulated cell motility, matrix invasion and branching morphogenesis 
by antagonists of Grb2 Src homology 2 domain interactions. J. Biol. 
Chem. 2001 Apr 27;276(17):14308-14314.
    3. C-Q Wei et al. Macrocyclization in the design of Grb2 SH2 
domain-binding ligands exhibiting high potency in whole cell systems. 
J. Med. Chem. 2003 Jan 16;46(2):244-254.
    Patent Status: U.S. Provisional Application No. 60/867,307 filed 27 
Nov 2006 (HHS Reference No. E-305-2006/0-US-01)
    Licensing Status: Available for exclusive and non-exclusive 
licensing.
    Licensing Contact: Adaku Madu, J.D.; 301/435-5560; 
<a href="/cdn-cgi/l/email-protection#a5c8c4c1d0c4e5c8c4ccc98bcbcccd8bc2cad3"><span class="__cf_email__" data-cfemail="462b27223327062b272f2a68282f2e68212930">[email protected]</span></a>
    Collaborative Research Opportunity: The National Cancer Institute 
Laboratory of Medicinal Chemistry is seeking statements of capability 
or interest from parties interested in collaborative research to 
further develop, evaluate, or commercialize macrocyclic Grb2 SH2 
domain-binding antagonists. Please contact John D. Hewes, Ph.D. at 301/
435-3121 or <a href="/cdn-cgi/l/email-protection#e78f829082948da78a868e8bc9898e8fc9808891"><span class="__cf_email__" data-cfemail="0d65687a687e674d606c646123636465236a627b">[email protected]</span></a> for more information.

Cyclic Phosphopeptide Inhibitors of Protein Phosphatase 2C Delta, Wip1

    Description of Technology: Wip1 (PP2Cdelta or PPM1D) is a protein 
phosphatase 2C (PP2C) family member that negatively regulates the p38 
MAP kinase pathway. By dephosphorylating p38 kinase, p38 is unable to 
activate the p53 pathway; this prevents p53-mediated cell-cycle arrest 
and apoptosis, suggesting that Wip1 overexpression and over-activity 
may have implications during oncogenesis. Significantly, Wip1 is 
overexpressed in several human cancers, including breast cancer, 
ovarian clear cell adenocarcinoma and neuroblastomas. Thus, inhibitors 
of Wip1 may have promise as anti-cancer therapeutics. Unfortunately, no 
specific inhibitors have been designed to show proof of this concept.
    The instant technology involves the development of specific 
peptides for the inhibition of the Wip1 catalytic site. The inventors 
have modified the optimal Wip1 substrate sequence in such a manner that 
it successfully inhibits Wip1 activity. Importantly, the peptide 
effectively inhibited Wip1 without significantly affecting the activity 
of other PP2C family members. Thus, this compound has potential for 
examination as an anti-cancer agent.
    Claims in this technology are directed to compositions comprising 
the Wip1 inhibitors, as well as methods of using the inhibitors to 
inhibit Wip1 activity in a cell.
    Application: The inhibitors can be developed as anti-cancer 
therapeutics.
    Market: The cancer therapeutic market is expected to reach $27 
billion by 2009.
    Development Status: The technology is at the pre-clinical stage. 
Optimization of the peptide sequence for delivery and efficacy, as well 
as the design of mimetics, are contemplated for further development.
    Inventors: Ettore Appella, Stewart R. Durell, Hiroshi Yamaguchi, 
Yawen Bai (NCI), et al.
    Publications:
    1. H Yamaguchi et al. Substrate specificity of the human protein 
phosphatase 2Cdelta, Wip1. Biochemistry 2005 Apr 12;44(14):5285-5294.
    2. DV Bulavin et al. Inactivation of the Wip1 phosphatase inhibits 
mammary tumorigenesis through p38 MAPK-mediated activation of the 
p16(Ink4a)-p19(Arf) pathway. Nat Genet. 2004 Apr;36(4):343-350.
    3. H Yamaguchi et al. Development of substrate-based cyclic 
phosphopeptide inhibitor of protein phosphatase 2Cdelta, Wip1. 
Biochemistry 2006 Nov 7;45(44):13193-13202.
    4. S Shreeram et al. Regulation of ATM/p53-dependent suppression of 
myc-induced lymphomas by Wip1 phosphatase. J. Exp. Med. 2006 Dec 
25;203(13): 2793-2799.
    Patent Status: U.S. Provisional Application No. 60/850,218 filed 06 
Oct 2006 (HHS Reference No. E-288-2006/0-US-01) Licensing Status: 
Available for non-exclusive or exclusive licensing.
    Licensing Contact: David Lambertson, PhD; 301/435-4632; 
<a href="/cdn-cgi/l/email-protection#721e131f10170006011d1c16321d165c1c1b1a5c151d04"><span class="__cf_email__" data-cfemail="ec808d818e899e989f838288ac8388c2828584c28b839a">[email protected]</span></a>

[[Page 1548]]

    Collaborative Research Opportunity: The NCI CCR, LCB is seeking 
statements of capability or interest from parties interested in 
collaborative research to further develop, evaluate, or commercialize 
Cyclic Phosphopeptide Inhibitors of Protein Phosphatase 2C Delta, Wip1. 
Please contact John D. Hewes, Ph.D. at 301/435-3121 or 
<a href="/cdn-cgi/l/email-protection#18707d6f7d6b72587579717436767170367f776e"><span class="__cf_email__" data-cfemail="d8b0bdafbdabb298b5b9b1b4f6b6b1b0f6bfb7ae">[email protected]</span></a> 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: (1) Novel therapeutic targets associated 
with tumor vessels; (2) New agents can be developed against these novel 
targets; (3) Novel endothelial markers that distinguish pathological 
angiogenesis from normal physiological angiogenesis; (4) Surrogate 
tumor endothelial markers that can be used to determine optimal 
biological dose (OBD) of anti-angiogenic drugs.
    Market: (1) Sales of the first FDA approved anti-angiogenic drug 
Avastin<SUP>TM</SUP> has reached $600 million; (2) Another promising 
anti-angiogenic molecule, Thalidomide<SUP>TM</SUP>, 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) Licensing Status: 
Available for exclusive and non-exclusive licensing.
    Licensing Contact: Adaku Madu, J.D.; 301/435-5560; 
<a href="/cdn-cgi/l/email-protection#e08d81849581a08d81898cce8e8988ce878f96"><span class="__cf_email__" data-cfemail="b5d8d4d1c0d4f5d8d4dcd99bdbdcdd9bd2dac3">[email protected]</span></a>
    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 <a href="/cdn-cgi/l/email-protection#0b636e7c6e78614b666a626725656263256c647d"><span class="__cf_email__" data-cfemail="59313c2e3c2a33193438303577373031773e362f">[email protected]</span></a> for 
more information.

A New Method for Improving the Therapeutic Efficacy of L-Asparaginase 
in Multiple Types of Cancer

    Description of Technology: For the last several decades, L-
asparaginase (L-ASP) has been widely used as a clinical treatment for 
leukemias. Studies show that cancer cells that contain less asparagine 
synthetase (ASNS) are more susceptible to L-ASP. The response to L-ASP 
therapy is often better when the expression of ASNS is limited.
    The present invention describes a new method for enhancing L-ASP 
activity by combining it with antagonists of ASNS--such as siRNAs, 
antisense nucleotides, antibodies or small-molecule inhibitors--for 
treatment of cancers. Reducing or suppressing the expression of ASNS 
potentiates the growth inhibitory activity of L-ASP.
    Additionally, the invention discloses a novel biomarker screening 
tool to identify leukemia, ovarian, and other cancer patients that 
would be most likely to respond to L-ASP treatment.
    Applications and Modality: A new method for improving the 
therapeutic efficacy of L-asparaginase.
    ASNS antagonists such as siRNA, antibodies, antisense nucleotides, 
or small-molecule inhibitors can potentially be used in combination 
with L-ASP in the treatment of cancers.
    ASNS gene or protein expression can serve as a therapeutic response 
biomarker for personalization of cancer therapy with the aforementioned 
combinations.
    Market: There were more than 500,000 deaths from cancer in 2006. 
The current technology has the potential of being used in conjunction 
with L-ASP in treating cancer patients.
    Oncaspar<SUP>TM</SUP>, the PEG-derivitized L-ASP developed by Enzon 
Pharmaceuticals, registered annual sales of about $25 million in 2006, 
largely on the basis of treatment of acute lymphoblastic leukemia. The 
present invention may make L-ASP applicable to treatment of types of 
cancers that are much more common.
    Development Status: The technology is currently in the pre-clinical 
stage of development. With respect to L-ASP treatment of patients with 
solid tumors, Phase I clinical trials have been initiated (Principal 
Investigator Daniel D. Von Hoff, TGen, Inc.) at three institutions 
using L-ASP in combination with gemcitabine.
    Inventors: Philip L. Lorenzi, John N. Weinstein and Natasha J. 
Caplen (NCI)
    Publication: PL Lorenzi et al. Asparagine synthetase as a causal, 
predictive biomarker for L-asparaginase activity in ovarian cancer 
cells. Mol Cancer Ther. Nov; 5(11):2613-2623. Epub 2006 Nov 6, doi 
10.1158/1535-7163.MCT-06-0447.
    Patent Status: U.S. Provisional Application No. 60/779,143 filed 03 
Mar 2006 (HHS Reference No. E-132-2006/0-US-01); U.S. Provisional 
Application No. 60/833,027 filed 25 Jul 2006 (HHS Reference No. E-132-
2006/0-US-02).
    Licensing Status: Available for exclusive and non-exclusive 
licensing.
    Licensing Contact: Mojdeh Bahar, J.D.; 301/435-2950, 
<a href="/cdn-cgi/l/email-protection#b0d2d1d8d1c2ddf0ddd1d9dc9eded9d89ed7dfc6"><span class="__cf_email__" data-cfemail="4725262f26352a072a262e2b69292e2f69202831">[email protected]</span></a>
    Collaborative Research Opportunity: The National Cancer Institute's 
Genomics & Bioinformatics Group in the Laboratory of Molecular 
Pharmacology is seeking statements of capability or interest from 
parties interested in collaborative research to further develop, 
evaluate, or commercialize the combination therapies described in this 
abstract. Please contact John D. Hewes, Ph.D. at 301/435-3121 or 
<a href="/cdn-cgi/l/email-protection#ed85889a889e87ad808c8481c3838485c38a829b"><span class="__cf_email__" data-cfemail="d9b1bcaebcaab399b4b8b0b5f7b7b0b1f7beb6af">[email protected]</span></a> for more information.

    Dated: November 8, 2007.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
 [FR Doc. E7-349 Filed 1-11-07; 8:45 am]
BILLING CODE 4140-01-P


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