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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.

      ( print page 53268)    

# 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.

## Engineered Biological Pacemakers

*Description of Invention:*                     A common symptom of many heart diseases is an abnormal heart rhythm or arrhythmia. While effectively improving the lives of many patients, implantable pacemakers have significant limitations such as limited power sources, risk of infections, potential for interference from other devices, and absence of autonomic rate modulation.                

                    The technology consists of biological pacemakers engineered to generate normal heart rhythm. The biological pacemakers include cardiac cells or cardiac-like cells derived from embryonic stem cells or mesenchymal stem cells. The biological pacemakers naturally integrate into the heart. Their generation of rhythmic electric impulses involves coupling factors, such as cAMP-dependent PKA and Ca2+                    -dependent CaMK II, which are regulatory proteins capable of modulating/enhancing interactions (                    *i.e.*                     coupling) of the sarcoplasmic reticulum-based, intracellular Ca2+                     clock and the surface membrane voltage clock, thereby converting irregularly or rarely spontaneously active cells into pacemakers generating rhythmic excitations.                

*Applications:*                     This technology can be utilized in heart disease characterized by arrhythmia or situations requiring an implantable cardiac pacemaker.                

*Advantages:*                     In contrast to current implantable cardiac pacemaker technology, this technology is not externally powered, has a lower risk of infection, has decreased potential for interference from other devices, and has full autonomic rate modulation.                

*Development Status:*                     Early stage.                

*Inventors:*                     Victor A. Maltsev                     *et al.*                     (NIA).                

*Publications:*

                    1. VA Maltsev and EG Lakatta. Synergism of coupled subsarcolemmal Ca2+                     clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model. Am J Physiol Heart Circ Physiol. 2009 Mar;296(3):H594-H615.                

                    2. VA Maltsev and EG Lakatta. Dynamic interactions of an intracellular Ca2+                     clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function. Cardiovasc Res. 2008 Jan 15;77(2):274-284.                

*Patent Status:*                     U.S. Provisional Application No. 61/180,491 filed 22 May 2009 (HHS Reference No. E-134-2009/0-US-01).                

*Licensing Status:*                     Available for licensing.                

*Licensing Contact:*                     Fatima Sayyid, M.H.P.M.; 301-435-4521;                     *sayyidf@mail.nih.gov*.                

*Collaborative Research Opportunity:*                     The National Institute on Aging, Cellular Biophysics 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 at 301-496-0477 or                     *conleyv@mail.nih.gov*                     for more information.                

## Sensitizing Cancer Cells to DNA Targeted Therapies

*Description of Invention:*                     Chk2 is a protein kinase activated in response to DNA double strand breaks. In normal tissues, Chk2 phosphorylates and thereby activates substrates that induce programmed cell death, or apoptosis, via interactions with p53, E2F1, PML proteins. In cancer tissues, where apoptosis is suppressed, Chk2 phosphorylates and inactivates cell cycle checkpoints (via interactions with Cdc25, phosphatases and Brca1 proteins), which allows cancer cells to repair and tolerate DNA damage. Hence, Chk2 inhibitors would be expected to protect normal tissues by reducing apoptosis, and to sensitize cancer cells to DNA-targeted agents.                

*Applications:*
      - Combination with DNA targeted chemotherapeutic agents for the treatment of cancers.
      - Single agents therapy for cancers with endogenously activated (“addicted to”) Chk2.
      - Antiviral agent against hepatitis, herpes viruses and retroviral infections (HIV).

*Advantages:*                     Selective enhancement of the antiproliferative and proapoptotic activities of DNA targeted chemotherapeutic agents in tumors with inactivated p53, while protection of normal tissues by blocking p53-mediated apoptosis (“side effects”) induced by the DNA targeted agents.                

*Development Status:*                     Optimization of chemical structure for improving drug delivery and pharmacokinetics.                

*Inventors:*                     Yves G Pommier                     *et al.*                     (NCI).                

*Related Publications:*

1. AG Jobson, JH Cardellina 2nd, D Scudiero, S Kondapaka, H Zhang, H Kim, R Shoemaker, Y Pommier. Identification of a Bis-guanylhydrazone [4,4'-Diacetyldiphenylurea-bis(guanylhydrazone); NSC 109555] as a Novel Chemotype for Inhibition of Chk2 Kinase. Mol Pharmacol. 2007 Oct;72(4):876-884.

2. AG Jobson, GT Lountos, PL Lorenzi, J Llamas, J Connelly, D Cerna, JE Tropea, A Onda, G Zoppoli, S Kondapaka, G Zhang, NJ Caplen, JH Cardellina, SS Yoo, A Monks, C Self, DS Waugh, RH Shoemaker, Y Pommier. Cellular inhibition of Chk2 kinase and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019. J Pharmacol Exp Ther. 2009 Sep 9; In press (Epub ahead of print).

3. GT Lountos, JE Tropea, D Zhang, AG Jobson, Y Pommier, RH Shoemaker, DS Waugh. Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor. Protein Sci. 2009 Jan;18(1):92-100.

*Patent Status:*                     U.S. Patent Application No. 11/989,737 filed 29 Jan 2008 (HHS Reference No. E-211-2005/0-US-06); Related international patent application filings.                

*Licensing Status:*                     Available for licensing.                

*Licensing Contact:*                     Betty B. Tong, Ph.D.; 301-594-6565;                     *tongb@mail.nih.gov*.                

*Collaborative Research Opportunity:*                     The National Cancer Institute, Laboratory of Molecular Pharmacology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or                     *hewesj@mail.nih.gov*                     for more information.                

      ( print page 53269)    
Dated: October 5, 2009.

Richard U. Rodriguez,

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

[FR Doc. E9-24869 Filed 10-15-09; 8:45 am]

BILLING CODE 4140-01-P