[Federal Register Volume 75, Number 107 (Friday, June 4, 2010)]
[Notices]
[Pages 31791-31794]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-13480]


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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 United States 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.

888-mel: A Target for Anti-Tumor Immune Responses

    Description of Invention: Scientists at the National Institutes of 
Health (NIH) have developed a human melanoma cell line designated 888-
mel from the resected tumor of a 26-year old Caucasian female (patient 
888) diagnosed with metastatic melanoma, a frequently terminal cancer. 
The 888-mel cell line was derived from three separate subcutaneous 
melanoma lesions on the patient and possesses many characteristics 
representative of melanoma cell lines developed by these researchers. 
Most prominently, the 888-mel cell line was used to develop a tumor 
infiltrating lymphocyte (TIL) culture with high affinity for the tumor 
cells of patient 888. When the TIL 888 culture was provided as an 
autologous adoptive immunotherapy treatment to patient 888 in 
combination with interleukin-2 (IL-2), a complete remission of 
subcutaneous, lung, and mucosal metastases was observed in the patient 
for over three years.
    Since this medical breakthrough, the 888-mel cell line has been 
well characterized through various laboratory procedures and data 
involving this cell line has been published as part of numerous 
articles. Studies have shown that the cell line expresses a variety of 
tumor associated antigens (TAAs), including tyrosinase, TRP1, TRP2, 
gp100, MART-1, p15, gp75, mutated beta-catenin, and p53. However, 888-
mel does not normally express the MAGE 1, 2, or 3 TAAs. Many melanoma 
cell lines are HLA-A2 restricted, but the 888-mel cell line is HLA-A2 
negative. The HLA class I typing for this cell line is as follows: HLA-
A0101, A2402, B55, B62, Cw5201, Cw55, DRbl*1502, DRbl*1610, DQbl*0601, 
DRb5*0102, DRb5*0203. 888-mel is a validated source of HLA class I 
peptides utilized in screens that test the reactivity of TIL cultures 
that are candidates for adoptive immunotherapy trials. 888-mel is also 
a standard cell line for studying immune responses in cancer, 
particularly T cell responses. Other experiments show that roscovitine, 
a cyclin-dependent kinase inhibitor, can induce apoptosis in the 888-
mel cell line, so these cells may be useful in various cell death 
studies.

[[Page 31792]]

Applications

     Research tool for investigating the key immune responses 
required to mediate the remission of metastatic melanoma in order to 
identify the immune cell types necessary to produce an effective 
immunotherapy.
     Research tool for investigating the tumor associated 
antigens that contribute to the dampening of the immune response in 
many melanoma tumors so that researchers can better understand how to 
boost immunogenicity against these antigens.
     Source material for tumor associated peptides that could 
serve as melanoma vaccine candidates or utilized to determine the 
reactivity of tumor infiltrating lymphocyte (TIL) cultures being 
considered for clinical trials.
     Source material for the development of TIL cultures for 
use in adoptive immunotherapy protocols to treat melanoma patients.

Advantages

     Cell line is derived from a melanoma patient that 
underwent complete tumor remission: Immune cell cultures capable of 
treating melanoma patients in adoptive immunotherapy protocols could be 
derived from the tumor associated antigen epitopes found on the 888-mel 
cell line. This cell line may be a source of novel antigenic peptides 
capable of triggering immune responses in melanoma patients that lead 
to tumor regression or stabilization. 888-mel cells have been shown to 
retain many features of primary melanoma samples, including the 
expression of common tumor associated antigens.
     888-mel is an HLA-A2 negative cell line: A majority of the 
cancer vaccines and immunotherapies developed to date have focused on 
utilizing HLA-A2 restricted tumor epitopes since this HLA allele is 
largely expressed in the human population. However, therapies 
restricted to HLA-A2 recognition will not be successful in melanoma 
patients that do not express this allele. For these patients, 
additional therapies are needed that are directed against melanoma 
tumor epitopes presented by different HLA alleles.
     The 888-mel cell line has been well characterized through 
multiple years of study and is a fundamental cell line for melanoma 
studies: The collection of tumor associated antigens expressed by this 
cell line have been determined through multiple studies, many of which 
were performed by researchers in the inventors' laboratory. A 
significant amount of data has also been compiled detailing the immune 
responses triggered by 888-mel cells.
    Inventors: Steven A. Rosenberg (NCI) et al.

Selected Publications

    1. J Weber et al. Expression of the MAGE-1 tumor antigen is up-
regulated by the demethylating agent 5-aza-2\1\-deoxycytidine. Cancer 
Res. 1994 Apr 1; 54(7):1766-1771. [PubMed: 7511051]
    2. PF Robbins et al. Recognition of tyrosinase by tumor-
infiltrating lymphocytes from a patient responding to immunotherapy. 
Cancer Res. 1994 Jun 15; 54(12):3124-3126. Erratum in: Cancer Res. 1994 
Jul 15; 54(14):3952. [PubMed: 8205528]
    3. PF Robbins et al. Multiple HLA class II-restricted melanocyte 
differentiation antigens are recognized by tumor-infiltrating 
lymphocytes from a patient with melanoma. J Immunol. 2002 Nov 15; 
169(10):6036-6047. [PubMed: 12421991]
    Patent Status: HHS Reference No. E-070-2010/0--Research Tool. 
Patent protection is not being pursued for this technology.
    Licensing Status: Available for licensing under a Biological 
Materials License Agreement.
    Licensing Contact: Samuel E. Bish, PhD; 301-435-5282; 
[email protected].
    Collaborative Research Opportunity: The Surgery Branch, National 
Cancer Institute, is seeking statements of capability or interest from 
parties interested in collaborative research to carry out genotypic as 
well as phenotypic analysis of the 888-mel cell line in order to better 
understand the nature of tumor cells that respond to therapy. In 
addition, this cell line can be used as a target of humoral or cell 
mediated immune responses as a part of studies characterizing the 
nature of immune responses directed against tumor cells. Please contact 
John Hewes, PhD at 301-435-3131 or [email protected] for more 
information.

UOK171, A Spontaneous Clear Cell Type Renal Cell Carcinoma (ccRCC) 
Human Cell Line Derived From a Surgically Removed Tumor

    Description of Invention: Scientists at the National Institutes of 
Health (NIH) have developed a renal cell carcinoma (RCC) cell line 
designated UOK171 from the resected tumor of a patient diagnosed with 
stage IV high nuclear grade clear cell type renal cell carcinoma 
(ccRCC). The UOK171 cell line was immortalized spontaneously by mincing 
the resected tumor into pieces followed by propagation of the cells 
over more than twenty generations. One of the most prominent 
characteristics of this cell line is its intact, nonmutated von Hippel-
Lindau (VHL) tumor suppressor gene. In the majority of sporadic and 
hereditary ccRCC cases, the VHL gene is functionally disrupted due to 
hypermethylation or the gene is completely lost. Thus, the UOK171 cell 
line is very useful as a positive control for VHL gene expression in 
studies of the genetic and molecular mechanisms underlying advanced 
ccRCC, a disease for which there is no effective treatment. 
Specifically, this cell line has been used as a non-methylated control 
cell line in studying the effects of 5-Aza-dCyd and Zebularine on VHL 
re-expression from methylated-VHL cell line models. These agents do not 
affect the methylation status of the VHL gene in UOK171. This cell line 
also exhibits decreased fibroblast growth factor 5 (FGF5) expression, 
unbalanced chromosome 3 translocations, translocations involving 
chromosome 14, the losses of chromosome 14 and 22, and chromosome 
structural aberration 1(8) (q10). UOK171 is also one of the 40-member 
cell lines in the National Cancer Institute (NCI) Urologic Oncology 
Branch (UOB) Tumor Cell Line Repository.

Applications

     Research tool for investigating the underlying molecular 
mechanisms contributing to advanced ccRCC, including the identification 
of new RCC tumor antigens for immunotherapy.
     Research tool for studying the methylation status of genes 
involved in ccRCC to reveal the genetic processes occurring in ccRCC 
tissues that may contribute to advanced disease.
     Positive control cell line for VHL gene expression and 
function studies, including cytogenetics, gene mutation research, and 
examination of chromosomal structural abnormalities that may contribute 
to ccRCC.
     Research tools for testing the activity of potential anti-
cancer drugs against ccRCC, a disease which has no effective treatment 
options.
     Possible starting material for developing a cancer vaccine 
against RCC.

Advantages

     Cell line is derived from a ccRCC patient: These cell 
lines are anticipated to retain many features of primary ccRCC samples 
and novel ccRCC antigens identified from this cell line are likely to 
correlate with antigens expressed on human ccRCC tumors. Studies 
performed using these cell lines may have a direct correlation to the 
initiation, progression, treatment, and prevention of ccRCC in humans.

[[Page 31793]]

     Expresses a non-mutated VHL gene: In the majority of 
advanced ccRCC patients the VHL gene has been mutated or deleted. The 
UOK171 cell line represents a tool that can be utilized to study the 
impact of this VHL gene and various mutations on advanced ccRCC.
     Molecular and genetic features are well characterized: 
This cell line is part of NCI Urologic Oncology Branch's Tumor Cell 
Line Repository. The inventor has elucidated many physical 
characteristics of the cell line, including chromosomal attributes and 
important ccRCC genes, under various conditions.
    Inventor: W. Marston Linehan (NCI).

Related Publications

    1. WG Alleman et al. The in vitro and in vivo effects of re-
expressing methylated von Hippel-Lindau tumor suppressor gene in clear 
cell renal carcinoma with 5-Aza-2'-deoxycytidine. Clin Cancer Res. 2004 
Oct 15; 10(20):7011-7021. [PubMed: 15501981]
    2. CP Pavlovich et al. Patterns of aneuploidy in stage IV clear 
cell renal carcinoma revealed comparative genomic hybridization and 
spectral karyotyping. Genes Chromosomes Cancer. 2003 Jul; 37(3):252-
260. [PubMed: 12759923]
    3. K Hanada et al. Identification of fibroblast growth factor-5 as 
an overexpressed antigen in multiple human adenocarcinomas. Cancer Res. 
2001 Jul 15; 61(14):5511-5516. [PubMed: 11454700]
    4. C Stolle et al. Improved detection of germline mutations in the 
von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998; 
12(6):417-423. [PubMed: 9829911]
    5. P Anglard et al. Molecular and cellular characterization of 
human renal cell carcinoma cell lines. Cancer Res. 1992 Jan 15; 
52(2):348-356. [PubMed: 1345811]
    Patent Status: HHS Reference No. E-033-2010/0--Research Tool. 
Patent protection is not being pursued for this technology.
    Licensing Status: Available for licensing under a Biological 
Materials License Agreement.
    Licensing Contact: Samuel E. Bish, Ph.D.; 301-435-5282; 
[email protected].
    Collaborative Research Opportunity: The Urologic Oncology Branch, 
Center for Cancer Research, is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize UOK171. Please contact John Hewes, 
Ph.D. at 301-435-3131 or [email protected] for more information.

Delivery of Transthyretin (TTR) Across the Blood Brain Barrier as a 
Treatment for Alzheimer's Disease

    Description of Invention: The invention describes products and 
methods of treating Alzheimer's disease. Alzheimer's disease is 
characterized by the formation of amyloid plaques and tangles in areas 
of the brain critical for learning and memory. The products are a 
transthyretin and other blood brain barrier impermeable proteins 
transformed into blood brain barrier permeable forms by the coupling of 
an Inter-Cellular Adhesion Molecule-1 (ICAM-1) targeting agent. 
Transthyretin binds to, and inhibits amyloid protein from forming 
plaque deposits. Deposition of amyloid is thought to underlie the 
disease pathology of Alzheimer's. Thus, this invention treats 
Alzheimer's by inhibiting the formation of amyloid plaques, which 
normally would result in amyloid plaque formation, inflammation, and 
neuronal cell death.

Applications

     Therapeutic for Alzheimer's disease.
     Therapeutic for other amyloid-related diseases.
    Development Status: Early stage.
    Market: As of 2007 over 5 million people in America are living with 
Alzheimer's disease.
    Inventors: Juan Marugan et al. (NHGRI)
    Patent Status: U.S. Provisional Application No. 61/286,205 filed 14 
Dec 2009 (HHS Reference No. E-268-2009/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contact: Steve Standley, Ph.D.; 301-435-4074; 
[email protected].
    Collaborative Research Opportunity: The NIH Chemical Genomics 
Center (NCGC) is open to collaborating in order to further develop this 
invention. Please contact Dr. Juan Marugan at [email protected] for 
more information about collaborative research opportunities.

Vaccines Comprising Sand Fly Salivary Proteins for Control of 
Leishmania Infection

    Description of Invention: This invention relates to the use of 
several peptides from the salivary glands of various sand fly species 
for the control of leishmania infection. Many of these peptides were 
shown to be effective in eliciting potent immune responses in animal 
models and are excellent candidates for the development of vaccines 
against the disease. A vaccine comprising one of the peptides was used 
to protect mice challenged with parasites and salivary gland 
homogenates. A DNA vaccine containing the cDNA for this same peptide 
also provided protection that lasted at least 3 months after 
immunization and produced both intense humoral and delayed-type 
hypersensitivity reactions. Other experiments have shown that B cell-
deficient mice immunized with the plasmid vaccine also successfully 
controlled leishmania infection. Current in-vivo studies continue to 
explore the use of these sand fly salivary peptides for use as animal 
vaccines.
    Leishmania parasites are transmitted to their vertebrate hosts by 
infected sand fly bites. Sand fly saliva helps to enhance infection but 
immunity to the saliva protects against the infection, allowing the 
possibility of vaccine development. A number of major salivary proteins 
from sand fly species such as Lutzomyia longipalpis, Phlebotomus 
ariasi, and Phlebotomus perniciosus are claimed in the invention.
    Leishmania infection affects as many as 12 million people 
worldwide, with 1.5-2 million new cases each year. Control of this 
disease will be a major milestone for public health efforts in endemic 
areas of the world. The current invention provides a potential means to 
achieve widespread vaccination that may lead to significantly control 
of the disease in areas such as South America, South Asia, and the 
Mediterranean where it is still a significant health problem. An 
effective veterinary vaccine will be of benefit to veterinary medicine 
and may pave the way for human vaccines against Leishmaniasis. The 
vaccination of animals may also have a positive impact on the 
epidemiology of the disease by reducing the number of animal reservoirs 
and the possibility of human infection.

Applications

     Vaccines to control leishmania infection.
     Use of peptides to elicit potent immune responses.
    Development Status: Early stage.
    Inventors: Jesus G. Valenzuela et al. (NIAID).

Related Publications

    1. Oliveira F, Jochim RC, Valenzuela JG, Kamhawi S. Sand flies, 
Leishmania, and transcriptome-borne solutions. Parasitol Int. 2009 Mar; 
58(1):1-5. [PubMed: 18768167]
    2. Valenzuela JG, Garfield M, Rowton ED, Pham VM. Identification of 
the most

[[Page 31794]]

abundant secreted proteins from the salivary glands of the sand fly 
Lutzomyia longipalpis, vector of Leishmania chagasi. J Exp Biol. 2004 
Oct; 207(Pt 21):3717-3729. [PubMed: 15371479]
    3. Valenzuela JG, Belkaid Y, Garfield MK, Mendez S, Kamhawi S, 
Rowton ED, Sacks DL, Ribeiro JM. Toward a defined anti-Leishmania 
vaccine targeting vector antigens: Characterization of a protective 
salivary protein. J Exp Med. 2001 Aug 6; 194(3):331-342. [PubMed: 
11489952]
    4. Belkaid Y., Valenzuela JG, Kamhawi S., Rowton E., Sacks DL, 
Ribeiro JM. Delayed-type hypersensitivity to Phlebotomus papatasi sand 
fly bite: An adaptive response induced by the fly? Proc Natl Acad Sci U 
S A. 2000 Jun 6; 97(12):6704-6709. [PubMed: 10841567]

Patent Status

     U.S. Patent Application No. 60/422,303 filed October 29, 
2002 (HHS Ref. No. E-285-2002/0-US-01).
     PCT Application No. PCT/US2003/03453 filed October 29, 
2003 (HHS Ref. No E-285-2002/0-PCT-02). Application filed in the 
following countries: the USA, Europe, Brazil, Japan, Mexico, India and 
Israel.
     U.S. Patent No. 7,485,386 issued February 3, 2009 (HHS 
Reference No. E-285-2002/0-US-03).
     European Patent Number No. 1572968 issued April 22, 2009 
(HHS Reference No. E-285-2002/0-EP-04).
     PCT Application No. PCT/US2009/042980 filed May 05, 2009 
(HHS Reference No. E-189-2008/2-PCT-01).
     U.S. Patent Application No. 60/421,327 filed September 19, 
2002 (HHS Ref. No. E-130-2002/0-US-01).
     PCT Application No. PCT/US03/29833 filed September 18, 
2003 (HHS Ref. No. E-130-2002/0-PCT-02). Application filed in the 
following countries: USA, Europe, Brazil, Japan, Mexico, India and 
Israel.
    Licensing Status: Available for licensing.
    Licensing Contact: John Stansberry, PhD; 301-435-5236; 
[email protected].
    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 
``Vaccines Comprising Sand Fly Salivary Proteins for Control of 
Leishmania Infection''. Please contact Dana Hsu at 301-451-3521 for 
more information.

    Dated: May 26, 2010.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 2010-13480 Filed 6-3-10; 8:45 am]
BILLING CODE 4140-01-P