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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.

## A549 Cells: A Well-Characterized Lung Carcinoma Cell Line Utilized for a Variety of Scientific Studies, Including Adenovirus Production and Testing

*Description of Technology:*                     Scientists at the National Institutes of Health have developed a cell line designated A549 that was derived from explanted cultures of human lung cancer tissue. The A549 cell line has been tested under the guidance of the United States Food and Drug Administration (FDA) so, under current Good Manufacturing Practices (GMP), these cells may be suitable for use in manufacturing constructs for use in clinical trials. The A549 cell line has also been found to be suitable for adenovirus production, most notably replicating adenovirus constructs that do not require complementation by the viral oncogene, early region 1A (E1A), which is responsible for viral gene transcription. This cell line is further utilized as a negative control in assays to measure the replication of adenoviruses that lack E1A and as a target cell line to detect replication competent adenoviruses (RCA). A549 cells have been well characterized through their use in a wide variety of molecular studies, such as anti-tumor drug permeability and                           ( print page 23728)                        efficacy analysis, infection assays, respiratory immunotoxicity tests, cell senescence studies, and cytokine expression profiling. These cells can also be utilized to study a variety of molecular characteristics for human tumors in culture.                

*Application:*
      - Cell bank tested under cGMP-compliance regulations and used to produce adenoviruses for use in clinical trials.
      - Research tool to analyze the efficacy of potential anti-cancer agents to devise better cancer treatments for malignancies, such as non-small cell lung cancer (NSCLC).
      - Research tool to study the infectivity of viruses that cause asthma in order to develop better asthma treatments.
      - Standard research tool to analyze a variety of molecular biology procedures, for example, cell senescence, cytokine induction, protein expression, apoptosis, and receptor-ligand interactions.

*Advantages:*
      - A549 cells are a well-characterized standard among the human lung carcinoma/alveolar cell lines used in molecular biology.
      - The A549 cells stored at the NIH were tested under the guidance of the FDA's cGMP regulations.
      - The A549 cells stored at the NIH may be suitable for producing adenoviruses that can be used in clinical trials and analyzing adenoviral-based therapies and vaccine strategies.

*Inventors:*                     Wade P. Parks, Donald J. Giard, and Stuart Aaronson (all formerly NCI).                

*Publication:*                     DJ Giard et al. In vitro cultivation of human tumors: Establishment of cell lines derived from a series of solid tumors. J Natl Cancer Inst. 1973 Nov; 51(5):1417-1423.                

*Patent Status:*                     HHS Reference No. E-129-2009/0—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;                     *bishse@mail.nih.gov*.                

## Mobilizing the Body to Fight Cancer: T Cell Receptors Specific for the Tumor Antigen Survivin

*Description of Technology:*                     A major drawback of current chemotherapy-based cancer treatments is the harsh side-effects associated with many cancer drugs. Thus, there is an urgent need to develop new therapeutic strategies combining fewer side-effects and more specific anti-tumor activity. Immunotherapy is a promising new cancer therapeutic approach that directs 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.

Scientists at the National Institutes of Health (NIH) have developed genetically modified T cells, which possess TCRs that specifically recognize human survivin, a tumor antigen expressed in many adult and pediatric cancers that is absent from most normal tissues. Non-human T cells that recognized human survivin peptides with high affinity in the context of human leukocyte antigen (HLA) alleles were identified. Then, using recombinant DNA technology, the survivin-specific TCRs from the non-human T cells were fused to human TCR backbones and expressed in human T cells. The resulting survivin-specific human T cells could prove to be powerful new immunotherapeutic tools for attacking survivin-expressing tumors after infusion into patients.

*Applications:*
      - Immunotherapeutics to treat and/or prevent the reoccurrence of a variety of human cancers that overexpress human survivin by inserting survivin-specific TCR sequences into patient T cells
      - A drug component of a combination immunotherapy regimen aimed at targeting the specific tumor-associated antigens expressed by cancer cells within individual patients.

*Advantages:*
      - Survivin is overexpressed in virtually all cancers, including lung, colon, breast, pancreatic, stomach, liver, ovarian and prostate cancer, as well as in melanoma and hematopoietic malignancies, but this antigen is not expressed on normal cells. Thus, survivin is an ideal antigen for targeted treatment. Anti-survivin TCR immunotherapy could treat a host of cancer types while reducing the side-effects of treatment.
      - The survivin-specific TCR sequences can be derived in non-human species in the context of a wide variety of HLA molecules and, thus, TCRs specific for each patient's HLA profile can be generated rapidly.
      - The survivin-specific T cells should not be rejected by a patient's immune system since the survivin-specific TCR sequences are fused to a human TCR backbone.

*Development Status:*                     This technology is in the pre-clinical stage of development. The inventors plan to initiate a clinical trial in the next 6-12 months.                

*Market:*                     Cancer continues to be a medical and financial burden on U.S. public health. According to U.S. 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:*                     Crystal L. Mackall                     *et al.*                     (NCI).                

*Publications:*

1. Manuscript in preparation.

2. CJ Cohen et al. Recognition of fresh human tumor by human peripheral blood lymphocytes transduced with a bicistronic retroviral vector encoding a murine anti-p53 TCR. J Immunol. 2005 Nov 1;175(9):5799-5808. (Erratum in: J Immunol. 2006 Oct 15;177(8):5746.)

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. 61/140,338 filed 23 Dec 2008 (HHS Reference No. E-325-2008/0-US-01)                

*Licensing Status:*                     Available for licensing.                

*Licensing Contact:*                     Samuel E. Bish, PhD; 301-435-5282;                     *bishse@mail.nih.gov*.                

*Collaborative Research Opportunity:*                     The National Cancer Institute Pediatric Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize genetically engineered lymphocytes with specificity for human survivin. Please contact John D. Hewes, PhD at 301-435-3121 or                     *hewesj@mail.nih.gov*                     for more information.                

## Fused Azepinone Cyclin Dependent Kinase Inhibitors

*Description of Technology:*                     The invention describes a class of cyclin dependent kinase (CDK) inhibitors that have anti-proliferative activity in human tumor cell lines. CDKs are important in                           ( print page 23729)                        the control of the cell cycle and alterations in CDK expression, function, or regulation and are associated with diseases characterized by cellular proliferation. Increasing CDK activity has been reported in many cancers. Likewise, the loss of inhibitory activity has been observed in a wide variety of primary human tumors and human tumor-derived cell lines, including lung, breast, brain, bone, skin, bladder, kidney, ovary, liver, colon, and pancreas as well as in leukemia. These compounds have also been found to potently inhibit GSK3beta activity which has recently been linked to a variety of cellular processes and several disparate areas of biology. In particular, GSK3beta activity has been strongly implicated in Alzheimer's as well as cardiac failure. Thus, the compounds of this invention offer unique opportunities for a variety of indications.                

*Applications:*                     CDK/GSK3beta inhibitor therapeutics for the treatment of several indications including various cancers, neurodegenerative diseases, and cardiac conditions.                

*Development:*                     Pre-clinical stage of development.                

*Inventors:*                     Daniel W. Zaharevitz                     *et al.*                     (NCI).                

*Publication:*                     DW Zaharevitz et al. Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res. 1999 Jun 1;59(11):2566-2569.                

*Patent Status:*                     HHS Reference No. E-025-1998/0—                
      - U.S. Patent No. 6,610,684, issued August 26, 2003;
      - Australian Patent Nos. 780528 and 778735, issued March 24, 2005 and December 16, 2004;
      - Canada Patent Application No. 2335115, filed June 16, 1999;
      - Japanese Patent Application No. 2000-554735, filed June 16, 1999;
      - United Kingdom Patent No. 1086105, validated March 01, 2006 ((E-025-1998/0-GB-09);
      - French Patent No. 1086105, validated March 01, 2006 (E-025-1998/0-FR-10); and
      - German Patent No. 69930120.3, validated March 16, 2006 (E-025-1998/0-DE-11).

*Licensing Status:*                     Available for licensing.                

*Licensing Contact:*                     Whitney A. Hastings; 301-451-7337;                     *hastingw@mail.nih.gov*.                

Dated: May 13, 2009.

Richard U. Rodriguez,

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

[FR Doc. E9-11706 Filed 5-19-09; 8:45 am]

BILLING CODE 4140-01-P