[Federal Register Volume 72, Number 179 (Monday, September 17, 2007)]
[Notices]
[Pages 52889-52892]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-18192]


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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.

New and Improved Chemotherapy Adjuvants: Folate Based Inactivators of 
O\6\-alkylguanine-DNA alkyltransferase (alkyltransferase)

    Description of Technology: O6-Benzylguanine derivatives, 
some O6-benzylpyrimidines, and related compounds are known 
to be inactivators of the human DNA repair protein O6-
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 O6-
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 
O6-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 similar alkyltransferase inactivator, 
O6-(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, based on folate ester derivatives 
of O6-benzyl-2'-deoxyguanosine and of O6-[4-
(hydroxymethyl)benzyl] guanine. All the folate ester derivatives of 
O6-benzyl-2'-deoxyguanosine were able to sensitize human 
tumor cells to killing by 1, 3-bis (2-chloroethyl)-1-nitrosourea with 
O6-benzyl-3'-O-[[gamma]-folyl]-2'-deoxyguanosine being the 
most active. The 3' ester was found to be more potent than the 5' ester 
and was more than an order of magnitude more active than O6-

[[Page 52890]]

benzylguanine, which is currently in clinical trials.

Applications

    Promising candidates as chemotherapy adjuvants for the treatment of 
cancer.
    Therapeutic application for drug resistant tumors where acquired 
resistance is caused by O6-alkylguanine-DNA 
alkyltransferase.

Advantages

    The folate ester derivatives are highly water soluble.
    Conjugation of folic acid to an alkyltransferase inactivating 
compound should allow targeting of delivery to cells that express 
folate receptor as many tumor cells are known to do.
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Inventors: Drs. Gary Pauly (NCI), Robert C. Moschel (NCI), Sahar 
Javanmard (NCI), et al.
    Patent Status: This technology consists of U.S. Provisional 
Application No. 60/915,510 foreign equivalents, entitled ``Inactivators 
of O6-Alkylguanine-DNA Alkyltransferase'' (HHS Reference No. 
E-200-2007/0).
    Related Technology: HHS Reference No. E-274-2003/0, entitled ``2-
Amino-O4-Substituted Pteridines and Their Use as 
Inactivators of O6-Alkylguanine-DNA Alkyltransferase''.
    Licensing Status: Available for exclusive and non-exclusive 
licensing.
    Licensing Contact: Adaku Nwachukwu, J.D.; 301/435-5560; 
[email protected].

Papilloma Pseudovirus for Detection and Therapy of Tumors

    Description of Technology: There is extensive literature on the use 
of viral vectors, particularly those based on the adenovirus and AAV, 
to increase the potency of anti-tumor gene therapy. However, these 
approaches have had limited success because of limited anti-tumor 
effects and unacceptable toxicity. This invention describes the use of 
papillomavirus pseudoviruses (PsV) as a gene transfer technology and a 
tumor diagnostic method. Preliminary studies showed that PsV bind to 
cells that were transplanted with human ovarian tumor (Shin-3) while 
normal tissues were not affected. PsV does not infect several other 
normal intact tissues but continues to selectively infect additional 
cell types that are damaged. Additionally, the inventors have 
constructed oligoT PsV vectors that can be engineered to express 
certain cytotoxic genes to induce tumor regression and simultaneous 
increase human papilloma virus' immunogenicity. This technology could 
be an effective anti-tumor therapy because it has shown increased 
infection of compromised cells with an inability to infect normal cells 
thereby reducing potential toxicity to patients. In addition to a 
potential anti-cancer therapeutic, this technology could also be used 
as a diagnostic tool in the detection of tumor masses. Detection can be 
achieved through the use of fluorescent dye coupled particles of PsV 
that have preferential binding to tumor tissues and not normal tissues.

Applications

    Method to treat and selectively target cancer with limited 
toxicity.
    Method to accurately diagnose cancer.
    Anti-tumor therapeutic vaccines.
    Anti-tumor cytoxic gene therapy constructs.

Market

    An estimated 1,444,920 new cancer cases in 2007.
    600,000 cancer deaths in the U.S. in 2006.
    It is estimated that market for cancer drugs would double to $50 
billion a year in 2010 from $25 billion in 2006.
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Inventors: Jeffrey Roberts, John T. Schiller, Douglas R. Lowy 
(NCI).

Publications

    1. CB Buck, et al. Generation of HPV pseudovirions using 
transfection and their use in neutralization assays. Methods Mol Med. 
2005;119:445-462.
    2. CB Buck, et al. Efficient intracellular assembly of 
papillomaviral vectors. J Virol. 2004 Jan;78(2):751-757.
    Patent Status: U.S. Provisional Application No. 60/928,495 filed 08 
May 2007 (HHS Reference No. E-186-2007/0-US-01).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Jennifer Wong; 301/435-4633; 
[email protected].

New Synthetic Variants of 2-(4-isothiocyanatobenzyl)-6-
methyldiethylenetriamine Pentaacetic Acid (1B4M-DTPA): Novel 
Macromolecular MRI Contrast Agents

    Description of Technology: The present invention describes the 
synthesis and use of two protected variants of the 2-(4-
isothiocyanatobenzyl)-6-methyldiethylenetriamine pentaacetic acid 
(1B4M-DTPA) (also known as the commercial bifunctional chelator, 
tiuxetan), bearing either an isothiocyanate or a succinimidyl ester 
moiety, respectively. These molecules were synthesized for the 
following uses: (1) Use in the introduction of the chelator to the N-
terminus of peptides, aptamers, PNA, etc. wherein deprotection or 
cleavage from resin or solid phase support of the product is possible 
and (2) introduction of the chelator to macromolecular structures such 
as dendrimer wherein this is accomplished in organic solvents 
eliminating the gross inefficiency of the prior aqueous methods.
    In both uses, the elimination or delay of any aqueous chemistry 
steps in the synthesis process obviates the possibilities of 
contamination by spurious metals. Metal contaminations could compromise 
latter radiolabeling or can also hinder the introduction of 
paramagnetic ions such as Gd(II1) for MRI applications. The chemistry 
used in this synthetic process is very flexible and provides the basis 
for an extensive list of conjugation functional groups to be 
introduced.
    Comparative MR imaging with these dendrimer based molecules 
revealed equivalent enhancement of the vessels and organs such as the 
kidney and liver.

Applications

    Useful in the conjugation of nearly all peptides for targeting 
antigens/peptides associated with cancers.
    Useful for modification of macromolecules such as dendrimer, carbon 
tubes, etc., for labeling with radioactive metal ions suitable for 
imaging and/or therapy and paramagnetics for MRI.

Advantages

    The chemistry is very flexible and provides the basis for an 
extensive list of conjugation functional groups to be introduced.
    The elimination of aqueous chemistry steps obviates the 
possibilities of contamination by spurious metals that could compromise 
subsequent radiolabeling.
    The elimination of aqueous steps aids in the introduction of 
paramagnetic ions such as Gd(III) for MRI applications.
    The general synthesis process provides a procedure for preparing 
dendrimer-based MR agents with higher yields and efficiency while 
enhancing versatility.
    Benefits: In spite of advances in cancer therapeutics and 
diagnostics, more than 600,000 cancer deaths are estimated to occur in 
2007. Early and accurate detection is a key component of successful 
clinical management of cancer. This technology can contribute to the 
development of better MRI agents

[[Page 52891]]

for diagnosing cancer and thus improve overall survival and quality of 
life of patients suffering from cancer.
    Inventors: Drs. Martin Brechbiel and Heng Xu (NCI).
    Development Status: Synthesis process and data available.
    Patent Status: U.S. Provisional Application No. 60/864,503 filed 06 
Nov 2006 (HHS Reference No. E-226-2006/0-US-01).
    Publication: H Xu, CA Regino, M Bernardo, Y Koyama, H Kobayashi, PL 
Choyke, MW Brechbiel. Toward improved syntheses of dendrimer-based 
magnetic resonance imaging contrast agents: New bifunctional 
diethylenetriaminepentaacetic acid ligands and nonaqueous conjugation 
chemistry. J Med Chem. 2007 Jul 12;50(14):3185-3193. Epub 2007 Jun 7.
    Licensing Contact: Mojdeh Bahar; 301/435-2950; [email protected].

Methods and Compositions for Treating FUS1 Related Disorders

    Description of Technology: The FUS1 gene residing in the 3p21.3 
chromosome region may function as a tumor suppressor gene. In animal 
models, disruption of FUS1 is associated with an increased frequency of 
spontaneous vascular tumors and signs of autoimmune disease. The 
investigators have in vivo data that demonstrate that FUS1 null mutants 
show a consistent defect in NK cell maturation that correlate with 
changes in the expression of IL-15. Injection of IL-15 into FUS1 
knockout mice completely rescued the NK cell maturation defect 
suggesting that FUS1 plays an important role in the development and 
activation of the mammalian immune system.

Applications

    Method to treat cancer, autoimmune diseases, and immune disorders 
such as HIV.
    Method to boost immunity in conjunction with cancer and immune 
disorder therapies.
    Method to diagnose FUS1 related disorders.
    Animal model to study anti-tumor response and autoimmunity.

Market

    An estimated 1,444,920 new cancer diagnoses in the U.S. in 2007.
    600,000 deaths caused by cancer in the U.S. in 2006.
    Cancer is the second leading cause of death in United States.
    It is estimated that market for cancer drugs would double to $50 
billion a year in 2010 from $25 billion in 2006.
    An estimated 8.5 million Americans are afflicted with autoimmune 
diseases.
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Inventors: Michael I. Lerman, et al. (NCI).
    Publication: AV Ivanova, et al. Autoimmunity, spontaneous 
tumourigenesis, and IL-15 insufficiency in mice with a targeted 
disruption of the tumour suppressor gene Fus1. J Path. 2007 
Apr;211(5):591-601.
    Patent Status: PCT Patent Application No. PCT/US2006/026533 (HHS 
Reference No. E-137-2005/0-PCT-02).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Jennifer Wong; 301/435-4633; 
[email protected].
    Collaborative Research Opportunity: The National Cancer Institute 
Basic Research Laboratory is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize cancer and immune disorder 
therapies Please contact John D. Hewes, Ph.D. at 301-435-3121 or 
[email protected] for more information.

Tumor Suppressor Genes

    Description of Technology: Members of the inhibitor of growth (ING) 
family of tumor suppressor genes are involved in the regulation of 
diverse processes including cell cycle progression, apoptosis, and DNA 
repair as important cofactors of p53. ING members contain a highly 
evolutionary conserved sequence common in chromatin-regulating 
proteins, and there are overlapping functions between ING family 
members in negative regulation of cell growth as well as a dependent 
regulation between various ING members and p53.
    Available for licensing are compositions for new tumor suppressor 
designated p28ING5, p33ING2, and p47ING3 (pING). Overexpression of 
these proteins has been shown to inhibit cell proliferation in human 
cancer cells lines, and these characteristics suggest that they may 
have important implications in cancer diagnosis and therapy. These 
compositions include nucleic acids, polypeptides, and antibodies that 
specifically bind to their respective ING members. Also claimed are 
cancer diagnostic and treatment methods.

Applications

    Methods to treat and diagnose cancer with pING compositions.
    Methods to identify pING modulating agents.
    Research tool to study cell cycle regulation and p53 pathways. pING 
compositions.

Market

    Cancer is the second leading cause of death in United States.
    An estimated 600,000 deaths caused by cancer in 2006.
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Inventors: Curtis C. Harris (NCI), et al.

Publications

    1. T Okano, et al. Alterations in novel candidate tumor suppressor 
genes, ING1 and ING2 in human lung cancer. Oncol Rep. 2006 
Mar;15(3):545-549.
    2. H Kataoka, et al. ING1 represses transcription by direct DNA 
binding and through effects on p53. Cancer Res. 2003 Sep 
15;63(18):5785-5792.
    3. M Nagashima, et al. A novel PHD-finger motif protein, p47ING3, 
modulates p53-mediated transcription, cell cycle control, and 
apoptosis. Oncogene. 2003 Jan 23;22(3):343-350.
    4. M Nagashima, et al. DNA damage-inducible gene p33ING2 negatively 
regulates cell proliferation through acetylation of p53. Proc Natl Acad 
Sci USA. 2001 Aug 14;98(17):9671-9676.

Patent Status

U.S. Patent No. 6,790,948 issued 14 Sep 2004 (HHS Reference No. E-272-
1998/0-US-02)
U.S. Patent Application No. 10/868,270 filed 14 Jun 2004 (HHS Reference 
No. E-272-1998/0-US-03)
PCT Patent Application No. PCT/US2001/04425 filed 09 Feb 2001 (HHS 
Reference No. E-254-1999/ 0-PCT-02)
U.S. Patent Application No. 10/203,532 filed 02 Aug 2002 (HHS Reference 
No. E-254-1999/0-US-03)
PCT Patent Application No. PCT/US2003/02174 filed 23 Jul 2003 (HHS 
Reference No. E-300-2001/0-PCT-02)
U.S. Patent Application No. 10/502,431 filed 22 Jul 2004 (HHS Reference 
No. E-300-2001/0-US-03)

    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Jennifer Wong; 301/435-4633; 
[email protected].

Peptide Inhibitor of Cyclin Dependent Kinase 4 (CDK4) Derived From MyoD

    Description of Technology: This invention pertains to cell cycle 
regulation and the activity of the G1 cyclin-dependent kinase 4 (CDK4). 
The invention describes a 15 amino acid peptide and variants thereof 
derived from muscle determination factor,

[[Page 52892]]

MyoD, which is an inhibitor of the CDK4. CDK4 is one of a number of 
cyclin-dependent kinases which control progression through the cell 
cycle through their ability to phosphorylate particular substrates at 
the correct phase of the cell cycle. CDK4 has been shown to be involved 
in cell cycle control through its ability to regulate the activity of 
the retinoblastoma protein, pRb, an activator of genes essential for 
cell division.
    Inhibitors of the cyclin-dependent kinases, such as the peptides 
described in this invention, prevent cell cycle progression and induce 
cells to exit the cell cycle into the Go state. The peptides described 
in this invention prevent the phosphorylation of pRb by CDK4, an 
obligate step for entry into the cell cycle. Osteosarcomas and 
habdosarcomas are two types of tumors known to over-express pRb. The 
inhibitor described in this invention may be useful in treating these 
cancers or other diseases which have been specifically linked to over-
expression of active pRb.

Applications

    Method to treat proliferative disorders, including cancer.
    Anti-proliferative therapeutics.
    Research tool to study the cell cycle.
    Advantages: Expression of this peptide either as a fusion protein 
with GST or GFP results in the cessation of cell growth.

Market

    An estimated 1,444,920 new cancer diagnoses in the U.S. in 2007.
    600,000 deaths caused by cancer in the U.S. in 2006.
    Cancer is the second leading cause of death in the United States.
    It is estimated that market for cancer drugs would double to $50 
billion a year in 2010 from $25 billion in 2006.
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Inventors: Bruce M. Paterson and Jian-min Zhang (NCI).
    Publication: JM Zhang, et al. Coupling of the cell cycle and 
myogenesis through the cyclin D1-dependent interaction of MyoD with 
cdk4. EMBO J. 1999 Feb 15;18(4):926-933.
    Patent Status: U.S. Patent Application No. 10/018,964 filed 11 Apr 
2002, claiming priority to 18 Jun 1999 (HHS Reference No. E-153-1998/0-
US-03).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Jennifer Wong; 301/435-4633; 
[email protected].
    Collaborative Research Opportunity: The National Cancer Institute's 
Laboratory of Biochemistry and Molecular Biology is seeking statements 
of capability or interest from parties interested in collaborative 
research to further develop, evaluate, or commercialize the described 
cdk4 inhibitory peptides or equivalent peptide mimetics. Please contact 
John D. Hewes, PhD at 301-435-3121 or [email protected] for more 
information.

    Dated: September 6, 2007.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
 [FR Doc. E7-18192 Filed 9-14-07; 8:45 am]
BILLING CODE 4140-01-P