[Federal Register Volume 64, Number 137 (Monday, July 19, 1999)]
[Notices]
[Pages 38675-38678]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-18374]


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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 agencies 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

[[Page 38676]]

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.

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

Peter J. Basser (NICHD), Sinisa Pajevic (CIT)
DHHS Reference No. E-192-99/0 filed 21 May 1999
Licensing Contact: John Fahner-Vihtelic; 301/496-7735, ext. 270; e-
mail: [email protected]

    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 MIR 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.

Magnetic Resonance Tracking of Magnetically Labeled Cells

J. Bulte, I. Duncan, and J. Frank (CC)
DHHS Reference No. E-013-99/0 filed 21 May 1999
Licensing Contact: Leopold J. Luberecki, Jr., J.D.; 301/496-7735, ext. 
223; e-mail: [email protected]

    Demyelination is a common pathological finding in human 
neurological diseases and frequently persists as a result of failure of 
endogenous repair. It has recently been demonstrated that transplanted 
oligodendrocytes and their precursor cells can remyelinate axons. The 
survival, acute dispersion, and migratory pattern of these cell lines 
is crucial for the extent and limit of remyelination. Presently, the 
assessment of survival and migratory pattern is unpredictable and 
requires invasive, irreversible procedures. This invention describes a 
real time in vivo imaging of neural cells using nuclear magnetic 
resonance (NMR) imaging. The technique involves an ex vivo delivery of 
the contrasting agent into the target cells, which are then either 
injected or transplanted into the subject. These target cells can then 
be non-invasively monitored for their translocation. This technique has 
been successfully applied to the imaging of spinal cord samples and has 
potential for monitoring the treatment of neurodegenerative diseases 
and for monitoring the successful delivery and location of genetically 
modified cells for treatment of Parkinson's Disease. It may also have 
possible applications in the monitoring of cellular differentiation.

Oligodeoxynucleotide and Its Use To Induce an Immune Response

Dennis Klinman (FDA), Daniela Verthelyi (FDA), Kenji Ishii (NINDS)
Serial No. 60/128,898 filed 12 Apr 1999
Licensing Contact: Peter Soukas; 301/496-7056, ext. 268; e-mail: 
[email protected]

    This invention comprises oligodeoxynucleotides (ODNs) having at 
least 10 nucleotides with an unmethylated central CpG motif that are 
immunostimulatory in humans. The inventors have shown that the various 
ODNs of this invention (having different CpG notifs and backbones) 
induce immune responses from human non-B and B cells. The motif that 
stimulates non-B cells induces production and release of multiple T 
cell cytokines and chemokines; specifically, the Th1 cytokine IFN-
, which facilitates the development of a cytotoxic T cell 
response. In contrast, the motif that stimulates B cells induces 
production and release of various cytokines, including, but not limited 
to IL-6, which supports a Th2 antibody response. The inventors have 
generated in vitro and ex vivo data showing the ODNs of this invention 
have utility in precisely regulating the type and magnitude of the 
immune response in human cells. The present invention has multiple 
therapeutic uses, including but not limited to cancer, vaccine 
adjuvants, treating autoimmune disorders and immune system 
deficiencies, as well as an anti-infective agent and in combination 
with any antisense therapy.

Methods of Treating Colitis Using STAT-4 Antisense Oligonucleotide

Warren Strober, Ivan Fuss, Markus Neurath, Atsushi Kitani (NIAID)
Serial No. 60/125,877 filed 24 Mar 1999
Licensing Contact: Richard U. Rodriguez; 301/496-7056, ext. 287; e-
mail: [email protected]

    This invention described in this patent application relates to 
compositions and methods which can be used to treat diseases such as 
Crohn's disease, a form of inflammatory bowel disease. This disease has 
been linked to the interferon gamma (IFN) response induced by 
interleukin 12 (IL-12) production. Recent work has shown that 
IFN production is also a product of the activation of the 
signal transduction molecule Signal Transducer and Activator of 
Transcription-4 (STAT-4). Therefore, regulation of IFN 
production rather than IL-12 production may be a more effective means 
of treatment.
    The methods and compositions described in this patent application 
are antisense oligonucleotides derived from STAT-4 which inhibit the 
STAT-4 pathway. The antisense compositions have been studied in animal 
models, IL-10 knockout mice and mice having TNBS colitis. In these 
studies local administration of the antisense oligonucleotides rapidly 
reversed intestinal inflammation.

Ac-HEHA and Related Compounds, Methods of Synthesis and Methods of 
Use

Martin W. Brechbiel, Kim Deal (NCI) Serial No. 60/125,764 filed 23 Mar 
1999 Licensing Contact: Girish C. Barua; 301/496-7056 ext. 263; e-mail: 
[email protected]

    The invention is directed to a chelation complex comprising 
225 Actinium (225 Ac) and 1,4,7,10,13,16-
hexaazacyclohexadecane-N,N', N'',N''',N'''',N'''''-hexaacetic acid 
(HEHA) as well as bi-functional complexes consisting of 
225 Ac, HEHA and targeting agents in various combinations. 
Radioisotopes are chosen, in part, by the type of disease to be 
treated, and two important functions are tissue penetration of the 
emitted particles and

[[Page 38677]]

the toxicity of the treatment agents. 225 Ac, an alpha-
emitter, offers high cytotoxicity with a short tissue range, and HEHA 
chelates 225 Ac in such a manner as to provide increased in 
vivo stability to enable its use as a radiotherapeutic agent. 
Additionally, 225 Ac's radioactive decay chain ends in a 
non-radiocative material. A targeting agent can be conjugated to 
225 Ac-HEHA in order to selectively affect a defined 
population of cells through a receptor, a substrate, an antigenic 
determinant or any other binding site on the target cell population. 
Therefore, the invention yields improvements over existing related 
technologies for the radiotherapeutic treatment of disease states such 
as cancer. The disclosed complexes could also be used in radioimaging, 
decontamination and detoxification protocols.

Low Level Exposure to Extract of Neurotoxin for Protection From 
Brain Injury

WB Jonas (OD) and FC Tortella (U.S. Army) Serial No. 09/271,009 filed 
17 Mar 1999 Licensing Specialist: Leopold J. Luberecki, Jr., J.D.; 301/
496-7735 ext. 223; e-mail: [email protected]

    Approximately 438,000 persons will suffer a stroke per year; 
approximately 200,000 deaths can be attributed to stroke, thereby 
ranking stroke as the third leading cause of death in the United 
States. Strokes may affect anyone, but strokes strike approximately 
two-thirds of those individuals over 65 years of age. Reducing brain 
damage due to strokes or ischemic events would save many lives and 
significantly reduce the associated long-term health care costs 
associated of a stroke victim. This technology embodies an injectable 
preparation of the plant-derived neurotoxin and combinations with low 
doses of the amino acid glutamate, and has been shown to have the 
ability to reduce the damage in an animal stroke model by 50%. In 
addition to the neuroprotective qualities when given post trauma, a 
formulation, in preliminary tests, indicates that the neurotoxin may 
have preventive neuroprotective qualities when given prior to the 
trauma. This would be very beneficial for individuals at high risk.

A Novel Chimeric Protein for Prevention and Treatment of HIV 
Infection

Edward A. Berger (NIAID), Christie M. Del Castillo Serial No. 60/
124,681 filed 16 Mar 99 Licensing Contact: Carol Salata; 301/496-7735 
ext. 232; e-mail: [email protected]

    This invention relates to bispecific fusion proteins effective in 
viral neutralization. Such proteins have two different binding domains, 
an inducing-binding domain and an induced-binding domain, functionally 
linked by a peptide linker. More specifically, the invention is a 
genetically engineered chimeric protein containing a region of CD4 
attached via a flexible polypeptide linker to a human single chain MAb 
directed against CD4-induced, highly conserved HIV gp120 determinants 
involved in binding to coreceptor. The molecule is expected to have the 
properties of a potent, broadly cross-reactive neutralizing antibody 
against HIV. This novel agent will have considerable potential in the 
prevention of infection during or immediately following HIV exposure 
(e.g. vertical transmission; post-exposure prophylaxis) and possibly in 
the treatment of chronic infection. Such proteins, nucleic acid 
molecules encoding them, and their production and use in preventing or 
treating viral infections are claimed.

UPA, a Universal Protein Array System for Quantitative Detection of 
Protein-Protein, Protein-DNA, Protein-RNA and Protein-Ligand 
Interactions

Dr. Hui Ge (NICHD), Serial No. 60/123,586 filed 08 Mar 1999, Licensing 
Contact: Marlene Shinn; 301/496-7057 ext. 285; e-mail: [email protected]

    The Universal Protein Array (UPA) system is a newly developed 
research tool for the analysis and screening of potential drug targets. 
This technology uses the three dimensional structure of active proteins 
(without denaturation and renaturation) to determine specific protein-
protein, protein-DNA, protein-RNA, protein-ligand or protein-chemical 
interactions. Unlike most conventional DNA chips or DNA microarrays 
currently on the market, the UPA system requires no sophisticated 
equipment and is in fact more sensitive than existing methods. The UPA 
system is able to analyze thousands of protein samples in a single 
experiment, thereby making it a highly efficient way to screen proteins 
for potential drug targets. Also, because it can be used multiple times 
for different targets, it is economically affordable for most 
laboratories or hospitals.
    In addition to being useful as a screening tool, the UPA system can 
also be used to study gene regulation pathways such as transcription, 
RNA processing, replication, translation, and signal transduction, to 
name a few. The technology found in the UPA system could also 
potentially be commercialized in a kit form and be applied to the 
diagnosis of disease states in patients in the clinical setting.

Methods for Mitochondrial Gene Therapy

Steven J. Zullo (NIMH), Jerome M. Eisenstadt, Wayne A. Fenton, DHHS 
Reference No. E-121-99/0 filed 08 Mar 1999, Licensing Contact: Dennis 
Penn; 301/496-7056 ext. 211; e-mail: [email protected]

    Although the role of the mitochondrion in providing energy for the 
cell by the process of oxidative phosphorylation has been known for a 
long time, the role of the mitochondrial genome and the consequences of 
defects in the mitochondrial genome are just being understood. These 
mutations or defects in the mitochondrial genome are responsible for 
many diseases, conditions, or syndromes.
    This invention is directed to methods for functionally 
complementing at least one defect, mutation, or deletion in the 
mitochondrial genome which comprises: (1) Selecting a mitochondrial 
gene; (2) determining the nucleic acid sequence of the gene; (3) 
optionally, where the nucleic acid sequence encodes a protein and at 
least one of the codons encoding the protein has a different meaning in 
the mitochondrial genetic code and the universal genetic code, mutating 
the nucleic acid sequence to reflect the difference between the 
mitochondrial and universal genetic codes so that, in the mutated 
sequence, a polypeptide that is expressed as the result of nuclear 
transcription of the nucleic acid sequence, and cytoplasmic translation 
of the messenger RNA, has the same amino acid sequence as the 
polypeptide originally expressed in the mitochondrion; (4) optionally, 
attaching the coding sequence of a functional mitochondrial protein 
targeting sequence to the nucleic acid sequence for nuclear expression; 
(5) operatively linking the protein targeting sequence, if present, and 
the nucleic acid sequence to at least one control element that provides 
constitutive expression to generate a nucleic acid construct; and (6) 
inserting the nucleic acid construct into the nuclear genome of a 
eukaryotic cell for expression of the nucleic acid segment in the cell 
to provide functional complementation of at least one defect, mutation, 
or deletion in the mitochondrial genome. The method can also be used 
for the total replacement of mitochondrial genome function, including 
the use of transgenic techniques.

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Monoclonal Antibodies Specific and Inhibitory to Human Cytochrome 
P450 2C8, 2C9, 2C18 And 2C19--New Avenues for Drug Discovery

Harry V. Gelboin, Frank J. Gonzalez, Kristopher W. Krausz, (NCI),
DHHS Reference No. E-077-99/0 filed 12 Feb 99
Licensing Contract: Dennis Penn; 301/496-7056 ext. 211; e-mail: 
[email protected]

    The cytochrome P450 family of enzymes has primary responsibility 
for the metabolism of xenobiotic drugs and non-drug carcinogens and 
environmental chemicals, as well as some endobiotics. This laboratory 
has isolated monoclonal antibodies (MAbs) that are specific to and 
inhibit the ten major human cytochrome P450s (CYPs) that are 
responsible for the metabolism of most drugs. The MAb based analytic 
system identifies the P450s responsible for metabolism of a drug and is 
thus an entirely new system for Drug Discovery. Drug-drug toxicity can 
be due to drug partners competing for an individual P450 and be a cause 
of drug toxicity. Certain drugs given to genetically polymorphic 
individuals that are defective in a specific P450 can cause serious 
toxicity to the defective individual. In one case 6-10% of the world 
population are missing an important P450 (2D6).
    The 2C family of cytochrome P450s metabolizes a very large and 
extensive number of drugs which include tolbutamide, S-Warfarin, 
mephenytoin, diazepam and taxol. The invention reports the production 
of inhibitory MAbs to the P450 2C family. The invention describes MAb 
5-1-5 and 281-1-1 that specifically inhibit CYP 2C8. MAb 292-2-3 that 
specifically inhibit CYP 2C9 and MAb 592-2-5 that specifically inhibit 
both CYP 2C9 and 2C18. MAb 5-7-5 specifically inhibits CYP 2C9, 2C18, 
and 2C19. In addition MAb 1-68-11 previously reported specifically 
inhibits all four members of the 2C family, 2C8, 2C9, 2C18, and 2C19. 
The MAbs may be used as diagnostic probes identifying the single or 
several P450s responsible for a drugs metabolism and also yield 
important information on inter-individual differences. The MAb system 
identifies and characterizes the P450 based metabolism of drugs 
currently in use and drugs in the screening and development stages of 
Drug Discovery.

    Dated: July 13, 1999.
Jack Spiegel, Ph.D.
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 99-18374 Filed 7-16-99; 8:45 am]
BILLING CODE 4140-01-P