[Federal Register Volume 70, Number 75 (Wednesday, April 20, 2005)]
[Notices]
[Pages 20576-20578]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-7848]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, DHHS.

ACTION: Notice.

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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.

Methods for Tumor Treatment Using Dendrimer Conjugates

Hisataka Kobayashi and Peter Choyke (NCI)
U.S. Provisional Application filed 11 Mar 2005 (DHHS Reference No. E-
107-2005/0-US-01)
Licensing Contact: Michael Shmilovich; 301/435-5019; 
[email protected].

    Available for licensing and commercial development are dendrimer 
based methods for treating cancer. The dendrimer conjugate comprises an 
effective amount of an anti-tumor agent. A generation 5 DAB, generation 
2 polylysine, or generation 6-8 PAMAM dendrimer (e.g., PAMAM-G6) 
conjugate is administered to a cancer patient. The anti-tumor agent is 
selectively concentrated in the lymphatic system to treat metastatic 
disease. The anti-tumor agent can be one that is activated after 
selective aggregation in the lymphatic system. When an activatable 
anti-tumor agent is used, it may be activated by applying physical 
energy to the subject's body, for example by external application of 
that energy to the body. In particular examples, the external energy is 
heat, ultrasound, or electromagnetic energy. In particular, the 
physical energy can be a particle beam, such as a neutron beam.
    The dendrimer conjugates may include an imaging agent, which 
permits the lymphatic system to be imaged when selective intra-
lymphatic concentration of the dendrimer occurs. Further, when the 
dendrimer conjugate includes an activatable anti-tumor agent, the 
method may include selectively applying physical energy to the 
subject's body to selectively activate the anti-tumor agent in the 
lymphatic system. The dendrimer conjugate can include gadolinium, 
wherein the gadolinium acts as a contrast agent to image the lymphatic 
system.
    In a particular example, the dendrimer conjugate includes a 
gadolinium-imaging agent that is activatable by a neutron beam. Once 
the gadolinium containing dendrimer conjugate is concentrated in the 
lymphatic system, detecting selective concentration of the dendrimer 
conjugate in the lymphatic system images the lymphatic system. The 
presence of tumor in lymph nodes can also be detected using this 
imaging technique. A neutron beam is then selectively applied to the 
imaged lymphatic system to selectively activate the anti-tumor agent at 
target areas in the lymphatic system for the treatment of metastatic 
tumor. In this example, the target area may be a lymph node, such as a 
sentinel lymph node, or a lymphatic vessel. The target area, when 
imaged, may show evidence of primary or metastatic tumor.
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

A Universal Antigen Delivery Platform for Enhanced Immune Response

John T. Patton and Zenobia F. Taraporewala (NIAID)
U.S. Provisional Application No. 60/633,036 filed 03 Dec 2004 (DHHS 
Reference No. E-322-2004/0-US-01)
Licensing Contact: Chekesha Clingman; 301/435-5018; 
[email protected].

    The present invention relates to a universal antigen delivery 
platform based on rotavirus NSP2 fusion proteins and methods for the 
use of such fusion proteins to enhance an immune response to an 
antigen. This technology

[[Page 20577]]

can potentially be used for rapid production of subunit vaccines 
against a wide range of infectious agents. Additional uses of the 
technology include development of diagnostic systems and production of 
specific antisera for research purposes. The antigen delivery platform 
comprises a monomeric fusion protein including (a) a self-aggregating 
polypeptide component (e.g. a viral NSP2 polypeptide); (b) a linear 
linking peptide; and (c) an antigenic polypeptide. Upon expression in 
prokaryotic or eukaryotic systems, multiple monomeric fusion protein 
subunits form a self-aggregating stable multimeric ring structure, 
which allows multivalent display of the antigen and enhances the immune 
response. Additionally, this delivery platform can be efficiently 
produced and recovered and is physically robust. The patent application 
also includes pharmaceutical compositions of vaccines for prophylactic 
and therapeutic administration.
    Relevant publications: P. Schuck et al., ``Rotavirus nonstructural 
protein NSP2 self-assembles into octamers that undergo ligand-induced 
conformational changes,'' J. Biol. Chem. (2001 March 30) 276(13):9679-
9687, doi:10.1074/jbc.M009398200; H. Jayaram et al., ``Rotavirus 
protein involved in genome replication and packaging exhibits a HIT-
like fold,'' Nature (2002 May 16) 417(6886):311-315, doi:10.1038/
417311a.
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

Peptide Inhibitors of Yersinia Phosphatase (YopH) as Potential 
Treatments Against Plague

Terrence R. Burke, Jr., Kyeong Lee, Yang Gao, Jason Phan, David S. 
Waugh (NCI) U.S. Patent Application No. 10/341,607 filed 14 Jan 2003; 
International Application Number PCT/US04/00669 filed 12 Jan 2004, 
which published as WO 2004/065411 A3 on 05 Aug 2004 (DHHS Reference No. 
E-263-2002/0)
Licensing Contact: Cristina Thalhammer-Reyero; 301/435-4507; 
[email protected].

    Available for licensing and commercial development are compounds 
that are useful as inhibitors of protein-tyrosine phosphatases (PTPs), 
and in particular, as inhibitors of the Yersinia pestis PTP (YopH). The 
compounds are tripeptides of the formula P-A-B-C, or prodrugs thereof, 
wherein A is an amino acid having a carboxy alkyl group (e.g., carboxy 
C1-C6 alkyl group), B is a substituted tyrosine or phenylalanine, C is 
a hydrophobic amino acid, and P is an amine protecting group protecting 
the amine end of A. The inventors have discovered that a certain group 
on a specific residue is absolutely required to be present on those 
peptides in order to be active against YopH, and that another specific 
group results in higher affinity. These requirements are distinct from 
the requirements by other PTPs. Also disclosed are pharmaceutical 
compositions comprising such a compound and a pharmaceutically 
acceptable carrier. The invention also provides a method of inhibiting 
the YopH enzyme as well as a method of treating plague in an animal, 
e.g., a human, exposed to or infected by Yersinia pestis. The compounds 
may be useful as anti-bioterrorism agents, and are potentially 
important for therapeutic development because they may facilitate 
bioavailablility, given the low ionic charge of the inhibitors.
    The bacterium Yersinia pestis causes bubonic, pneumonic and 
septicemic plague, and it is considered as a potential bioterrorism 
agent. Within Yersinia is a 70 kb virulence plasmid, which encodes for 
a system of secreted proteins, called ``Yops'', which act either as 
intracellular effectors or as translocators. Yersinia's Yop system 
represents the archetype for one of the major virulence mechanisms in 
various pathogenic bacteria, referred to as type III, where 
extracellular bacteria that are in close contact with a eukaryotic cell 
deliver bacterial proteins into the cytosol of the cell. Other animal 
pathogens with related systems include the genera Salmonella, Shigella, 
Pseudomonas, Chlamidia, and Bortedella, as well as E. coli. One such 
effector protein, YopH, is a protein-tyrosine phosphatase (PTP) with a 
C-terminal catalytic domain that is essential to Yersinia's virulence, 
playing an antiphagocytic role by dephosporylating focal adhesion 
proteins. The phosphatase activity of YopH is required for bacterial 
pathogenesis.

Selections of Genes and Methods of Using the Same for Diagnosis and for 
Targeting the Therapy of Select Cancers

Javed Khan, Jun S. Wei and Braden T. Greer (NCI)
U.S. Provisional Application No. 60/598,728 filed 03 Aug 2004 (DHHS 
Reference No. E-324-2001/2-US-01)
Licensing Contact: Cristina Thalhammer-Reyero; 301/435-4507; 
[email protected].

    Available for licensing and commercial development are selections 
of expressed genes that function to characterize neuroblastoma in 
patients, and methods of using the same for targeting the therapy of 
neuroblastoma and for predicting the outcome of the therapy. The 
invention also relates to the use of supervised pattern recognition 
methods, such as artificial neural networks using high dimensional 
data, such as gene expression profiling data, for the prognosis of 
patients with neuroblastoma to predict their outcome.
    Currently, patients with neuroblastoma are classified into risk 
groups (e.g., according to the Children's Oncology Group risk-
stratification) to guide physicians in the choice of the most 
appropriate therapy. Despite this careful stratification, the survival 
rate for patients with high-risk neuroblastoma remains <30%, and it is 
not possible to predict which of these high-risk patients will survive 
or succumb to the disease. The inventors performed gene expression 
profiling using cDNA microarrays containing 42,578 clones and used 
artificial neural networks to develop an accurate predictor of survival 
for each individual patient with neuroblastoma. Using principal 
component analysis we found that neuroblastoma tumors exhibited 
inherent prognostic specific gene expression profiles, achieving 88% 
accuracy. They identified 19 genes, including 2 prognostic markers 
reported previously, MYCN and CD44, which correctly predicted outcome 
for 98% of these patients.
    The technology is further described in: Jun S. Wei, Braden T. 
Greer, Frank Westermann, Seth M. Steinberg, Chang-Gue Son, Qing-Rong 
Chen, Craig C. Whiteford, Sven Bilke, Alexei L. Krasnoselsky, Nicola 
Cenacchi, Daniel Catchpoole, Frank Berthold, Manfred Schwab, and Javed 
Khan, ``Prediction of Clinical Outcome Using Gene Expression Profiling 
and Artificial Neural Networks for Patients with Neuroblastoma'', 
Cancer Research 64, 6883-6891, October 1, 2004.

Amine Modified Random Primers for Microarray Detection

Charles Xiang and Michael J. Brownstein (NIMH)
U.S. Provisional Application No. 60/283,423 filed 11 Apr 2001; 
International Application PCT/US02/11656 filed 11 Apr 2002, which 
published as WO02083922 on 24 Oct 2002; corresponding U.S. Patent 
Application No. 10/474,611 filed 09 Oct 2003, and EP, CA and AU 
applications (DHHS Reference No. E-098-2001/0)

[[Page 20578]]

Licensing Contact: Cristina Thalhammer-Reyero; 301/435-4507; 
[email protected].

    Available for licensing and commercial development is a new method 
for labeling nucleic acid molecules for use in hybridization reactions, 
and kits employing these methods. The fluorescence-labeled cDNA probes 
for DNA microarray studies only use about \1/20\th as much input RNA as 
the conventional methods. The method allows making high quality probes 
from as little as 1 ug of total RNA without RNA or signal 
amplification. It is based on priming cDNA synthesis with random 
hexamers to the 5' ends of which amino allyl modified bases have been 
added. Coupling of the fluorescent dye to the amine residues is 
performed after the cDNA is reverse transcribed. The method can be used 
in tandem with RNA amplification (and/or signal amplification) to label 
probes from 10 or fewer cells.
    Furthermore, the invention also relates to a novel method to 
amplify RNA derived from single cells using T3-random 9mers and a new 
lysing method, which allow probe-labeling capabilities that are 
approaching the single cell level.
    DNA Microarray technology has become one of the most important 
tools for high throughput studies in medical research with applications 
in the areas of gene discovery, gene expression and mapping. The 
suitability of DNA Microarray for profiling diseases and for 
identifying disease-related genes has also been also well documented. 
Most studies using DNA arrays involve preparation of fluorescent-
labeled cDNA from the mRNA of the studied organism. The cDNA probes are 
then allowed to hybridize to the DNA fragments printed on the array, 
and the array is scanned and the data analyzed. Good results depend on 
a number of factors including high quality arrays and well-labeled 
probes. In order to achieve adequate sensitivity and reproducibility, 
probes have had to be prepared from rather large amounts of RNA using 
other methods.
    The technology is further described in Xiang CC, Kozhich OA, Chen 
M, Inman JM, Phan QN, Chen Y, Brownstein MJ. ``Amine-modified random 
primers to label probes for DNA microarrays.'' Nat Biotechnol. 2002 
Jul; 20(7): 738-42.

Methods for Manipulating Nucleic Acids

Charles Xiang and Michael J. Brownstein (NIMH)
U.S. Patent Application No. 10/269,515 filed 11 Oct 2002, published as 
US2003170675 on 11 Sept 2003 (DHHS Reference No. E-098-2001/1) and 
International Application PCT/US03/33319 filed 10 Oct 2003, published 
as WO 200/033669 on 22 April 2004 (DHHS Reference No. E-098-2001/2)
Licensing Contact: Cristina Thalhammer-Reyero; 301/435-4507; 
[email protected].

    Available for licensing and commercial development are methods of 
labeling nucleic acid probes for the detection of nucleic acids 
molecules, for instance producing labeled probes for detecting 
hybridization signals, such as those from a microarray. This disclosure 
provides new methods for amplifying nucleic acid templates from very 
small samples, even as small as one cell. Nucleic acid templates 
amplified by the disclosed methods can be used in combination with any 
method that requires amplified nucleic acid. In addition, the amplified 
nucleic acid can be labeled with any labeling method, such as the 
labeling method disclosed herein. Also provided are methods for 
preparing modified nucleotide probes, from either amplified or 
unamplified nucleic acid templates. In one embodiment, the method 
includes the incorporation of modified nucleic acids into random 
primers that are used to initiate polymerization of a probe molecule. 
In another embodiment, the random primers include nucleotides that are 
modified by amine groups (such as aminoallyl moieties). In yet other 
embodiments, the modified nucleotides comprise a detectable molecule, 
such as a fluorophore or hapten. The disclosure also provides an 
improved method of extracting RNA from fixed cells or tissue sections 
for subsequent use as RNA templates or for generating labeled probe. In 
one specific embodiment, the cells are fixed with Dithio-bis 
(Succinimidyl Propionate) (DSP). Also disclosed are kits for producing 
a labeled hybridization probe, using a modified random primer, or for 
probing an array, and kits for amplifying nucleic acid templates from 
very small samples.
    The technology is further described in: Xiang CC, Chen M, Kozhich 
OA, Phan QN, Inman JM, Chen Y, Brownstein MJ. ``Probe generation 
directly from small numbers of cells for DNA microarray studies.'' 
Biotechniques. 2003 Feb;34(2):386-8, 390, 392-3; Xiang CC, Chen M, Ma 
L, Phan QN, Inman JM, Kozhich OA, Brownstein MJ. ``A new strategy to 
amplify degraded RNA from small tissue samples for microarray 
studies.'' Nucleic Acids Res. 2003 May 1; 31(9):e53; Xiang CC, 
Brownstein MJ. ``Preparing fluorescent probes for microarray studies.'' 
Methods Mol Biol. 2003; 224:55-60; and Xiang CC, Mezey E, Chen M, Key 
S, Ma L, Brownstein MJ. ``Using DSP, a reversible cross-linker, to fix 
tissue sections for immunostaining, microdissection and expression 
profiling'' Nucleic Acids Res. 2004 Dec 16; 32(22): e185.

    Dated: April 11, 2005.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 05-7848 Filed 4-19-05; 8:45 am]
BILLING CODE 4140-01-P