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###### Department of Health and Human Services

###### National Institutes of Health

# AGENCY:

National Institutes of Health, Public Health Service, DHHS.

# ACTION:

Notice.

# SUMMARY:

                        The inventions listed below are owned by agencies of the U.S.                               ( print 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: reichmau@od.nih.gov. 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                           ( print page 63874)                        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