[Federal Register Volume 73, Number 41 (Friday, February 29, 2008)]
[Notices]
[Pages 11123-11126]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-3837]


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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.

A Pharmacophore for Isatin-[beta]-Thiosemicarbazone Compounds With 
MDR1-Inverse Activity

    Description of Technology: One of the major hindrances to 
successful cancer chemotherapy is multi-drug resistance (MDR), which is 
frequently caused by the increased expression or activity of ABC 
transporter proteins. Research has generally been directed to 
overcoming MDR during cancer therapy by inhibiting the activity of ABC 
transporters. However, compounds that inhibit ABC transporter activity 
often elicit strong and undesirable side-effects, restricting their 
usefulness in therapy.
    In an alternative approach to reducing the debilitating effects of 
MDR in cancer therapy, scientists at the National Cancer Institute 
identified a family of compounds whose antiproliferative effects were 
actually enhanced in cells with MDR. These compounds included NSC 
73306, a specific compound that increased the chemosensitivity of cells 
that overexpress ABC transporters without inhibiting ABC transporter 
activity. This invention concerns new analogs of NSC 73306 with 
improved selectivity and solubility, and the use of the analogs as 
therapeutics.
    Applications:
    Treatment of cancers associated with multi-drug resistance, either 
alone or in combination with other therapeutics.
    Development of a pharmacophore for improved effectiveness in 
treating cancers associated with multi-drug resistance.
    Advantages:
    The agents capitalize on one of the most common drawbacks to cancer 
therapies (MDR) by using it as an advantage to treating cancer.
    Increased specificity allows these analogs to be tailored to 
treating cancers associated with the overexpression and hyperactivity 
of particular ABC transporters.
    Increased solubility allows greater access of the agent to tumor 
cells, increasing therapeutic effectiveness of the agents.
    Benefits: Cancer is the second leading cause of death in United 
States and it is estimated that there will be approximately 600,000 
deaths caused by cancer in 2007. Improving the quality of life and 
duration of life of cancer patients will depend on chemotherapies with 
increased effectiveness and reduced toxicity, thus this technology can 
contribute significantly to a social cause. Furthermore, small molecule 
cancer therapy technologies have a potential market of more than $2 
billion.
    Inventors: Matthew D. Hall et al. (NCI).

[[Page 11124]]

    U.S. Patent Status: Provisional U.S. Application (HHS Reference No. 
E-017-2008/0-US-01).
    Licensing Contact: David A. Lambertson, PhD; 301-435-4632; 
[email protected].
    Collaborative Research Opportunity: The National Cancer Institute's 
Laboratory of Cell Biology is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize for the clinic, compounds that 
demonstrate MDR1-inverse activity. Please contact John D. Hewes, PhD at 
301-435-3121 or [email protected] for more information.

An Improved Non Viral System for Tumor Specific Suicide Gene Therapy

    Description of Technology: Numerous tumor specific promoters have 
been identified and developed for targeted gene therapy. Survivin 
promoter activity is upregulated in 75% of tumors, however the activity 
is specific but low, resulting in sub-optimal suicide gene expression. 
Combination of survivin promoter with Bax, a proapoptotic gene, 
previously used in such therapy has demonstrated low efficacy.
    Scientists at NCI have made a plasmid construct consisting of 
survivin promoter driven mutant form of bax that is constitutively 
active. This construct is more potent than the wild type bax, improving 
its efficacy several-fold, while, retaining specificity for tumors, as 
determined by in vitro and in vivo studies.
    This new technology does not use CMV or SV-40 promoters, 
alleviating the need for modifications for commercialization.
    Advantages:
    Can be used with cationic liposomes or other DNA delivery systems.
    Can be incorporated into adenoviral and lentiviral vectors.
    Excludes viral promoters.
    Can be modified easily to use other promoters/suicide genes.
    Applications:
    Cancer therapeutics
    Targeted Gene therapy
    Market: In patients with advanced solid tumors or recurrences 
despite surgery, chemotherapy can provide quality survival. However, 
responses are usually partial, often disappointingly brief and 
unpredictable and coupled with side effects. These limitations of 
traditional cytotoxic chemotherapy make it necessary to explore other 
therapies such as targeted gene therapy. Viruses, while the carrier of 
choice in most gene therapy studies, present a variety of potential 
problems to the patient--toxicity, immune and inflammatory responses, 
and gene control and targeting issues. In addition, there is a fear 
that the viral vector may recover its ability to cause disease in the 
patient. Our new technology addresses some of the above issues making 
it a suitable agent for cancer and gene therapy.
    Development Status: Early.
    Inventors: Himanshu Garg and Robert P. Blumenthal (NCI).
    Patent Status: HHS Reference No. E-245-2007/0--Research Tool. 
Patent protection is not being sought for this technology.
    Licensing Status: Available for non-exclusive licensing.
    Licensing Contact: John Stansberry, PhD; 301-435-5236; 
[email protected].
    Collaborative Research Opportunity: The National Cancer Institute 
Center for Cancer Research Nanobiology Program is seeking statements of 
capability or interest from parties interested in collaborative 
research to further develop, evaluate, or commercialize tumor specific 
suicide gene therapy using survivin promoter driven mutant bax. Please 
contact John D. Hewes, PhD at 301-435-3121 or [email protected] for 
more information.

Eeyarestatins: Novel Deubiquitination Inhibitors for the Treatment of 
Drug-Resistant Cancers

    Description of Technology: The ubiquitin-proteasome system has 
recently been recognized to play a central role in tumor biology. 
Bortezomib, an inhibitor of the chymotrypsin-like activity of the 
proteasome, has clinical activity in a variety of hematologic 
malignancies and is FDA approved for use in Multiple Myeloma and Mantle 
Cell Lymphoma.
    The present invention for the first time describes that 
Eeyarestatins, a new class of small molecules, are potential anti-
cancer agents. The compounds inhibit the deubiquitination of proteins 
by targeting the deubiquitination enzymes in the protein degradation 
pathway. More specifically, the inventors have demonstrated that the 
Eeyarestatins successfully kill different leukemia and lymphoma cell 
lines as well as leukemia cells isolated from patients with chronic 
lymphocytic leukemia by inducing the expression of Noxa, a pro-
apoptotic member of the Bcl-2 protein family. Additionally, 
Eeyarestatins are active against cells that are resistant to Bortezomib 
and thus can be effective against drug-resistant tumors.
    Applications:
    Eeyarestatins can be developed for the treatment of 
deubiquitination related disorders such as cancers and proliferative 
disorders.
    Eeyarestatins can potentially have broader use against HIV and 
immune related disorders considering the role of deubiquitination in 
budding of retroviruses and immune regulation.
    Advantages:
    Eeyarestatins are active against cells that are resistant to 
Bortezomib.
    In vitro data shows activity of Eeyarestatins against primary cells 
from patients with chronic lymphocytic leukemia. Clinical trials show 
that Bortezomib is inactive against patients suffering from chronic 
lymphocytic leukemia.
    Market: The current cancer chemotherapeutic market is valued at $42 
billion and expected to grow. Additionally, this compound has potential 
use in HIV and immune related disorders.
    Development Status: In vitro studies are completed and in vivo 
animal model studies are planned.
    Inventors: Adrian Wiestner (NHLBI), Yihong Ye (NIDDK), Qiuyan Wang 
(NIDDK), Helena Mora-Jensen (NHLBI)
    Publication: Q Wang, L Li, Y Ye. Inhibition of p97-dependent 
protein degradation by Eeyarestatin I. J Biol Chem. 2008 Jan 16; Epub 
ahead of print, doi 10.1074/jbc.M708347200.
    Patent Status: U.S. Provisional Application No. 60/961,202 filed 17 
Jul 2007 (HHS Reference No. E-208-2007/0-US-01)
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Surekha Vathyam; 301-435-4076; 
[email protected].
    Collaborative Research Opportunity: The National Institutes of 
Health laboratories of Dr. Adrian Wiestner (NHLBI) and Dr. Yihong Ye 
(NIDDK) are seeking statements of capability or interest from parties 
interested in collaborative research to further develop, evaluate, or 
commercialize Eeyarestatins. Please contact Dr. Wiestner (301-594-6855, 
[email protected]) or Dr. Ye (301-594-0845, [email protected]) 
for more information.

Synergistic Effect of TGF-Beta Blockade and Immunogenic Agents on 
Tumors

    Description of Technology: Overcoming immune suppression in cancer 
patients is a major challenge for the success of cancer immunotherapy. 
TGF-[beta] and its receptors are expressed in essentially all tissues, 
and they have been found to be important in many cellular processes 
including cell growth inhibition. The inhibition of TGF-[beta]

[[Page 11125]]

signaling has been shown to have an inhibitory effect on tumor growth. 
However, TGF-[beta] also has immunosuppressive properties.
    Cancer vaccines are one of many therapies available for treatment 
and prevention. In particular, vaccines that elicit immune responses 
have been used to treat or control tumor growth that has evaded 
immunosurveillance. However, these vaccines have demonstrated limited 
success.
    Available for licensing is a method for synergistically affecting 
tumor growth involving the administration of an agent that blocks the 
TGF-[beta] signaling pathway, in combination with an immunogenic agent. 
The agent that blocks the TGF-[beta] signaling pathway may inhibit the 
immunosuppressive effects of TGF-[beta], while the immunogenic agent is 
believed to enhance an immune response. Surprisingly, the combination 
of such elements produces a synergistic effect. The administration of 
the 1D11.16 anti-TGF-[beta] antibody in combination with the human 
papilloma virus E7(49-57) peptide enhances tumor regression in an 
animal model. The administration of the 1D11.16 anti-TGF-[beta] 
antibody in combination with irradiated CT26 cells enhances tumor 
regression in another mouse model. The investigators found that 
administering the combination of agents is more effective than the sum 
of their individual effects.
    Applications: A method of cancer combination therapy based on 
immunotherapeutics.
    Development Status: The invention is in the clinical stages of 
development.
    Inventors: Masaki Terabe (NCI) et al.
    Publications:
    1. PCT patent publication WO 2006/089251, August 24, 2006.
    2. M Terabe et al. Transforming growth factor-beta production and 
myeloid cells are an effector mechanism through which CD1d-restricted T 
cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: 
abrogation prevents tumor recurrence. J Exp Med. 2003 Dec 
1;198(11):1741-1752.
    Patent Status: U.S. Provisional Application No. 60/654,329 filed 17 
Feb 2005 (HHS Reference No. E-019-2005/0-US-01); PCT Application No. 
PCT/US2006/005888 filed 16 Feb 2006 (HHS Reference No. E-019-2005/0-
PCT-02); U.S. Patent Application No. 11/816,410 filed 15 Aug 2007 (HHS 
Reference No. E-019-2005/0-US-06)
    Licensing Status: Available for exclusive and non-exclusive 
licensing.
    Licensing Contact: Jennifer Wong; 301-435-4633; 
[email protected].

Biologically Active Macrolides, Compositions and Uses Thereof

    Description of Technology: The current invention embodies the 
identification of a novel class of potent vacuolar-type (H+)-ATPase-
inhibitory compounds. Vacuolar-type (H+)-ATPases are present in many 
tissues and cells of the body and are involved in the maintenance of 
various physiological functions. The modification of these functions, 
via inhibition of vacuolar-type (H+)-ATPases, may represent an 
effective means of treating various disease states, including 
Alzheimer's disease, glaucoma, and osteoporosis. In addition, these 
inhibitors may also be of particular value for use against cancer, as 
vacuolar-type (H+)-ATPases have been implicated in processes relating 
to cellular proliferation, angiogenesis, tumor cell invasiveness, 
metastasis, and drug resistance.
    Inventors: Michael R. Boyd (NCI), Kirk R. Gustafson (NCI), et al.
    Patent Status: U.S. Patent No. 7,144,918 issued 05 Dec 2006 (HHS 
Reference No. E-203-2000/0-US-04); U.S. Patent Application No. 11/
435,189 filed 16 May 2006 (HHS Reference No. E-203-2000/08-US-08)
    Licensing Status: Available for exclusive and non-exclusive 
licensing.
    Licensing Contact: Adaku Nwachukwu, J.D.; 301-435-5560; 
[email protected].

Human p53 Mutations and a Genetic System in Yeast for Functional 
Identification of Human p53 Mutations

    Description of Technology: The tumor suppressor gene p53, a key 
regulator of cellular mechanisms that maintain genome integrity, is the 
most commonly inactivated gene target associated with neoplastic 
transformation. p53 is mutated in about 50% of all human tumors and 
more than 80% of these mutations are missense, leading to single amino 
acid changes. This invention relates to human p53 mutants and 
identification methods using screening assays in the yeast 
Saccharomyces cerevisiae to functionally categorize expressed p53 
mutant proteins at varying levels of expression towards several human 
target response sequences. Additionally, the invention relates to 
methods of detecting or generating novel human p53 mutations with 
properties that can include toxicity in yeast and growth suppression in 
human cells, enhanced or reduced transactivation relative to wildtype 
p53, altered promoter selectivity, and reactivation by mutation or 
chemical modification of common tumor mutations for the transactivation 
function of major p53 downstream genes. In particular, the inventors 
have discovered a V122A p53 mutation exhibits strong cell proliferation 
inhibition. This feature suggests that p53 alleles such as V122A might 
be valuable both for functional studies of p53-regulated cellular 
responses and possibly for p53 based cancer gene therapy.
    Applications:
    Cancer therapeutics.
    Model to screen for small molecules or peptides that can modify p53 
functions.
    Pharmaceutical screen for p53 drug modifiers.
    Market:
    An estimated 1,444,920 new cancer diagnoses in the U.S. in 2007.
    Cancer drug market is estimated to be $50 billion a year in 2010.
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Inventors: Michael A. Resnick and Alberto Inga (NIEHS)
    Publications:
    1. A Jegga, A Inga, D Menendez, BJ Aronow, MA Resnick. Functional 
evolution of the p53 regulatory network through its target response 
elements. Proc Natl Acad Sci. USA. 2008 Jan 22;105(3):944-949.
    2. MM Horvath, X Wang, MA Resnick, DA Bell. Divergent evolution of 
human p53 binding sites: cell cycle versus apoptosis. PLoS Genet. 2007 
Jul;3(7):1284-1295.
    3. D Menendez, A Inga, J Snipe,O Krysiak, G Sch[ouml]nfelder, MA 
Resnick. A single-nucleotide polymorphism in a half-binding site 
creates p53 and estrogen receptor control of vascular endothelial 
growth factor receptor 1. Mol Cell Biol. 2007 Apr;27(7):2590-2600.
    4. P Monti, Y Ciribilli, J Jordan, P Menichini, DM Umbach, MA 
Resnick, L Luzzato, A Inga, G Fronza. Transcriptional functionality of 
germ line p53 mutants influences cancer phenotype. Clin Can Res. 2006 
Jul 1;13(13):3789-3795.
    5. D Menendez, A Inga, J Jordan, MA Resnick. Changing the p53 
master regulatory network: ELEMENTary, my dear Mr. Watson. Oncogene. 
2007 Apr 2;26(15):2191-2201.
    6. D Menendez, A Inga, J Jordan, MA Resnick. The biological impact 
of the human master regulator p53 can be altered by mutations that 
change the spectrum and expression of its target genes. Mol Cell Biol. 
2006 Mar;26(6):2297-2308.
    7. DJ Tomso, A Inga, D Menendez, G Pittman, M Campbell, D Bell, MA

[[Page 11126]]

Resnick. Functionally distinct polymorphic sequences in the human 
genome that are targets for p53 transactivation. Proc Natl Acad Sci 
USA. 2005 May 3;102(18):6431-6436.
    8. MA Resnick and A Inga. Functional mutations in the sequence-
specific transcription factor p53 and implications for master genes of 
diversity. Proc Nat Acad Sci USA. 2003 Aug 19;100(17):9934-9939.
    9. A Inga, F Storici, TA Darden, MA Resnick. Differential 
transactivation by the p53 transcription factor is highly dependent on 
p53 level and promoter target sequence. Mol Cell Biol. 2002 
Dec;22(24):8612-8625, 2002.
    Patent Status:
    U.S. Patent No. 7,256,260 issued 14 Aug 2007 (HHS Reference No. E-
183-1999/0-US-07)
    U.S. Patent Application No. 11/893,037 filed 14 Aug 2007 (HHS 
Reference No. E-183-1999/0-US-09)
    European Patent Application No. 0094897.0 filed 28 July 2007, 
recently allowed (HHS Reference No. E-183-1999/0-EP-05)
    Australian Patent No. 784293 issued 14 Aug 2007 (HHS Reference No. 
E-183-1999/0-AU-03)
    Australian Patent Application No. 2006202361 filed 2 Jun 2006 (HHS 
Reference No. E-183-1999/0-AU-08)
    Canadian Patent Application No. 2380631 filed 28 July 2000 (HHS 
Reference No. E-183-1999/0-CA-04)
    Japanese Patent Application No. 2001-514117 filed 28 July 2000 (HHS 
Reference No. E-183-1999/0-JP-03)
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Jennifer Wong; 301-435-4633; 
[email protected].

    Dated: February 21, 2008.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E8-3837 Filed 2-28-08; 8:45 am]
BILLING CODE 4140-01-P