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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.                               ( print page 56849)                            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. 

## Transgenic Mice With Conditionally-Enhanced Bone Morphogen Protein (BMP) Signaling: A Model for Human Bone Diseases 

*Description of Technology:*                     This technology relates to novel animal models of several human bone diseases that have been linked to enhanced BMP signaling. More specifically, this mouse model expresses a mutant receptor for BMP, known as Alk2 that is always actively signaling. This receptor is under the control of the Cre-loxP system, which allows control of expression of the mutant Alk2 in both a developmental and tissue-specific manner. As a result, the enhanced signaling conditions exhibited in multiple human bone-related diseases can be studied with the same animals.                 

*Applications:*                     The mouse model can be applied to the study of BMP signaling-related human diseases such as fibrodysplasia ossificans progressiva, which involves the postnatal transformation of connective tissue into bone. Another example of BMP signaling-related disease is Craniosynostosis, which involves the premature closing of the sutures in childhood so that normal brain and skull growth are inhibited. This mouse model can potentially be used in other human diseases where BMP signaling might play a pivotal role, for example cleft lip and cleft palate, breast cancer, osteoarthritis, lung fibrosis, multiple myeloma, juvenile polyposis, cephalic neural tube closure defects, diabetes and other types of blood glucose control problems, and pulmonary hypertension.                 

*Development Status:*                     Early-stage development.                 

*Inventors:*                     Yuji Mishina, Manas Ray, Greg Scott (NIEHS).                 

*Relevant Publications:*

                    1. T Fukada                     *et al.*                     Generation of a mouse with conditionally activated signaling through the BMP receptor, ALK2. Genesis. 2006;44:159-167.                 

                    2. L Kan                     *et al.*                     Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype. Am J Path. 2004 Oct;165(4):1107-1115.                 

                    3. EM Shore                     *et al.*                     A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressive. Nat Genet. 2006 May;38(5):525-527.                 

*Patent Status:*                     HHS Reference No. E-328-2008/0—Research Material. Patent protection is not being pursued for this technology.                 

*Licensing Status:*                     Available for non-exclusive licensing.                 

*Licensing Contact:*                     Steve Standley, Ph.D.; 301-435-4074;                     *sstand@mail.nih.gov*.                

## Production of Endotoxin Free TEV Protease 

*Description of Technology:*                     This technology relates to an efficient method of purifying proteins. More specifically, this technology relates to a method of obtaining an endotoxin-free `TEV protease,' a common name for a 27 kDa catalytic domain of the Nuclear Inclusion a (NIa) protein from Tobacco Etch Virus. TEV protease is a site-specific protease that can be used to cleave purified fusion proteins that have been engineered to contain a TEV protease cleavage site. This is typically done to enable stable expression and purification of a protein of interest. The technology consists of (a) the DNA construct (created by Dom Esposito) to allow expression of the protein in insect cells, (b) the insect cell line, and (c) the purification protocol. TEV protease itself is expressed as a fusion to MBP (Maltose Binding Protein) to enhance solubility.                 

*Advantages:*                     TEV protease expressed and produced in                     *E. coli*                     contains substantial amounts of endotoxin, which presents a barrier to use where the final purified product is required to be endotoxin-free. It is important to note that all proteins which are used for therapeutic purposes must have little or no endotoxin for safety reasons. The method of obtaining an endotoxin-free TEV protease is to express and purify TEV protease using a baculovirus/insect cell expression system, instead of                     *E. coli*                     which results in an endotoxin-free TEV protease.                

*Development Status:*                     Early stage development.                 

*Inventors:*                     William K. Gillette, Dominic Esposito, and Ralph Hopkins (SAIC/NCI).                 

*Relevant Publication:*                     RB Kapust and DS Waugh. Controlled intracellular processing of fusion proteins by TEV protease. Protein Expr Purif. 2000 Jul;19(2):312-318.                 

*Patent Status:*                     HHS Reference No. E-139-2008/0—Research Material. Patent protection is not being pursued for this technology.                 

*Licensing Status:*                     Available for non-exclusive licensing.                 

*Licensing Contact:*                     Steve Standley, PhD; 301-435-4074;                     *sstand@mail.nih.gov*.                

## Association of the ECHDCI/RNF146 Gene Region on Human Chromosome 6q With Breast Cancer Risk and Protection 

*Description of Technology:*                     The technology describes a genetic locus (ECHDC l/RNF146 gene region on human chromosome 6q) that may be predictive for risk of breast cancer in relatives of individuals diagnosed with breast cancer. Furthermore, the invention provides evidence that one or more polymorphism alleles in chromosome 6q22.33 indicates a lower risk or increased risk of developing breast cancer in individuals.                 

*Applications:*
      - The invention has the potential of being developed into a predictive diagnostic test, for people at a risk of breast cancer, together with other risk factors for the disease, such as age, parity, and other genetic contributions especially for predicting risk of breast cancer in individuals free of BRCA1 and BRCA2 polymorphism.
      - The invention may help to develop pharmaceuticals through elucidation of the contributing biochemical, etiologic pathway.

*Advantages:*                     This study was a clinical study in a cohort of individuals. Thus the relevance of the data is of considerable significance.                 

*Development Status:*                     Validation of the correlation between the polymorphisms and risk of breast cancer is ongoing using different cohorts.                 

*Inventors:*                     Bert Gold                     *et al.*                     (NCI).                 

*Patent Status:*                     U.S. Provisional Application No. 61/023,936 filed 28 Jan 2008 (HHS Ref. No. E-065-2008/0-US-01).                 

*Licensing Contact:*                     Surekha Vathyam, PhD; 301-435-4076;                     *vathyams@mail.nih.gov*.                 

## Novel Chemoattractant-Based Toxins to Improve Vaccine Immune Responses for Cancer and Infectious Diseases 

*Description of Technology:*                     Cancer is one of the leading causes of death in the United States and it is estimated that there will be more than half a million                           ( print page 56850)                        deaths caused by cancer in 2008. A major drawback of the current chemotherapy-based therapeutics is the cytotoxic side-effects associated with them. Thus there is a dire need to develop new therapeutic strategies with fewer side-effects. Immuno-therapy has taken a lead among the new therapeutic approaches. Enhancing the innate immune response of an individual has been a key approach for the treatment against different diseases such as cancer and infectious diseases.                 

This technology involves the generation of novel chemoattractant toxins that deplete the T regulatory cells (Treg) or other immunosuppressive or hyperactivated cells locally. Treg controls activation of immune responses by suppressing the induction of adaptive immune responses, particularly T cell responses. Immunosuppressive cells such as tumor infiltrating macrophages or NKT and other cells down regulate antitumor immune responses. The chemoattractant toxins consist of a toxin moiety fused with a chemokine receptor ligand, chemokines and other chemoattractants that enables specific targeting and delivery to the Treg cells. This technology is advantageous over the more harmful antibodies and chemicals that are currently used for the systemic depletion of Treg cells. The current technology can be used therapeutically in a variety of ways. They can be used together with vaccines to increase efficacy of the vaccine for the treatment of cancer, and can be used to locally deplete Treg cells or other immuno suppressive cells to induce cytolytic cell responses at the tumor site or to eliminate chronic infectious diseases such as HIV and tuberculosis. 

*Applications:*
      - New chemoattractant based toxins targeted towards Treg cells.
      - New chemoattractant based toxins targeted towards immunosuppressive NKT, and macrophages.
      - New chemoattractant based toxins targeted towards local depletion of hyperactivated CD4 T cells to treat autoimmune diseases.
      - Chemoattractant based toxins depleting Treg cells or other immunosuppressive cells causing enhanced vaccine immune responses.
      - Novel immunotherapy by increasing vaccine efficacy against cancer and infectious diseases.

*Market:*
      - 565,650 deaths from cancer related diseases estimated in 2008.
      - The technology platform involving novel chemo-attractant based toxins can be used to improve vaccine immune responses. The cancer vaccine market is expected to increase from $135 million in 2007 to more than $8 billion in 2012.
      - The technology platform has additional market in treating several other clinical problems such as autoimmune diseases.

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

*Inventors:*                     Arya Biragyn (NIA), Dolgor Bataar (NIA),                     *et  al.*

*Related Publications:*

1. Copy of manuscript from this technology can be provided once accepted for publication. 

2. M Coscia, A Biragyn. Cancer immunotherapy with chemoattractant peptides. Semin Cancer Biol 2004 Jun;14(3):209-218. 

                    3. R Schiavo                     *et  al.*                     Chemokine receptor targeting efficiently directs antigens to MHC class I pathways and elicits antigen-specific CD8+ T-cell responses. Blood 2006 Jun 15;107 (12):4597-4605.                 

*Patent Status:*                     U.S. Patent Application filed 28 Mar 2008, claiming priority to 30 Sep 2005 (HHS Reference No. E-027-2005/0-US-06).                 

*Licensing Status:*                     Available for non-exclusive or exclusive licensing.                 

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

*Collaborative Research Opportunity:*                     The NIA Laboratory of Immunology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize novel chemoattractant-based toxins. Please contact John D. Hewes, Ph.D. at 301-435-3121 or                     *hewesj@mail.nih.gov*                     for more information.                 

Dated: September 18, 2008. 

Richard U. Rodriguez, 

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

[FR Doc. E8-22889 Filed 9-29-08; 8:45 am] 

BILLING CODE 4140-01-P