Notice: Government-Owned Inventions; Availability for Licensing

Federal Register: July 1, 2009 (Volume 74, Number 125)      
                  Page 31446-31450

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.

New Inhibitors of Polo-like Kinase 1 (PLK1) as Anti-Cancer Agents

    Description of Technology: Tumor formation is the result of 
uncontrolled cellular growth and invasion. Polo-like kinase 1 (PLK1) is 
a regulator of cell growth whose overexpression has been associated 
with several types of cancer (e.g., breast cancer, prostate cancer, 
ovarian cancer, non-small cell lung carcinoma). It has been shown that 
inhibition of PLK1 causes cell death (apoptosis) in tumor cells but not 
normal cells. This suggested that inhibiting PLK1 could be an effective 
treatment for cancer patients without causing unwanted side-effects.
    PLK1 contains a unique protein domain known as the polo box domain 
(PBD), which is essential for its function. One strategy for inhibiting 
PLK1 involves preventing the PBD domain from interacting with PLK1 
substrates. A synthetic peptide with the ability to selectively bind to 
the PBD was recently identified. Using this peptide as a platform, NIH 
inventors have designed peptide mimetics that interact with the PBD 
with greater affinity than the wild-type peptide. By inhibiting PLK1 
and selectively inducing apoptosis in cancer cells, these mimetics 
could serve as potential anti-cancer therapies.
    Applications:
     New anti-cancer therapies that specifically target PLK1
     Platform for the development of further improved PLK1 
inhibitors
    Advantages:

[[Page 31447]]

     The peptide mimetics have an increased affinity for the 
polo box domain of PLK1 compared to the wild-type peptide, making them 
superior as inhibitors of PLK1.
     The peptide mimetics provide greater metabolic stability 
and potential effectiveness over synthetic peptides prepared using 
coded amino acids.
     Inhibiting PLK1 provides an opportunity for successful 
treatment of cancer with fewer side effects because only tumor cells 
are killed.
    Development Status: Preclinical stage of development
    Inventors: Terrence R. Burke Jr. et al. (NCI)
    Patent Status: US Provisional Application No. 61/178,593 (HHS 
Reference No. E-181-2009/0-US-01)
    For more information, see:
    1. F Liu et al. SAR by oxime-containing peptide libraries: 
application to Tsg101 ligand optimization. Chembiochem. 2008 Aug 
11;9(12):2000-2004.
    2. F Liu et al. Protected aminooxyprolines for expedited library 
synthesis: Application to Tsg101-directed proline-oxime containing 
peptides. Bioorg Med Chem Lett. 2008 Feb 1;18(3):1096-1101.
    3. PCT Application WO 2004/046317, ``Crystal structure of human 
Polo-like kinase Plk1, Polo Box domain-binding phosphopeptide core 
sequences, and their therapeutic uses for cancer.''
    Licensing Status: Available for licensing.
    Licensing Contact: David A. Lambertson, PhD; 301-435-4632; 
lambertsond@mail.nih.gov.

Increasing the Effectiveness of Cancer Treatment: T Cell Receptors 
Designed To Release Interleukin-12 Specifically at Cancer Sites

    Description of Technology: Many conventional chemotherapy drugs 
currently utilized to treat cancer also yield harsh side effects in 
patients. In addition, many patients do not respond to generalized 
chemotherapy and radiation treatments for cancer. There is an urgent 
need to develop new therapeutic strategies combining fewer side-effects 
and more specific anti-tumor activity in individual patients. Adoptive 
immunotherapy is a promising new approach to cancer treatment that 
engineers an individual's innate and adaptive immune system to fight 
against specific diseases, including cancer.
    T cell receptors (TCRs) are proteins that recognize antigens in the 
context of infected or transformed cells and activate T cells to 
mediate an immune response and destroy abnormal cells. TCRs consist of 
two domains, one variable domain that recognizes the antigen and one 
constant region that helps the TCR anchor to the membrane and transmit 
recognition signals by interacting with other proteins. When a TCR is 
stimulated by an antigen, such as a tumor antigen, some signaling 
pathways activated in the cell lead to the production of cytokines, 
which mediate the immune response.
    Scientists at the National Institutes of Health (NIH) have 
developed T cells genetically engineered to express the human 
interleukin 12 (IL-12) cytokine only in the tumor environment. 
Specifically, these T cells have been designed to express a human IL-12 
gene under the control of the nuclear factor of activated T cells 
(NFAT) promoter. When the TCR on these T cells recognizes a tumor 
antigen, IL-12 expression is induced through activation of the NFAT 
promoter. Thus, IL-12 is only released at the cancer site and only 
after the activation of the T cell. This technology makes it possible 
to control the expression of IL-12 to enhance T cell cytolytic activity 
while also reducing or eliminating the IL-12 toxicity observed with 
other IL-12 related therapies. Infusing these IL-12 expressing T cells 
into patients via adoptive immunotherapy could prove to be powerful new 
tools for attacking tumors.
    Applications:
     Immunotherapeutics to treat and/or prevent the recurrence 
of a variety of human cancers by adoptively transferring the gene-
modified T cells into patients.
     A drug component of a combination immunotherapy regimen 
aimed at targeting the specific tumor-associated antigens expressed by 
cancer cells within individual patients.
    Advantages: The combination of enhanced T cell activity with 
reduced IL-12 toxicity: IL-12 has shown remarkable properties as an 
anti-tumor agent, but its clinical development has been hindered by its 
toxicity. This current technology delivers IL-12 only when and where it 
is needed--at the tumor site.
    Development Status: Clinical trials utilizing this technology are 
currently in the planning stage.
    Market: Cancer continues to be a medical and financial burden on US 
public health. According to US estimates, cancer is the second leading 
cause of death with over 565,000 deaths reported in 2008 and almost 1.5 
million new cases were reported (excluding some skin cancers) in 2008. 
In 2007, the NIH estimated that the overall cost of cancer was $219.2 
billion dollars and $89 billion went to direct medical costs. Despite 
our increasing knowledge of oncology and cancer treatment methods, the 
fight against cancer will continue to benefit from the development of 
new therapeutics aimed at treating individual patients.
    Inventors: Richard A. Morgan et al. (NCI)
    Publications:
    1. L Zhang et al. Improving adoptive T cell therapy using NFAT 
driven human single chain IL-12 expression vector. 2009 American 
Society of Gene Therapy, abstract submitted.
    2. B Heemskerk et al. Adoptive cell therapy for patients with 
melanoma, using tumor-infiltrating lymphocytes genetically engineered 
to secrete interleukin-2. Hum Gene Ther. 2008 May;19(5):496-510.
    3. RA Morgan et al. Cancer regression in patients after transfer of 
genetically engineered lymphocytes. Science 2006 Oct 6;314(5796):126-
129.
    Patent Status: U.S. Provisional Application No. 61/174,046 filed 30 
Apr 2009 (HHS Reference No. E-170-2009/0-US-01)
    Licensing Status: Available for licensing.
    Licensing Contact: Samuel E. Bish, Ph.D.; 301-435-5282; 
bishse@mail. nih.gov.
    Collaborative Research Opportunity: The National Cancer Institute, 
Surgery Branch, is seeking statements of capability or interest from 
parties interested in collaborative research to further develop, 
evaluate, or commercialize adoptive immunotherapies or the development 
of cancer therapeutics based on the use of T cell receptors. Please 
contact John D. Hewes, PhD at 301-435-3121 or hewesj@mail.nih.gov for 
more information.

A Novel System for Producing Infectious Hepatitis C Virus (HCV) Virions 
and Development of a Novel Reporter System for Studying HCV Entry

    Description of Technology: HCV has infected an estimated 3% of the 
world population in whom viral infection persists for more than two 
third of the cases, often resulting in life-threatening complications. 
The standard of care (pegylated interferon alpha-2 plus ribavirin) is 
efficient in only 50% of treated patients, costly and has numerous side 
effects. In addition, viral resistance to newly developed drugs--
targeting viral protease or RNA polymerase--has been described, but no 
vaccine is yet available. The difficulty in developing HCV vaccines is 
largely due to the broad sequence-diversity

[[Page 31448]]

displayed by HCV, the frequent occurrence of viral mutations within 
immunogenic epitopes in vivo, and the lack of proper standard/
definition for viral neutralization.
    One alternative strategy in HCV-vaccine or drug development 
comprises measuring viral entry, the first step in viral infection. 
Such measurements are limited by the available screening systems, in 
that, HCV pseudo-typed retroviral particles have a different envelope 
conformation and contain foreign components that are likely to 
interfere with the measured HCV entry. Moreover, HCV lab strain 
requires intensive replication for its in vitro production, resulting 
in numerous mutations that impede development of convenient screening 
tools.
    The inventors have developed a system for generating infectious HCV 
particles and HCV-like particles (HCV-LP) suitable for a qualitative 
single-cycle entry assay, completely independent of HCV replication. To 
adapt this system as a single assay to study HCV-LP entry, HCV non-
structural genes were replaced with a heterologous gene that upon 
viral-entry triggers firefly luciferase and EGFP expressions in target 
as well as non-permissive cells. The pretreatment of HCV-replication 
permissive HuH-7.5 cells with siRNA targeting HCV candidate receptors 
inhibited viral entry. These new systems enable production of authentic 
HCV infectious particles as well as HCV-LPs suitable for single-cycle 
entry assays adaptable to high throughput screening.
    Applications:
     Screening a library expressed in non-permissive cells for 
identifying new HCV candidate receptor(s) or entry molecule(s).
     Testing drugs or compounds inhibiting HCV particle entry 
or viral genome uncoating, or neutralizing antibodies in target cells.
     Testing drugs or compounds that inhibit virus assembly, 
maturation and/or egress, or genome packaging, in producer cells.
     Incorporating a `tag' in the genome of various HCV 
genotypes to more conveniently study virus spreading and dissemination 
in an organ, tissue and/or small animal model.
     Enhancing immune response in patients: one way to trigger 
high level anti-HCV immunity is by isolating antigen-presenting cells 
from patients and incubating them with HCV particles produced with this 
system using replication-defective viral genome (with or without an 
immunogenic tag and/or in combination with other viral epitopes) and 
eventually re-inject their primed cells to the patients.
    Advantages:
     These systems do not use pseudo-typed HCV particles, i.e. 
no foreign proteins present in the virus particles.
     Particle production in the producing cells is independent 
of HCV RNA replication, hence avoids the occurrence of adaptive 
mutations that could be detrimental for virus particle's infectivity or 
could alter tags or nucleotide sequences incorporated in the viral 
genome.
     These systems are not specifically dedicated to HCV of a 
particular genotype, i.e. they can be used to generate HCV particles of 
various genotypes without requiring the use of chimeras.
    Development Status:
     Proof of concept.
     Preliminary tools and techniques for screening strategies.
    Inventors: Bertrand Saunier, Miriam Triyatni, Edward A. Berger (all 
NIAID)
    Patent Status: U.S. Provisional Application No. 61/195,088 filed 03 
Oct 2008 (HHS Reference No. E-005-2009/0-US-01)
    Licensing Status: Available for licensing.
    Licensing Contact: RC Tang JD, LLM; 301-435-5031; 
tangrc@mail.nih.gov.
    Collaborative Research Opportunity: The NIAID OTD is seeking 
statements of capability or interest from parties interested in 
collaborative research to further develop, evaluate, or commercialize a 
novel system for producing infectious HCV virions and developing a 
reporter system for studying HCV entry. Please contact Michael Piziali 
at 301-496-2644 for more information.

Recombinant Virus-Like Particle (VLP) and DNA Vaccines for Chikungunya 
Virus (CHIKV) and Other Alphaviruses

    Description of Technology: Available for licensing and commercial 
development are compositions and methods of use as vaccines of virus-
like particles (VLPs) expressing one or more Alphavirus capsid and 
envelope proteins, and in particular Chikungunya virus (CHIKV) core and 
envelope proteins. The invention also describes DNA, viral or other 
gene-based vector and VLP vaccines, methods of making and methods of 
their use in inducing immunity, for example to CHIKV infection.
    Alphaviruses are RNA-containing viruses that cause a wide variety 
of mosquito-transmitted diseases, including equine encephalitis. CHIKV, 
an Alphavirus in the family Togaviridae, was first isolated in Tanzania 
in 1952 and is transmitted to humans by mosquitoes. The disease caused 
by CHIKV resembles infection by dengue virus, characterized by rash, 
high fever, and severe, sometimes persistent arthritis. By 2007, an 
estimated 1.4-6.5 million people in India, Southeast Asia, Africa and 
Europe had been infected. Vaccines or anti-viral therapies against 
CHIKV are not available, raising concerns about its continued evolution 
and spread in humans. There has been limited success to date in 
developing a safe and effective CHIKV vaccine. A live CHIKV vaccine 
candidate caused transient arthralagia in volunteers. Other efforts to 
develop a CHIKV vaccine include a live attenuated vaccine, a formalin-
killed vaccine, a Venezuelan equine encephalitis/CHIKV chimeric live 
attenuated vaccine and a consensus-based DNA vaccine, but development 
of a safe and effective CHIKV vaccine will require additional 
evaluation in humans.
    This invention provides CHIKV vaccines based on plasmid expression 
vectors encoding structural proteins of the virus, which gave rise to 
VLPs in transfected cells and also served as DNA vaccines. The VLPs 
consisted of the core, E1 and E2 proteins and were similar in buoyant 
density and morphology to replication-competent virus. To evaluate the 
potency and specificity of neutralizing antibodies, pseudotyped 
lentiviral vectors bearing the CHIKV glycoproteins E1/E2 were developed 
that showed pH-dependent entry and antibody inhibition similar to 
CHIKV. Mice were immunized with VLPs (West African strain, 37997) or 
with DNA vaccines encoding viral gene products from 37997 as well as 
the latest outbreak strain, OPY-1. Immunization with VLPs elicited high 
titer neutralizing antibodies against homologous and heterologous 
strain envelope at >100 fold higher titers than DNA vaccines. These 
vaccines also induced CD4 and CD8 T-cell responses by analysis with 
intracellular cytokine staining (ICS). These VLP vaccines are likely to 
confer protection against emerging CHIKV outbreaks and represent a 
strategy that could be applied to other pathogenic viruses to prevent 
their infection and spread.
    Applications:
     Development of vaccines against CHIKV
     Development of vaccines against other Alphavirus
    Advantages:
     Immunization of mice with VLPs plus adjuvant results in 
neutralizing antibodies against both homologous and heterologous 
strains with titers at least two orders of magnitude greater than 
immunization with a DNA vaccine.

[[Page 31449]]

     VLPs induce innate immunity responses as well as CD8 T-
cell responses.
     VLPs closely resemble mature virions but they do not 
contain viral genomic material. Therefore, VLPs are non-replicative in 
nature, which make them safe for administration in the form of 
immunogenic compositions in vaccines.
    Development Status: This technology is in the pre-clinical stage of 
development.
    Inventors: Gary J. Nabel and Wataru Akahata (NIAID)
    Patent Status: U.S. Provisional Application No. 61/201,118 filed 05 
Dec 2008, entitled ``Virus Like Particle Compositions and Methods of 
Use'' (HHS Reference No. E-004-2009/0-US-01)
    Licensing Status: Available for licensing.
    Licensing Contact: Cristina Thalhammer-Reyero, PhD, MBA; 301-435-
4507; thalhamc@mail.nih.gov.

Inflammatory Genes and MicroRNA-21 as Biomarkers for Colon Cancer 
Prognosis

    Description of Technology: Colon adenocarcinoma is the leading 
cause of cancer mortality world-wide and accounts for approximately 
50,000 deaths annually in the United States. Adjuvant therapies improve 
survival for stage III colon cancer patients; however, it remains 
controversial if stage II patients should be given these therapies. 
Some stage II patients will benefit from therapy (such as patients with 
undetectable micro-metastases where surgery will not be curative); but 
therapy for others will harm quality of life with little therapeutic 
benefit (such as patients where surgery removed all cancerous tissue 
and therefore do not need additional therapy). Thus, there is a need 
for biomarkers capable of accurately identifying high risk, stage II 
patients that are suitable for therapeutic intervention.
    The investigators have identified an inflammatory gene and microRNA 
biomarker portfolio that can predict aggressive colon cancer, colon 
cancer patient survival, and patients that are candidates for adjuvant 
therapy. These biomarkers provide clinicians with a powerful tool to 
diagnose colon cancer patients and chose effective treatment methods.
    Applications:
     Method to predict aggressive form of colon cancer, 
especially in stage II cancer patients
     Method to determine appropriate colon cancer patients for 
adjuvant therapy
     Diagnostic arrays
    Advantages:
     Rapid, easy to use arrays to accurately predict colon 
cancer and patients suitable for adjuvant therapy
     Method to stratify colon cancer patients for adjuvant 
therapy to minimize negative side effects
     Method to identify stage II patients that are likely to 
have undetectable micro-metastases
    Development Status: The technology is currently in the pre-clinical 
stage of development.
    Market:
     Global cancer market is worth more than eight percent of 
total global pharmaceutical sales
     Cancer industry is predicted to expand to $85.3 billion by 
2010
    Inventors: Curtis C. Harris and Aaron J. Schetter (NCI)
    Relevant Publication: AJ Schetter et al. MicroRNA expression 
profiles associated with prognosis and therapeutic outcome in colon 
adenocarcinoma. JAMA. 2008 Jan 30;299(4):425-436.
    Patent Status: U.S. Provisional Application No. 61/194,340 filed 25 
Sep 2008 (HHS Reference No. E-314-2008/0-US-01)
    Licensing Status: Available for licensing.
    Licensing Contact: Jennifer Wong; 301-435-4633; 
wongje@mail.nih.gov.
    Collaborative Research Opportunity: The NCI Laboratory of Human 
Carcinogenesis is seeking statements of capability or interest from 
parties interested in collaborative research to further develop, 
evaluate, or commercialize cancer biomarkers and therapeutic targets. 
Please contact Curtis_Harris@nih.gov for more information.

Differentiation of Human Embryonic Stem Cells Into Dopaminergic Nerve 
Cells

    Description of Technology: The invention described here is a novel 
method of differentiating human embryonic stem cells (hESCs) into 
dopaminergic nerve cells, which is preferable to the currently 
available dopaminergic differentiation techniques.
    This invention potentially provides a source of sufficient 
dopaminergic cells not only for the clinical transplantation of 
dopaminergic tissue but also for in vitro studies of human cells useful 
for pharmaceutical screens related to neurodegenerative disorders and 
substance abuse.
    Neurodegenerative disorders encompass a range of debilitating 
conditions including Parkinson's disease, Alzheimer's disease, and 
Huntington's disease. The primary cause of cognitive dysfunction for 
these three disorders has been directly linked to neuron degeneration, 
usually in specific areas of the brain. Transplantation of fetal 
dopaminergic neurons in affected areas of the brain in late stage 
Parkinson's disease has demonstrated clinical utility in human 
patients. However, fetal transplantation therapy generally requires 
human tissue from at least 3-5 embryos to obtain a clinically reliable 
improvement in the patient, thus demonstrating a need for a larger and 
more reliable source of dopaminergic cells. HESCs are a promising 
alternative source of cells because they can grow in culture 
indefinitely and have the ability to differentiate into a variety of 
cell types. One of the most efficient methods for conversion of hESCs 
to dopaminergic neurons requires the presence of mouse stromal cells 
which have an undefined dopaminergic inducing activity. However, the 
major disadvantage of this method is the exposure of hESC to mouse 
cells, which hinders any downstream clinical application due to 
possible transfer of animal cells and pathogens. This invention has 
unveiled the molecular nature of the activity of the mouse cells and 
established an efficient alternative approach for dopamine neuron 
generation, which is more suitable for clinical application. This 
innovative approach potentially provides a large and reliable source of 
dopaminergic cells sufficient for clinically relevant transplantation 
of dopaminergic tissue as well as in vitro pharmacologic studies of 
human dopaminergic cells.
    Applications:
     Human dopaminergic cell source for neuronal 
transplantation, with potential clinical application to Parkinson's 
disease and possibly other neurodegenerative disorders.
     Human dopaminergic cell source for in vitro models for 
pharmaceutical screens relevant to neurodegenerative disorders and 
substance abuse.
    Market: Parkinson's disease, the second most common neurological 
disorder, affects approximately 4.1 million people worldwide. In 2006, 
global sales of Parkinson's disease therapeutics were $3.1 billion, 
with sales expected to exceed $4.6 billion by 2012.
    Development Status: Early stage.
    Inventors: William Freed and Tandis Vazin (NIDA).
    Publication: In preparation.
    Patent Status: U.S. Provisional Application No. 61/199,652 filed 18

[[Page 31450]]

Nov 2008 (HHS Reference No. E-176-2008/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contact: Norbert Pontzer, J.D., PhD; 301-435-5502; 
pontzern@mail.nih.gov.
    Collaborative Research Opportunity: The National Institute on Drug 
Abuse, Development and Plasticity Section, is seeking statements of 
capability or interest from parties interested in collaborative 
research to further develop, evaluate, or commercialize this 
technology. Please contact Vio Conley, M.S. at 301-496-0477 or 
conleyv@mail.nih.gov for more information.

    Dated: June 22, 2009.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E9-15578 Filed 6-30-09; 8:45 am]

BILLING CODE 4140-01-P