[Federal Register Volume 74, Number 157 (Monday, August 17, 2009)]
[Notices]
[Pages 41443-41445]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-19691]


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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, HHS.

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.

Superior Method of Preparing Dendrimers for Use as Magnetic Resonance 
Imaging (MRI) Contrast Agents

    Description of Technology: There is a need to develop more 
efficient gadolinium-containing (Gd) contrast agents for magnetic 
resonance imaging (MRI) as the small molecules presently used 
clinically have the disadvantage of being rapidly cleared from 
circulation and excreted by the kidneys.
    Dendrimer-based macromolecular MRI contrast agents in which 
numerous chelated Gd ions are covalently attached to a multivalent 
dendritic architecture are a promising class of diagnostic agents for 
medical imaging applications. Clinical development of the dendrimer-
based agents has been limited as the current methods for synthesizing 
them result in a complex mixture that produces inconsistent imaging 
results.
    The present technology describes the development of a new method of 
pre-forming the metal-ligand chelate in alcohol prior to conjugation to 
the dendrimer. Specifically, for example, a 1B4M-DTPA-Gd chelate is 
preformed in methanol and purified prior to conjugation to a PAMAM 
dendrimer molecule. This results in a dendrimer-based MRI contrast 
agent with greatly improved homogeneity and stability, and possessing 
an unexpectedly greater molar relaxivity that allows the use of much 
less of the agent than previously required to obtain comparable images. 
The use of a DOTA-Gd chelate is equally possible.
    Application: An improved method for synthesis of dendrimer-based 
MRI contrast agents that is greatly suited for clinical development.

Advantages

     Efficient preparation of stable dendrimer-based contrast 
agents suitable for medical imaging.
     Higher molar relaxivity translates into a lower dosage 
needed for imaging.
     Ability to control dendrimer size conducive for 
development of compartment-specific imaging agents.
    Market: Dendrimers show particular promise for the development of 
cancer imaging agents. The ability to exquisitely control dendrimer 
size enables delivering them to specific compartments such as small 
tumors allowing for early cancer detection. Gadolinium (Gd) chelates 
are extensively used as MRI contrast agents and have proven to be safe. 
The combination of gadolinium chelates with dendrimer chemistry could 
greatly enhance the versatility of MRI imaging.
    Inventors: Kido Nwe and Martin W. Brechbiel (NCI).

Publications

1. K Nwe, H Xu, CA Regino, M Bernardo, L Ileva, L Riffle, KJ Wong, 
MW Brechbiel. A new approach in the preparation of dendrimer-based 
bifunctional diethylenetriaminepentaacetic acid MR contrast agent 
derivatives. Bioconjugate Chem. 2009 Jul;20(7):1412-1418.
2. OA Gansow, MW Brechbiel, MA Magerstadt. Complexes of 
functionalized tetraazacyclododecane chelates with bismuth, lead, 
yttrium, actinium, or lanthanide metal ions. U.S. Patent 5,428,154 
issued 27 Jun 1995.

    Patent Status: U.S. Provisional Application No. 61/180,327 filed 21 
May 2009 (HHS Reference No. E-207-2009/0-US-01).
    Related Technology: OA Gansow, MW Brechbiel, MA Magerstadt, 
``Complexes of Functionalized Tetraazacyclododecane Chelates with 
Bismuth, Lead, Yttrium, Actinium, or

[[Page 41444]]

Lanthanide Metal Ions,'' U.S. Patent 5,428,154 issued 27 Jun 1995 (HHS 
Reference No. E-347-1996/0-US-22).
    Licensing Status: Available for licensing.
    Licensing Contact: Sabarni Chatterjee, Ph.D.; 301-435-5587; 
[email protected].
    Collaborative Research Opportunity: The Inorganic & Radioimmune 
Chemistry Section, ROB, CCR, NCI is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize macromolecular (dendrimer-based) MR 
contrast agents as well as multi-modality analogs. Please contact John 
D. Hewes, Ph.D. at 301-435-3121 or [email protected] for more 
information.

Two Types of Dentin Sialophosphoprotein (DSPP) Knockout Mice

    Description of Technology: Two types of dentin sialophosphoprotein 
knockout mice are available for licensing. The technology relates to 
two separate knockout mouse models of the role of dentin 
sialophosphoprotein in dentin mineralization and development of teeth. 
The first knockout mouse is a knockout of the entire DSPP gene, which 
results in a phenotype similar to human autosomal dominant 
dentinogenesis imperfecta, in which teeth have widened predentin and 
irregular dentin mineralization resulting in sporadic unmineralized 
areas in dentin and frequent pulp exposures. DSPP protein in 
odontoblasts is normally proteolytically cleaved into two products, 
dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). To 
distinguish the role of the proteolytic fragments, the second knockout 
mouse (DPPcKO) consists of a transgene expressing the DSP fragment in a 
DSPP null background. The DPPcKO mouse demonstrates a partial rescue of 
the DSPP knockout effect and indicates DSP and PPP have distinct roles 
in dentin development.

Applications

     Tool for studying dentin development.
     Tool for developing treatments for autosomal dominant 
dentinogenesis imperfecta.
    Inventors: Ashok Kulkarni and Shigeki Suzuki (NIDCR)

Related Publications

1. Sreenath T, Thyagarajan T, Hall B, Longenecker G, D'Souza R, Hong 
S, Wright JT, MacDougall M, Sauk J, Kulkarni AB. Dentin 
sialophosphoprotein knockout mouse teeth display widened predentin 
zone and develop defective dentin mineralization similar to human 
dentinogenesis imperfecta type III. J Biol Chem. 2003 Jul 
4;278(27):24874-24880.
2. Suzuki S, Sreenath T, Haruyama N, Honeycutt C, Terse A, Cho A, 
Kohler T, Muller R, Goldberg M, Kulkarni A. Dentin sialoprotein and 
dentin phosphoprotein have distinct roles in dentin mineralization. 
Submitted, 2009.

    Patent Status: HHS Reference No. E-201-2009/0--Research Tool. 
Patent protection is not being pursued for this technology.
    Licensing Status: This technology is available as a research tool 
under a Biological Materials License.
    Licensing Contact: Steve Standley, PhD; 301-435-4074; 
[email protected].

Novel Diagnostic and Therapeutic Biomarkers for Squamous Cell 
Carcinomas

    Description of Technology: Head and neck squamous cell carcinoma 
(HNSCC) includes tumors of the nasal cavities, paranasal sinuses, oral 
cavity, nasopharynx, oropharynx, hypopharynx, and larynx. HNSCC is an 
aggressive cancer with poor prognosis after metastasis. In patients 
where HNSCC is identified early, prognosis is better and patient 
survival increases. However, at present, very few if any biomarkers are 
available to diagnosis HNSCC. The overall 5-year survival rate for 
patients is only 50% and has not improved in over 30 years. New 
treatments and diagnostics for early detection are needed to improve 
patient survival and quality of life for this these types of cancers.
    Scientists at the National Institutes of Health (NIH) have 
discovered that the TGF-[beta] signaling pathway crosstalks with the 
PI3K/Akt signaling pathway to suppress squamous cell carcinomas (SCCs). 
When the TGF-[beta] pathway is inactivated and the PI3K pathway becomes 
hyperactive, HNSCC development is accelerated. Combined mutations in 
the transforming growth factor-[beta] receptor type 1 (TGF[beta]R1) 
gene and the phosphate and tensin homolog (PTEN) gene directly 
correlate with an individual having HNSCC or being increasingly 
susceptible to HNSCC. When tumor-associated mutations in both 
biomarkers were induced in animal subjects, spontaneous SCCs were 
developed in every test subject. Given this high correlation, this 
technology could be utilized to improve diagnosis of HNSCC at its early 
stages when the malignancy is most treatable. This technology also 
includes therapeutic combinations of TGF-[beta] and PI3K/Akt modulators 
as treatments for HNSCC and methods of treating patients diagnosed with 
HNSCC.

Applications

     Biomarkers to diagnose patients with HNSCC or predict 
patients who have a high susceptibility for developing HNSCC.
     Diagnostic tool to identify patients predicted to respond 
to specific HNSCC therapies as part of a personalized treatment 
strategy.
     Therapeutic drug combinations of TGF-[beta] pathway 
modulators and PI3K/Akt inhibitors to treat various head and neck 
cancers, including nasal, oral, pharyngeal, laryngeal, and cranial 
tumors.

Advantages

     Complete Penetrance: All test subjects exhibiting 
mutations in the TGF[beta]R1 and PTEN genes develop HNSCC. A diagnostic 
kit that includes assays for these mutations is predicted to have high 
accuracy for identifying HNSCC.
     Earlier diagnosis could yield more effective treatments: 
This technology could provide for a more accurate and earlier diagnosis 
of SCCs to revolutionize the treatment of this malignancy. Current SCC 
therapies may become more effective treatments and new therapies could 
be developed as better treatment options.
     Diagnostic for HNSCC susceptibility could lead to HNSCC 
prevention: This technology could identify patients predisposed to 
developing HNSCC in order to help prevent individuals from developing 
head and neck cancer.
    Development Status: This technology is in the pre-clinical stage of 
development. In vivo and in vitro mouse data is available.
    Market: Cancer continues to be a medical and financial burden on 
U.S. public health. The incidence of HNSCC is over 500,000 cases 
worldwide and approximately 47,000 new cases are diagnosed each year in 
the United States. Despite our increasing knowledge of cancer treatment 
and diagnosis methods, the fight against cancer will continue to 
benefit from the development of new technologies aimed at treating 
individuals with disease and diagnosing susceptible patients.
    Inventors: Ashok B. Kulkarni and Yansong Bian (NIDCR).

Publications

1. Y Bian et al. Progressive tumor formation in mice with 
conditional deletion of TGF-[beta] signaling in head and neck 
epithelia is associated with activation of the PI3k/Akt Pathway. 
Manuscript in preparation (accepted).

[[Page 41445]]

2. Y Honjo et al. TGF-beta receptor I conditional knockout mice 
develop spontaneous squamous cell carcinoma. Cell Cycle 2007 Jun 
1:6(11):1360-1366.

    Patent Status: U.S. Provisional Application No. 61/176,723 filed 08 
May 2009 (HHS Reference No. E-118-2009/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contact: Samuel E. Bish, Ph.D.; 301-435-5282; 
[email protected].

Antigen Mixtures for Serological Detection of HHV-8 Infection

    Description of Technology: This invention describes a highly 
specific and sensitive serological test for human herpesvirus 8 (HHV-8) 
infection that uses the Luciferase Immunoprecipitation System (LIPS). A 
mixture of four virus-specific antigens, including K8.1, v-cyclin, 
ORF65 and LANA, was shown to provide more robust detection of HHV-8 
infection than traditional methods due its ability to detect very low 
viral loads. In addition, one of the antigens, v-cyclin, was identified 
as a new serological marker for HHV-8 infection, and its similarity to 
a known human oncogene, cyclin-D, raises the possibility of its use as 
a diagnostic tool for detecting cancer.
    This test is more sensitive and amenable to a high-throughput 
format than other conventional tests for HHV-8 infection such as 
Immunofluorescent Assays, Western Blots, ELISAs and PCR based 
approaches. It simplifies data collection and analysis and allows for 
more rapid clinical output. Validation tests on patient sera samples 
using this 4-antigen mixture has shown 100% sensitivity and specificity 
compared to 94% for ELISAs.
    The test can be incorporated into routine screening panels for 
rapid screening of HHV-8 infection, and may be potentially adapted for 
use as a diagnostic tool for detecting cancer. A successful embodiment 
of the test can be incorporated into routine blood screening panels, 
and may lead a reduced risk of transfusion-transmitted HHV-8 infection 
in patients. It may also be useful for detecting HHV-8 induced cancer 
in HIV infected patients.

Applications

     Rapid and efficient serological screening of HHV-8 
infection.
     Cancer diagnostics.
    Development Status: Early Stage.
    Inventors: Peter D. Burbelo (NIDCR), Joseph A. Kovacs (CC), Michael 
J. Iadarola (NIDCR).
    Publication: PD Burbelo, HP Leahy, S Groot, LR Bishop, W Miley, MJ 
Iadarola, D Whitby, JA Kovacs. Four-antigen mixture containing v-cyclin 
for serological screening of human herpesvirus 8 infection. Clin 
Vaccine Immunol. 2009 May;16(5):621-627.
    Patent Status: U.S. Patent Application No. 61/152,058 filed 12 Feb 
2009 (HHS Reference No. E-063-2009/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contact: Jeffrey A. James, PhD; 301-435-5474; 
[email protected].

Oligo Microarray for Detection of All Known Mammalian and Avian 
Pathogenic Viruses

    Description of Technology: The spectrum of pathogenic viruses of 
importance in human disease, agriculture and biology is not only large 
and diverse, but continually evolving. The identification or isolation 
of viral pathogens, in correlation with the presence of specific 
disease phenotypes, is of paramount importance both to diagnosis of 
disease and the subsequent management or treatment of viral infection. 
The limitations of current viral detection methods, such as PCR and 
immunoassays, led to the development of a novel microarray system for 
specific detection of viruses. The technology offered here for 
licensing provides a method for high-throughput screening of known 
pathogenic viruses along with identification of ``new'' disease-
associated viruses.
    The novel method is based on a viral microarray containing 10,000 
immobilized DNA oligonucleotide features, representing all known 
mammalian and avian pathogenic viruses (approximately 600). Software 
was also developed to analyze the viral microarray results. The 
oligonucleotide features in this system are 60-mer long and distributed 
across both conserved and non-conserved regions of known viral 
sequences. This design serves the dual purpose of: (1) Facilitating 
validation via redundant signals associated with each represented virus 
and (2) allowing for the discovery of new viruses, which arise due to 
recombination. In addition, positive and negative controls against 
human and mouse housekeeping genes are included along with software for 
analysis of virus microarray results.
    Further advantages of the viral microarray include: (a) The use of 
sample inputs as little as 10ng of either total DNA or RNA extracted 
from virus infected cells, representing as few as 20 viral particles; 
(b) detection of viruses of both DNA and RNA classes; (c) a capacity 
for high-throughput screening of various sample types including serum, 
saliva and biopsy tissues; and (d) analysis of a large number of 
samples in parallel on identical arrays.
    The detection of viral DNA is unique to this technology, as other 
available technologies only detect viral genomic RNA or viral mRNA 
transcripts. Additionally, the viral chip was found to be highly 
specific and sensitive for detecting different viral genomic sequences 
in cell lines and multiple viral constructs co-infection in cultured 
cells.

Applications

     Detection and identification of viruses that cause 
disease.
     Efficient discovery of new pathogenic viruses.
     Diagnosis of human and animal disease outbreaks.
     Identification of viral agents used in bioterrorism.

Development Status

     The pre-clinical performance of the viral microarray was 
evaluated by application of four virally positive infected cell lines 
(JSC-1-harboring EBV and KSHV, BCBL-1 harboring KSHV, HeLa- harboring 
HPV18, Cem X 174 harboring SIV).
     Clinical performance was tested and validated through 
analysis of total RNA from cold (swab), Japanese Encephalitis, Dengue, 
Ebola and West Nile virus samples.
    Inventors: Cassio S Baptista and David J Munroe (NCI).
    Patent Status: U.S. Patent Application No. 11/800,080 filed 02 May 
2007 (HHS Reference No. E-206-2006/0-US-03).
    Licensing Status: Available for licensing.
    Licensing Contact: Jeffrey A. James Ph.D.; 301-435-5474; 
[email protected].
    Collaborative Research Opportunity: The NCI Laboratory of Molecular 
Technology is seeking statements of capability or interest from parties 
interested in collaborative research to further develop, evaluate, or 
commercialize this oligo microarray for identification and detection of 
all known mammalian and avian pathogenic viruses. Please contact John 
D. Hewes, PhD at 301-435-3121 or [email protected] for more 
information.

    Dated: August 10, 2009.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E9-19691 Filed 8-14-09; 8:45 am]
BILLING CODE 4140-01-P