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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                               ( print page 53434)                            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.                     

## Cyclized NGR Peptide for Tumor Targeting 

*Description of Technology:*                     Available for licensing and commercial development are patent rights and materials related to NGR peptides for targeting therapeutic and diagnostic agents to cancer cells. Specifically targeted are tumors that express aminopeptidase N isoform CD13. NGR peptides include the Asn-Gly-Arg peptide motif, a ligand for APN/CD13. NGR-containing peptides have been proven useful for delivering cytotoxic drugs, apoptotic peptides, and cytokines (such as tumor necrosis factor (TNF)) to tumor vasculature. In some embodiments of the invention, the NGR peptide is conjugated with a diagnostic moiety such as a fluorophore, nonmetallic isotope, an optical reporter, a boron neutron absorber, a paramagnetic metal ion, a ferromagnetic metal, a gamma-emitting radioisotope, a positron-emitting radioisotope, or an x-ray absorber. In another embodiment, the peptide can be conjugated with a therapeutic such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or a combination of these. The therapeutic agent, such as an anti-tumor or anti-neoplastic agent of choice, can be entrapped within a liposome; the liposomes are formulated to be of a size known to penetrate the endothelial and basement membrane barriers. The resulting liposomal formulation can be administered parenterally to a subject in need of such treatment, preferably by intravenous administration. Tumors characterized by an acute increase in permeability of the vasculature in the region of tumor growth are particularly suited for treatment by the present invention.                 

*Applications:*
      - Cancer diagnostics
      - Cancer therapeutics
      - Anti-angiogenesis
      - Imaging

*Inventors:*                     Bradford Wood, Matthew Dreher, Ayele Negussie (CC).                 

*Relevant Publications:*

                    1. W Arap                     *et al.*                     Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science. 1998 Jan 16;279(5349):377-380.                 

                    2. H Ellerby                     *et al.*                     Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med. 1999 Sep;5(9):1032-1038.                 

                    3. F Curnis                     *et al.*                     Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat Biotechnol. 2000 Nov;18(11):1185-1190.                 

                    4. G Colombo                     *et al.*                     Structure-activity relationships of linear and cyclic peptides containing the NGR tumor-homing motif. J Biol Chem. 2002 Dec 6;277(49):47891-47897.                 

                    5. F Pastorino                     *et al.*                     Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy. Cancer Res. 2003 Nov 1;63(21):7400-7409.                           ( print page 53435)    

                    6. F Pastorino                     *et al.*                     Targeting liposomal chemotherapy via both tumor cell-specific and tumor vasculature-specific ligands potentiates therapeutic efficacy. Cancer Res. 2006 Oct 15;66(20):10073-10082.                 

                    7. SV Garde                     *et al.*                     Binding and internalization of NGR-peptide-targeted liposomal doxorubicin (TVT-DOX) in CD13-expressing cells and its antitumor effects. Anti-Cancer Drugs. 2007 Nov;18(10):1189-1200.                 

*Patent Status:*                     U.S. Provisional Application No. 61/074,864 filed 23 Jun 2008 (HHS Reference No. E-147-2008/0-US-01).                 

*Licensing Status:*                     Available for licensing.                 

*Licensing Contact:*                     Michael A. Shmilovich, Esq.; 301-435-5019;                     *shmilovm@mail.nih.gov*.                 

## Microfabricated Particles Useful as MRI Contrast Agents 

*Description of Technology:*                     MRI contrast agents are versatile yet lack the sensitivity and multiplexing capabilities of optical agents. Available for licensing is an invention pertaining to microfabricated structures that can be used as MRI contrast agents with enhanced functionality or as micro-RFID (radio-frequency identification) tags. The microstructures can be engineered to appear as different effective colors when resolved using MRI as opposed to strictly grey-scale contrast of existing MRI agents. In this way they can be thought as radio-frequency analogs to quantum dots. A set of agents could be produced that would enable in vivo labeling and tracking of multiple different types of cells simultaneously. The agents can also act as radio-frequency probes of various physiological conditions. The invention can include a plurality of microstructures dispersed a liquid. The structures can have magnetic portions that vary in size, thickness and shape that are arranged to provide a substantially uniform Larmor precession frequency or a characteristic substantially uniform shift in Larmor precession frequency experienced by nuclear magnetic moments of a material when it is located in the substantially uniform field region created by the magnetic portions. In some embodiments, each of the nuclear magnetic resonance microstructures has a maximum dimension less than about 1 mm. The magnetic portions of the microstructure can be arranged proximate to each other, in contact with each other or be partially, substantially or totally coincident.                 

*Applications:*
      - Magnetic Resonance Imaging
      - Cancer
      - Cardiovascular diseases imaging
      - Drug development
      - Drug candidate distribution tracking
      - Diagnostics
      - Microfluidics

*Inventors:*                     Gary Zabow, Stephen Dodd (NINDS), Alan Koretsky (NINDS), John Moreland (NIST).                 

*Publications:*

                    1. G Zabow                     *et al.*                     Micro-engineered local field control for high-sensitivity multispectral MRI. Nature 2008 Jun 19;453(7198):1058-1063.                 

                    2. KA Hinds                     *et al.*                     Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Blood 2003 Aug 1;102(3):867-872.                 

*Patent Status:*                     U.S. Provisional Application No. 61/071,263 filed 18 Apr 2008 (HHS Reference No. E-081-2008/0-US-01).                 

*Licensing Status:*                     Available for licensing.                 

*Licensing Contact:*                     Michael A. Shmilovich, Esq.; 301-435-5019;                     *shmilovm@mail.nih.gov.*

*Collaborative Research Opportunity:*                     NINDS Laboratory of Functional and Molecular Imaging is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the use of microfabricated devices as MRI contrast agents. Please contact Dr. Melissa Maderia at 301-451-3943 or                     *maderiam@mail.nih.gov*                     for more information.                 

## Active Guidewire Visualization Device and System for MRI Guided Interventions 

*Description of Technology:*                     Available for licensing and commercial development is a guidewire device and system for MRI guidance of vascular interventions. The guidewire design, and its coupled system, enables interventionalists to visualize the location of the tip and distal shaft of an MRI compatible guidewire relative to the vascular system and surrounding anatomy. Visualization of both the shaft and tip enables interventionalists to advance the guidewire through tortuous vessels reducing the risk of puncturing vessel walls and also steering it through labyrinthine vasculature. The guidewire provided by the present invention includes distal and proximal ends with a space therein, a dipole antenna disposed in the space reserved within the guidewire body, the dipole antenna being adapted to be electrically connected to a signal processing system through a first signal channel through the proximal end of the guidewire body, and a loop antenna disposed in the space reserved within the guidewire body toward the distal end of the guidewire body, the loop antenna being adapted to be electrically connected to the signal processing system through a second signal channel through the proximal end of the guidewire body. The dipole antenna and the loop antenna are each constructed to receive magnetic resonance imaging signals independently of each other and to transmit received signals through the first and second signal channels, respectively, to be received by the signal processing system. More specifically, both loop and dipole antenna are tuned to resonate at the same Larmour frequency as produced by the magnet.                 

*Applications:*
      - Interventional cardiology
      - MRI guided surgery

*Inventors:*                     Ozgur Kocaturk (NHLBI).                 

*Publications:*

                    1. McKinnon GC,                     *et al.*                     Towards active guidewire visualization in interventional magnetic resonance imaging. MAGMA. 1996 Mar;4(1):13-18.                 

                    2. Ladd ME,                     *et al.*                     Active MR visualization of a vascular guidewire in vivo. J Magn Reson Imaging. 1998 Jan-Feb;8(1):220-225.                 

*Patent Status:*                     U.S. Provisional Application No. 61/006,265 filed 03 Jan 2008 (HHS Reference No. E-209-2007/0-US-01)                 

*Licensing Status:*                     Available for licensing.                 

*Licensing Contact:*                     Michael A. Shmilovich, Esq.; 301-435-5019;                     *shmilovm@mail.nih.gov.*

*Collaborative Research Opportunity:*                     The National Institutes of Health / Cardiac Catheter Core Lab is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Active two channel 0.035′′ guidewire. Please contact Ozgur Kocaturk at 301-402-9430 or                     *kocaturko@nhlbi.nih.gov.*

## Respiratory Syncytial Virus (RSV) Vaccines Based on Promoter-Proximate Attenuation 

*Description of Technology:*                     Available for licensing and commercial development is a patent estate and related biological materials for producing therapeutic or prophylactic vaccines against Respiratory Syncytial Virus (RSV). The claimed vaccine strategy relates to the engineering and creation of live-attenuated RSV vaccine candidates by shifting the position of one or more viral genes relative to the viral promoter (aka promoter-proximal                           ( print page 53436)                        attenuation). The gene shifts can be constructed by insertion, deletion or rearrangement of genes or genome segments within the recombinant genome or antigenome. Viral replication can increase or decrease depending on the position of expressed viral gene and depending on the nature and degree of the positional shift. Viral gene rearrangements are selected to maintain sufficient non-infectious replication of RSV while eliciting host anti-RSV immune responses. Viral genes targeted for such rearrangement include any of the NS1, NS2, N, P, M, SH, M2(ORF1), M2(ORF2), L, F or G genes or genome segment.                 

One modification of particular interest is the placement of the G and F protective antigen genes in a promoter-proximal position for increased expression. The gene position-shifted RSV can be further manipulated by the addition of specific nucleotide and amino acid point mutations or host range restriction determinants to yield desired phenotypic and structural effects. 

*Applications:*
      - Infectious Disease—Respiratory Syncytial Virus
      - Vaccines
      - Therapeutics
      - Prophylactics
      - Childhood Vaccines

*Inventors:*                     Christine D. Krempl, Peter L. Collins,                     *Brian R. Murphy,*                     Ursula Buchholz, Stephen S. Whitehead (NIAID)                 

*Publications:*

                    1. C Krempl                     *et al.*                     Recombinant respiratory syncytial virus with the G and F genes shifted to the promoter-proximal positions. J Virol. 2002 Dec;76(23):11931-11942.                 

2. Y Aloni, N Hay. Attenuation may regulate gene expression in animal viruses and cells. CRC Crit Rev Biochem. 1985;18(4):327-383. 

*Patent Status:*

HHS Reference No. E-225-2000/0— 
      - U.S. Patent No. 6,923,971 issued 02 Aug 2005
      - U.S. Patent Application No. 11/033,055 filed 10 Jan 2005
      - U.S. Patent Application No. 11/054,343 filed 08 Feb 2005
      - International Patent Application PCT/US2001/20107, which published as WO 2002/00693 on 03 Jan 2002 (expired)
      - Australian Patent 2001268709
      - Brazilian Patent Application PI0112276-2
      - Canadian Patent Application 2413786
      - Chinese Patent Application 01814362.8
      - European Patent Application 01946696.0
      - Israeli Patent Application 153530
      - Japanese Patent Application 10-2002-505815
      - Korean Patent Application 10-2002-7017577 and
      - Mexican Patent Application 2002-012818.

*Licensing Status:*                     Available for licensing.                 

*Licensing Contact:*                     Michael A. Shmilovich, Esq.; 301-435-5019;                     *shmilovm@mail.nih.gov.*

*Collaborative Research Opportunity:*                     The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize live attenuated vaccines. Please contact Michael Piziali at 301-451-3527 for more information.                 

## Quantitative Assessment of Changes in Tissue Status in Disease, Development, Aging, or Degeneration Using Diffusion Tensor Magnetic Resonance Imaging 

*Description of Technology:*                     This invention significantly enhances the quality and utility of diffusion tensor magnetic resonance imaging (DT-MRI) data. The patent application for the invention describes quantitative statistical methodology to extract novel clinical and biological information from DT-MRI data. These parametric and non-parametric statistical methods help distinguish changes in tissue state from background noise inherent in all MRI measurements. The invention also includes hypothesis tests to determine the statistical significance of changes observed in MRI “stains” (e.g., the Trace of the diffusion tensor, Trace(D), and the mean apparent diffusion coefficient, ADC), which are widely used in the diagnosis of stroke. Further, this invention describes how to detect systematic artifacts in each pixel of a diffusion weighted image (e.g., artifacts caused by patient motion). Indeed, this new statistical methodology for analyzing and interpreting diffusion tensor MRI data should improve the efficacy of drug screening studies, as well as streamline multi-site and longitudinal studies designed to assess the safety and efficacy of drugs undergoing clinical evaluation.                 

*Inventors:*                     Peter J. Basser (NICHD), Sinisa Pajevic (CIT).                 

*Patent Status:*                     U.S. Patent No. 6,845,324 issued 15 Jan 2005 (HHS Reference No. E-192-1999/0-US-07)                 

*Licensing Status:*                     Available for licensing.                 

*Licensing Contact:*                     Michael A. Shmilovich, Esq.; 301-435-5019;                     *shmilovm@mail.nih.gov.*

## Human-Bovine Chimeric Respiratory Syncytial Virus (RSV) Vaccines 

*Description of Technology:*                     Available for licensing and commercial development is a patent estate and related biological materials for making human-bovine chimeric virus particles for formulating live attenuated vaccines against human respiratory syncytial virus (RSV). Chimeric human-bovine RSVs are recombinantly engineered to incorporate nucleotide sequences from both human and bovine RSV strains and produce infectious, chimeric viruses that elicit anti-RSV immunological responses in humans and non-human primates. The chimeras incorporate partial or complete human or bovine RSV background genomes with one or more recombinantly integrated heterologous genes or genome segments of a different RSV strain.                 

Heterologous genes of interest for making chimeric recombinants include NS1, NS2, N, P, M, SH glycoprotein (or an immunogenic domain or epitope thereof), M2(ORF1), M2(ORF2), L, F or G genes or a genome segment including a protein or portion thereof or alternatively a leader, trailer or intergenic region of the RSV genome, or a segment thereof. A variety of additional mutations and nucleotide modifications are provided within the human-bovine chimeric RSV of the invention to yield desired phenotypic and structural effects. Exemplary human-bovine chimeric RSV of the invention incorporate a chimeric RSV genome or antigenome comprising both human and bovine polynucleotide sequences, as well as a major nucleocapsid (N) protein, a nucleocapsid phosphoprotein (P), a large polymerase protein (L), and an RNA polymerase elongation factor. Additional RSV proteins may be included in various combinations to provide a range of infectious subviral particles up to a complete viral particle or a viral particle containing supernumerary proteins, antigenic determinants or other additional components. 

*Applications:*
      - Infectious Disease—Respiratory Syncytial Virus
      - Vaccines
      - Therapeutics
      - Prophylactics
      - Childhood Vaccines

*Inventors:*                     Ursula Buchholz, Peter L. Collins, Brian R. Murphy, Stephen S. Whitehead, Christine D. Krempl (NIAID).                           ( print page 53437)    

*Publications:*

                    1. UJ Buchholz                     *et al.*                     Chimeric bovine respiratory syncytial virus with glycoprotein gene substitutions from human respiratory syncytial virus (HRSV): effects on host range and evaluation as a live-attenuated HRSV vaccine. J Virol. 2000 Feb;74(3):1187-1199.                 

                    2. A Karger                     *et al.*                     Recombinant bovine respiratory syncytial virus with deletions of the G or SH genes: G and F proteins bind heparin. J Gen Virol. 2001 Mar;82(Pt 3):631-640.                 

                    3. UJ Buchholz                     *et al.*                     Generation of bovine respiratory syncytial virus (BRSV) from cDNA: BRSV NS2 is not essential for virus replication in tissue culture, and the human RSV leader region acts as a functional BRSV genome promoter. J Virol. 1999 Jan;73(1):251-259.                 

*Patent Status:*

HHS Reference No. E-178-1999/0— 
      - International Patent Application PCT/US00/17755, which published as WO 2001/04335 on 09 Jan 2001 (expired)
      - Australian Patent 784216
      - Chinese Patent 00810119.1
      - Canadian Patent Application 2378552
      - European Patent Application 00941756.9
      - Israeli Patent Application 147447
      - Japanese Patent Application 2001-509539
      - Korean Patent Application 10-2002-7000318
      - Mexican Patent Application 2002-000220
      - Brazilian Patent Application PI0013195-4 and
      - Chinese Patent Application 200710167112.6

HHS Reference No. E-178-1999/1— 
      - U.S. Patent Application No. 11/097,946 filed 31 Mar 2005

HHS Reference No. E-178-1999/2— 
      - U.S. Patent Application No. 10/704,116 filed 07 Nov 2003

*Licensing Status:*                     Available for licensing.                 

*Licensing Contact:*                     Michael A. Shmilovich, Esq.; 301-435-5019;                     *shmilovm@mail.nih.gov.*

*Collaborative Research Opportunity:*                     The NIAID Office of Technology Development is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize attenuated live vaccines against respiratory syncytial virus (RSV). Please contact Barry Buchbinder at 301-594-1696 for more information.                 

Dated: September 9, 2008. 

Richard U. Rodriguez, 

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

[FR Doc. E8-21519 Filed 9-15-08; 8:45 am] 

BILLING CODE 4140-01-P