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###### Department of Health and Human Services

###### National Institutes of Health

# 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.                    

## An XMRV Tool Box: Expression Plasmids, Genes, and Proteins for All Components of the Xenotropic Murine Leukemia Virus-Related Virus (XMRV)

*Description of Invention:*                     The xenotropic murine leukemia virus-related virus (XMRV) has been implicated as a possible causative agent of prostate cancer and chronic fatigue syndrome (CFS). Scientists at the National Institutes of Health (NIH) and Science Applications International Corporation in Frederick, MD (SAIC-Frederick) have developed sixty four (64) protein expression plasmids for components of XMRV. One or more                           ( print page 52759)                        XMRV proteins made available through these expression plasmids could have clinical relevance to diagnosing or treating human disease. The work to develop this technology was performed in the Protein Expression Laboratory at SAIC-Frederick in collaboration with expert retrovirologists from the National Cancer Institute's Frederick, MD campus, a site well-positioned to develop these expression plasmids from initial cloning to final validations. The development of these XMRV tools is expected to save researchers months in laboratory production time and thousands of dollars in labor costs.                

                    The XMRV strain utilized to generate these expression plasmids is a reference strain isolated from a human patient. Each expression plasmid encodes one of the ten proteins that comprise the XMRV retrovirus (matrix, p12, capsid, nucleocapsid, protease, reverse transcriptase, integrase, surface, transmembrane, and envelope). Nine of the ten XMRV proteins expressed by these clones have been successfully purified in large quantities using scale-up processes. The expression vectors were generated utilizing the Gateway® cloning system and consist of Gateway® entry clones, bacterial (                    *Escherichia coli*) expression clones, baculovirus expression clones, and mammalian expression clones. Expression of the appropriate XMRV protein from its corresponding expression clone has been confirmed. The entry clones have been validated for Gateway® subcloning and the baculovirus clones have been validated for baculovirus production and can be transposed into baculoviral genomes. The plasmids have been fully mapped and sequenced and contain one or more elements to facilitate laboratory use, such as antibiotic resistance genes, specialized promoter sequences, maltose-binding protein and His tags, TEV protease sites, Kozak-ATG sequences, signal peptides, and other elements.                

*Applications:*
      - Research tool whose large-scale production capability can be utilized to develop serological assays for detecting XMRV and other retroviruses to possibly establish these viruses as causative agents for CFS, prostate cancer, and other diseases with unknown origins.
      - Collection of research tools that could be utilized to develop a complete set of diagnostic assays for detecting each of these XMRV proteins in patient samples.
      - Research tool to serve as a platform for developing therapeutic moieties, such as neutralizing antibodies and other biologics, for treating prostate cancer, chronic fatigue syndrome, and any other disease where XMRV is later identified as the causative agent.
      - A logical starting point for generating clinical-grade XMRV constructs for use in clinical vaccine, immunotherapy, and gene therapy studies.

*Advantages:*
      -  First complete set of plasmids available for the expression of each XMRV protein individually:                      Researchers looking to study XMRV can save months of time and thousands of dollars by using this set of XMRV tools. The plasmids have been fully-mapped and validated for protein expression. This plasmid portfolio offers a variety of vectors for expressing these XMRV proteins including Gateway® entry clones, bacterial vectors, baculoviral vectors, and mammalian expression systems.                
      -  Clones were developed from an XMRV isolate taken from a patient with a confirmed XMRV infection:                      The proteins produced by these expression plasmids are anticipated to have direct clinical applicability to human XMRV diseases.                
      -  Launching pad for any commercial entity desiring to develop diagnostics or therapeutics for XMRV:                      This technology is likely to give companies in the prostate cancer arena or the emerging chronic fatigue syndrome market a competitive advantage for developing anti-XMRV products faster than competitors. The molecular targets needed as a starting point for therapeutic development are provided by this technology.                

*Market:*                     Apart from cancers of the skin, prostate cancer is the most common form of cancer found in men, especially in men over the age of 65. In the United States, an estimated 200,000 men are diagnosed with prostate cancer each year and around 100 men die of the disease daily. About $5 billion dollars is spent annually on treatments for prostate cancer.                

The Center for Disease Control (CDC) estimates that over 1 million Americans are living with chronic fatigue syndrome and approximately 80% of these individuals are undiagnosed. This debilitating disease likely affects over 17 million people worldwide and the cause of CFS is currently unknown. Those individuals diagnosed with CFS are a vocal patient group desiring expanded research into the cause of CFS and possible treatments and/or cures. In the United States alone, an estimated $9 billion dollars is lost annually due to CFS-induced decreases in worker productivity.

*Inventors:*                     Dominic Esposito (SAIC), Alan Rein (NCI), Stuart Le Grice (NCI), James Hartley (SAIC), William Gillette (SAIC), Ralph Hopkins III (SAIC), Troy Taylor (SAIC).                

*Selected Publications:*

                    1. VC Lombardi,                     *et al.*                     Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009 Oct 23;326(5952):585-589. [PubMed: 19815723]                

                    2. A Urisman,                     *et al.*                     Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2006 Mar;2(3):e25. [PubMed: 16609730]                

*Patent Status:*                     HHS Reference No. E-155-2010/0—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;                     *bishse@mail.nih.gov.*

## Tempol: A Commercially Available Nitroxide as Cancer Therapeutics

*Description of Invention:*                     The invention is the discovery that a commercially available stable nitroxide, namely TEMPOL can effectively reduce the level of hypoxia-inducible transcription factor (HIF)-2α. Elevated HIF-2α is associated with clear cell kidney cancer characterized by mutation of the VHL tumor suppressor gene and with many other cancers. Therefore, TEMPOL can potentially be developed into a cancer drug to treat patients with elevated HIF-2α, whether due to compromised VHL function or not.                

*Applications:*                     Known compound (TEMPOL) found to be effective in treating several cancers.                

*Advantages:*                     Animal data confirms effectiveness of TEMPOL against cancer support.                

*Development Status:*                     Pre-clinical,                     *In vivo*                     animal data available.                

*Target Market:*                     The potential drug will target a population that suffers from genetic diseases such as inherited von Hippel-Lindau (VHL) disease, which is associated with elevated expression of HIF-2α and patients with kidney and other cancers characterized by elevation of HIF-2α. Inherited VHL disease is a cancer syndrome caused by germ line mutations of the VHL tumor suppressor gene. VHL is characterized by angiomas and hemangioblastomas of the brain, spinal cord, and retina. These can lead to cysts and/or tumors of the kidney, pancreas, and adrenal glands (                    *e.g.,*      ( print page 52760)                        pheochromocytoma and endolymphatic sac tumors).                

                    Renal clear cell carcinoma (RCC) develops in approximately 75% of VHL patients by age 60 and is a leading cause of death in this population. Inactivation (mutation or methylation) of the VHL gene is associated with greater than 90% of all clear cell RCC (including sporadic cases) (Nickerson                     *et al.*                     Clin Cancer Res 2008;14:4726-34). Thus, subjects with compromised VHL function represent a significant population that has or is at risk for developing cancer, including RCC. There is data that HIF-2α may be important in all or most cancers (Franovic                     *et al.*                     Proc Natl Acad Sci U S A 2009;106:21306-11).                

*Inventors:*                     W. Marston Linehan (NCI), Tracey A. Rouault (NICHD), James B. Mitchell (NCI), Murali K. Cherukuri (NCI).                

*Patent Status:*                     U.S. Provisional Application No. 61/265,194 filed 30 Nov 2009 (HHS Reference No. E-133-2009/0-US-01).                

*Licensing Status:*                     Available for licensing.                

*Licensing Contact:*                     Sabarni Chatterjee, Ph.D.; 301-435-5587;                     *chatterjeesa@mail.nih.gov.*

*Collaborative Research Opportunity:*                     The Center for Cancer Research, Urologic Oncology Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of Tempol to target HIF-2α in cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or                     *hewesj@mail.nih.gov*                     for more information.                

## Chimeric Anti-human ROR1 Monoclonal Antibodies

*Description of Invention:*                     Available for licensing are mouse anti-human receptor tyrosine kinase-like orphan receptor 1 (ROR1) monoclonal antibodies (mAbs). ROR1 is a signature cell surface antigen for B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) cells, two incurable B-cell malignancies that are newly diagnosed in approximately 15,000 and 3,500 patients per year, respectively, in the United States. Currently, there are no therapeutic mAbs that specifically target B-CLL or MCL cells. Anti-ROR1 mAbs may be linked to chemical drugs or biological toxins thus providing cytotoxic delivery to malignant B-cells and not normal cells. Additionally, these antibodies can be fused to radioisotopes and can be used to diagnose B-CLL and MCL malignancies.                

*Applications:*
      - B-CLL and MCL antibody therapeutics.
      - Method to diagnose B-CLL and MCL.

*Advantages:*                     Selective targeting to malignant B-CLL and MCL cells.                

*Development Status:*                     The technology is currently in the pre-clinical stage of development.                

*Market:*
      - The monoclonal antibody market is one of the fastest growing sectors of the pharmaceutical industry with a 48.1% growth between 2003 and 2004 and the potential to reach $30.3 billion in 2010. This growth rate is driven by the evolution of chimeric and humanized to fully humanized antibody therapeutics.
      - Approximately 18,500 patients with ROR1-expressing B-cell malignancies are newly diagnosed annually in the United States.

*Inventors:*                     Christoph Rader and Sivasubramanian Baskar (NCI).                

*Related Publications:*

                    1. S Baskar                     *et al.*                     Unique cell surface expression of receptor tyrosine kinase ROR1 in human B-cell chronic lymphocytic leukemia. Clin Cancer Res. 2008 Jan 15;14(2):396-404. [PubMed: 18223214]                

                    2. M Hudecek                     *et al.*                     The B-cell tumor associated antigen ROR1 can be targeted with T-cells modified to express a ROR1-specific chimeric antigen receptor. Blood. 2010 Aug 11; Epub ahead of print. [PubMed: 20702778]                

*Patent Status:*
      - U.S. Provisional Application No. 61/172,099 filed 23 Apr 2009 (HHS Reference No. E-097-2009/0-US-01).
      - PCT Application No. PCT/US10/32208 filed 23 Apr 2010 (HHS Reference No. E-097-2009/0-PCT-02).

*Licensing Status:*                     Available for licensing.                

*Licensing Contact:*                     Jennifer Wong; 301-435-4633;                     *wongje@mail.nih.gov.*

*Collaborative Research Opportunity:*                     The Center for Cancer Research, Experimental Transplantation and Immunology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-ROR1 mAbs, antibody-drug conjugates, radioimmunoconjugates, bispecific antibodies, and other therapeutic or diagnostic modalities. Please contact John D. Hewes, Ph.D. at 301-435-3121 or                     *hewesj@mail.nih.gov*                     for more information.                

Dated: August 23, 2010.

Richard U. Rodriguez,

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.

[FR Doc. 2010-21349 Filed 8-26-10; 8:45 am]

BILLING CODE 4140-01-P