[Federal Register Volume 65, Number 207 (Wednesday, October 25, 2000)]
[Notices]
[Pages 63872-63874]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-27355]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Invention; Availability for Licensing: Tissue 
Microarrays for Rapid Molecular Profiling

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.

[[Page 63873]]

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 may be obtained by contacting Uri 
Reichman, Ph.D., M.B.A., at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-3804; Telephone: 301/496-7736 ext. 240; Fax: 301/402-
0220; E-mail: [email protected]. A signed Confidential Disclosure 
Agreement will be required to receive copies of the patent 
applications.

SUPPLEMENTARY INFORMATION: Advances in medical research and the 
successful development of new, improved diagnostic tools and 
therapeutic agents are often dependent on the ability to screen 
thousands of clinical samples for molecular markers in a high-
throughput fashion. This is particularly critical in the ``post-
genomics'' era, where the number of genes to be analyzed is often much 
high than the number of samples evaluated. DNA microarray (``DNA 
chip'') and related genome-screening tools have made it possible to 
screen the genome to discover genes with medical utility. However, 
before they can be utilized in developing improved diagnostics and 
therapeutic applications these early discoveries in genomics and 
proteomics need to be tested and validated.
    The technology presented here, called Tissue Microarrays or 
``Tissue Chips'' is specifically designed to fill the need of the 
medical community for high throughput screening of hundreds of 
molecular markers in thousands of cell or tissue samples on a single 
microscope slide.
    Tissue Microarrays include hundreds or even thousands of tiny discs 
(approx. 1 mm in diameter) of tissue specimens, fixed and arranged on a 
single microscope slide. The technology provides an automated means to 
generate thousands of copies of this kind of slide, slides that then 
can be used for specific molecular analyses, such as DNA and mRNA in 
situ hybridization and protein immunostaining.
    A typical application of tissue microarrays in cancer research and 
product development is the analysis of several hundred breast tumors 
from patients at different stages of disease development (normal 
breast, atypia, in situ cancer, invasive cancer, metastases) to 
identify the specific step at which gene alterations take place, as 
well as the frequency of these alterations. In another example, tissue 
microarrays can be constructed from tissue materials in a retrospective 
study design, where one can immediately correlate the expression of a 
molecular marker with poor prognosis. Furthermore, tissue microarrays 
can be used to screen many different diseases at once, such as multiple 
different tumor types, non-malignant tissues, and normal tissues and 
cells.
    The data accumulated from these type of studies can serve as the 
basis for the development of diagnostic and prognostic tools for 
disease, classification of diseases into molecularly defined subgroups, 
as well as for identifying targets for therapeutic regimens for 
treating the disease.
    Tissue microarrays are useful in the early-stage discovery of gene 
targets in genomic research, in validation of such targets, in the 
testing and optimization of diagnostic tests, as well as in the quality 
control of molecular detection schemes. In the quality control field, 
it would be possible to provide a copy of a tissue microarray with 
commercial histological (IHC or ISH) test kits for QC procedure. Tissue 
microarrays could also be used to standardize pathology interpretations 
by sending copies of the same slides to different pathologists. 
Electronic database archives of previously analyzed tissue arrays could 
also be utilized as a teaching tool of anatomy and pathology for 
students, clinical lab technicians and physicians.
    The manufacturing of tissue microarrays is a critical step in the 
success of the technology. The NIH group has developed a manual tissue 
microarray device, which facilitates development of tissue microarrays. 
In addition, a prototype of an automated tissue microarrayer has been 
developed. This instrument consists of a donor specimen station and a 
recipient block station. An XY robotic arm retrieves cylindrical tissue 
specimens from the donor block and inserts them into assigned locations 
at cylindrical receptacles in the donor paraffin block. When the 
recipient tissue microarray block has been constructed, it is sectioned 
into 200 to 300 thin sections with a microtome. The resulting sections 
are then laid down and fixed on a microscope slide. The apparatus is 
controlled by a computer, which also stores the addressable sample 
locations.
    The commercial potential of the present technology is enormous. It 
is estimated that the total market for microarray high-throughput 
screening in 1999 was $176 million. With an estimated annual rate 
growth of 33%, the market size is expected to approach $1 billion by 
2005 (Source: Biosearch Online). Tissue microarray market is tied in 
with the other biochip markets, but it also presents an opportunity to 
expand microarray research and development into an entirely new 
direction. For example, most of the current microscopic tissue based 
analyses could in the future take place in a tissue microarray format, 
which provides several hundred-fold higher throughput than conventional 
analyses.
    The technology is available for licensing in its entirety or in 
parts. A list of the inventions available for licensing, along with a 
brief summary of each invention, is shown below.

Licensing of Tissue Microarrays Instrumentation and Related 
Fluorescence Systems

    (1) NIH Reference No. E-002-98/0 (USSN 60/075,979, PCT/US99/04001), 
entitled ``Tumor Tissue Microarrays for Rapid Molecular Profiling'', 
originally filed 02/25/98, PCT filed 02/24/99. Inventors: S. Leighton, 
O. Kallionemi and J. Kononen.
    (2) NIH Reference No. E-273-99/0 (USSN 60/170,461), entitled 
``Methods and Apparatus for Constructing Tissue Microarrays'', filed 
12/13/99. Inventors: O. Kallionemi, G. Sauter, S. Leighton and J. 
Kononen.
    These two patent applications disclose the specifics of the 
microarray-maker instrument. With the advances in the field of genomics 
it is predicted that the demand for tissue microarrays and thus the 
demand for tissue microarray instruments will increase rapidly in the 
next several years. Also offered for licensing (E-273-90/0) is an 
integrated tissue microarray system. The system includes three 
stations, i.e. array-making station, array processing station and a 
detection system (fluorescent imager). Licensing of either and/or both 
of the instrument inventions is particularly recommended for 
manufacturers of scientific and medical instrumentation.
    (3) NIH Reference No. E-272-99/0 (USSN 60/154,601), entitled 
``Signal Counting for In Situ Hybridization'', filed 9/17/99. 
Inventors: O. Kallionemi, J. Kononen, L. Buendorf, E. Dougherty and A. 
Grigoryan.
    The accurate detection and quantitation of fluorescence signal 
associated with FISH is critical for the molecular analysis of arrayed 
tissue specimens. In spite of recent improvements in fluorescence 
optics and related techniques, quantitation of FISH has not been 
perfected yet. This

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invention discloses a device and method for improving the accuracy of 
fluorescence spot counting. This has been accomplished mainly through 
the following improvements: (1) A method to analyze ratios of test and 
reference spot signals in a field of view, (2) an imaging system to 
acquire confocal images to cells to provide a set of different layers 
of the same cells, at different positions along the Z-axis, and (3) a 
software program to make use of the three-dimensional nature of the 
images, which makes the identification of FISH signals more accurate. 
Licensing of an algorithm for automated FISH spot counting is 
recommended for manufacturers of scientific and medical instrumentation 
and in particular for manufacturers of commercial imaging devices as 
well as companies that specialize in providing fluorescent probes for 
molecular biology research.

Licensing of Applications of Tissue Microarrays

    (4) NIH Reference No. E-007-99/0 (USSN 60/106,038, PCT/US99/04000), 
entitled ``Tissue Microarrays for Rapid Molecular Profiling'', 
originally filed 10/28/98, PCT filed 02/24/99. Inventors: O. 
Kallioniemi, G. Sauter and J. Kononen.
    (5) NIH Reference No. E-274-99/0 (USSN 60/171,262), entitled 
``Methods of Making and Using Microarrays'', filed 12/15/99. Inventors: 
O. Kallionemi and G. Sauter.
    These two inventions disclose methods of using tissue microarrays 
for a wide variety of clinical applications. E-007-99/0 describes in 
great detail high-throughput screening studies of thousands of tissue 
samples. These studies, ordinarily requiring many days to perform, can 
be completed in only a few hours when tissue microarrays are used. 
Licensees of this invention will be able to manufacture tissue 
microarrays using clinical samples and distribute the panels and 
companion reagents to the medical and research community. Commercially 
produced microarrays could be developed for use as reference standards 
for certain diseases or custom made for specific needs.
    E-274-99/0 describes the use of tissue microarrays for educational, 
standardization and OC (histological test kits) purposes. With respect 
to the first proposed use, licensees will be able, for example, to 
distribute microarray panels and companion reagents in medical teaching 
institutions. With respect to the latter two uses, standard microrray 
panels could be included in clinical test kits that are histological 
(IHC or ISH) procedures.
    Tissue Microarray technology and its applications have been 
described in several publications, such as Nature Medicine 4:844 
(1998), Cancer Research 59:803 (1999), J Natl Cancer Inst. 91:1758 
(1999), Clin Cancer Res 5:1966 (1999), J Natl Cancer Inst, 92:1252 
(2000).

    Dated: October 6, 2000.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer.
[FR Doc. 00-27355 Filed 10-24-00; 8:45 am]
BILLING CODE 4140-01-M