Federal Register / Vol. 72, No. 8 / Friday, January 12, 2007 / Notices 1547 

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. 

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 AntiAngiogenic 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; madua@mail.nih.gov 

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 

hewesj@mail.nih.gov 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 MAPKmediated 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; 

lambertsond@od.nih.gov 


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1548 Federal Register / Vol. 72, No. 8 / Friday, January 12, 2007 / Notices 

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 

hewesj@mail.nih.gov 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 

AvastinTM has reached $600 million; (2) 

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) Licensing Status: 

Available for exclusive and nonexclusive licensing. 

Licensing Contact: Adaku Madu, J.D.; 

301/435–5560; madua@mail.nih.gov 

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 

hewesj@mail.nih.gov 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 (LASP) 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 LASP 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. 

OncasparTM, the PEG-derivitized LASP 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, baharm@mail.nih.gov 

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 

hewesj@mail.nih.gov 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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