Federal Register announcement, June 1996. See U.S. patent 5,357,041.

DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes Of Health

Licensing Opportunity and/or Opportunity for a Cooperative Research and
Development Agreement (CRADA) for the Scientific and Commercial Development of
Novel Heparin-Binding Peptides

AGENCY: National Institutes of Health, Public Health Service, DHHS

ACTION: Notice

SUMMARY: The National Institutes of Health is seeking licensees and/or CRADA
partners for the further development, evaluation, and commercialization of
novel heparin-binding peptides. The inventions claimed in the patent
applications referenced below are available for either exclusive or non-
exclusive licensing (in accordance with 35 U.S.C. 207 and 37 CFR Part 404)
and/or further development under a CRADA for clinical and research
applications described below in Supplementary Information.

Heparin- and Sulfatide-Binding Peptides From the Type I Repeats of Human
Thrombospondin and Conjugates Thereof
DD Roberts, PJ Browning, J Bryant, JK Inman, HC Krutzsch, N Guo (NCI)
Serial No. 08/487,568, filed 07 Jun 95, which is a CIP of
Serial No. 08/215,085, filed 21 Mar 94, which is a CIP of
Serial No. 07/801,812, which issued as U.S. Patent No. 5,357,041 on 18 Oct 94

To expedite the research, development, and commercialization of these
compounds, the National Institutes of Health is seeking a CRADA with a
pharmaceutical or biotechnology company in accordance with the regulations
governing the transfer of Government-developed agents. Any proposal to use or
develop these compounds will be considered.

ADDRESS: CRADA proposals and questions about this opportunity should be
addressed to: Dr. Gary D. Colby, Office of Technology Development, National
Cancer Institute, Executive Plaza South, Suite 450, 6120 Executive Boulevard
MSC 7182, Bethesda, MD 20892-7182; telephone: 301/496-0477; fax: 301/402-2117.

Licensing proposals and questions about this opportunity should be addressed
to: Ms. Carol Lavrich, Technology Licensing Specialist, Office of Technology
Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325,
Rockville, Maryland 20852-3804; telephone: 301/496-7735, ext. 287; fax:
301/402-0220.

Information about the patent applications and pertinent information not yet
publicly described can be obtained under a Confidential Disclosure Agreement.
Respondees interested in licensing the invention(s) will be required to submit
an Application for License to Public Health Service Inventions. Respondees
interested in submitting a CRADA proposal should be aware that it may be
necessary to secure a license to the above patent rights in order to
commercialize products arising from a CRADA.

DATE: There is no deadline by which license applications must be received.
CRADA proposals must be received on or before September 16, 1996.

SUPPLEMENTARY INFORMATION: These inventions identify a family of related
peptides, peptide analogs, and peptidomimetics useful for blocking or
modifying the biological activities of heparin, sulfatides, fibronectin,
fibroblast growth factor and transforming growth factor- (TGF). Among the
activities exhibited by compounds within this family of agents are:

inhibition of tumor cell growth, including inhibition of breast tumor
growth in a mouse xenograft model;

inhibition of Kaposi's Sarcoma (KS) cell proliferation and migration in
vitro and KS-like lesion formation in vivo;

inhibition of endothelial and breast carcinoma cell proliferation,
adhesion, and motility in vitro;

inhibition of angiogenesis in vivo;

specific, high affinity binding to heparin and related sulfated
glycoconjugates, including preventing interaction with adhesion molecules,
growth factors, cells, and heparin-dependent enzymes; and

activation of latent TGF.

The compounds within this family of agents are based upon functional sequences
from the three type I repeats of human endothelial cell thrombospondin. The
inventions identify particular peptides, analogs, and peptidomimetics that
have particularly advantageous properties such as increased physiological
stability, enhanced activity, lack of electrostatic charge, and increased
solubility. The inventions also describe unique approaches to constructing
water-soluble conjugates which exhibit a number of interesting and useful
biological activities.

It is expected that the high potency of these agents will lower the effective
dose needed, and, subsequently, will reduce the immunological response against
the peptides and the risks of toxicity. Among the diseases for which these
agents may prove to be particularly useful therapeutic agents are:

Kaposi's sarcoma

Breast carcinoma

Melanoma

Other epithelial cancers

Other diseases involving abnormal vascular proliferation

The inventors of these agents seek collaborators for their ongoing research
and development efforts. Two research projects for which collaborators are
particularly sought involve investigation of means of controlling angiogenesis
and investigation of means for modulating the activity of TGF, particularly
to control fibrosis, using the agents described above.

Thrombospondin has been identified as an anti-angiogenic factor in human
epithelial tissue. Certain agents described above have shown particular
utility for inhibition of pathological angiogenesis in vivo. These agents
have been engineered to decrease both proteolytic degradation and the rapidity
of their clearance from the bloodstream and to increase their biological
activity. These agents have been shown to influence tumor cell adhesion and
growth in vitro and in vivo. Other peptides have been shown to inhibit
tumorigenesis and metastasis in vivo. Further development of agents, and
their application in therapeutic capacities, is planned.

The antiproliferative activities of certain agents upon epithelial and breast
carcinoma cells has been demonstrated to be independent of latent TGF
activation. Other agents, however, have been shown to activate latent TGF.
TGF-activating agents also exhibit anti-tumor activity in vivo. Further
development of TGF-modulating agents, particularly those useful for control
of fibrosis, is planned.

Particularly sought are companies dedicated to the development of small
therapeutic molecules, such as peptides and their analogs. Collaborators
should have particular in-house expertise relating to peptide research and
development. It is anticipated that fruitful collaboration will result from
sustained and meaningful contribution on the part of the collaborator.

The CRADA aims will include optimizing peptide and peptidomimetic activity in
vitro and in vivo, preclinical development of the synthetic peptides and
mimetics, and clinical studies as warranted. The CRADA partner will enjoy the
benefit of a right of first refusal for a license (on reasonable commercial
terms) to government-owned rights in any invention arising within the scope of
the CRADA. Furthermore, the CRADA partner will be responsible for
reimbursement of government expenses for patenting any resulting inventions
during the term of the CRADA.

The role of the National Cancer Institute will include the following:
1. The government will continue in vitro and in vivo preclinical
development of the peptides and mimetics as inhibitors of tumor growth and
metastasis and as modulators of TGF- activity.
2. The government will provide available data and expertise in
structure-function relationships and conformational analysis of the active
peptides and peptidomimetics. These data will be evaluated jointly in order
to assess an efficient research path.
3. As appropriate, the government will initiate collaborative clinical
trials under its extramural clinical trials network, thus ensuring the
clinical evaluation of the compounds.

The role of the collaborator will include the following:
1. Prepare and characterize GMP quality nonmetabolizable analogs (as
determined by both parties) of the active peptides and provide these to the
NCI for characterization as angiogenesis and metastasis inhibitors or as
modulators of TGF- activity.
2. Provide funds for preclinical development of the peptides in vitro
and for screening activities in appropriate animal models.
3. Collaborate in the planning and support for clinical development
leading to FDA approval and marketing.

Selection criteria for choosing the CRADA partner will include, but are not
limited to, the following:
1. Experience in preclinical and clinical drug development.
2. Experience and ability to produce, package, market, and distribute
pharmaceutical products, particularly peptides and peptide analogs, in the
United States.
3. A willingness to cooperate with the Public Health Service in the
collection, evaluation, publication, and maintenance of data from clinical
trials of investigational agents.
4. Willingness to share the costs associated with the development of
the peptides and mimetics. These costs include acquisition or synthesis or
both of the peptides and mimetics in amounts adequate for clinical trials and
marketing.
5. Agreement to be bound by DHHS rules and regulations regarding the
use of human subjects in clinical investigations, intellectual property
rights, ethical treatment of animals, and randomized clinical trials.
6. The aggressiveness of the development plan, including the
appropriateness of milestones and deadlines for preclinical and clinical
development.
7. Agreement with provisions for equitable distribution of patent
rights to any inventions developed under the CRADA(s). Generally, the rights
of ownership are retained by the organization which is the employer of the
inventor, with an irrevocable, non-exclusive, royalty-free license to the
Government (when a company employee(s) is the sole inventor) or a first option
to negotiate an exclusive or non-exclusive license to the company on terms
that are appropriate (when the Government employee(s) is the sole or a joint
inventor).