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Information on Recently Published Patents - IMAT Funded Research Grants

The eight patents below are the most recently published patents identified through the IMAT-grant query of the U.S. Patent and Trademark Office (USPTO) Issued Patent Database. Note that all information in the tables below was directly copied from the USPTO database and has not been modified in any way.

Example 1. Systems and Methods for Volumetric Tissue Scanning Microscopy, Approved in 2008.

United States Patent 7,372,985
Date May 13, 2008
Title Systems and methods for volumetric tissue scanning microscopy
Abstract In accordance with preferred embodiments of the present invention, a method for imaging tissue, for example, includes the steps of mounting the tissue on a computer controlled stage of a microscope, determining volumetric imaging parameters, directing at least two photons into a region of interest, scanning the region of interest across a portion of the tissue, imaging a plurality of layers of the tissue in a plurality of volumes of the tissue in the region of interest, sectioning the portion of the tissue and imaging a second plurality of layers of the tissue in a second plurality of volumes of the tissue in the region of interest, detecting a fluorescence image of the tissue due to said excitation light; and processing three-dimensional data that is collected to create a three-dimensional image of the region of interest.
Inventors So; Peter (Cambridge, MA), Engelward; Bevin (Jamacia Plain, MA), Ragan; Timothy (Cambridge, MA), Bahlmann; Karsten (Cambridge, MA), Kim; Ki Hean (Cambridge, MA), Hsu; Lily (Arlington, MA), Huang; Hayden (Somerville, MA)
Assignee Massachusetts Institute of Technology (Cambridge, MA)
Appl. No.: 10/642,447
Government Support R2I/33 CA84740 from the National Institute of Health
Summary of the Invention The systems and methods of the present invention include imaging techniques that provide quantification of morphological, biochemical and/or genetic states of cells inside tissues. Preferred embodiments of the present invention include a high-speed, two-photon, or multi-photon scanning microscope used, for example, for deep tissue imaging in highly scattering media with minimal photodamage. Real-time tissue images with submicrometer resolution in three- or two-dimensions can be obtained. A main advantage of two-photon video-rate imaging lies with its low phototoxicity. The short, pixel dwell time due to high scanning speed involves the need for optimization of the light budget.

Another preferred embodiment improves on the excitation efficiency and includes compressing the laser pulse width by means of group velocity compensation and increasing the pulse repetition rate to approximate the inverse of typical fluorescence decay lifetimes. High-speed, three-dimensional (3-D) resolved two-photon microscopy provides new opportunities for the development of noninvasive biomedical applications, including optical biopsy, quantitative study of 3-D tissue architecture, and monitoring of wound healing and tissue regeneration.

A method for imaging tissue, for example, includes the steps of mounting the tissue on a computer controlled stage of a microscope, determining volumetric imaging parameters, directing at least two photons into a region of interest, scanning the region of interest across a portion of the tissue, imaging a plurality of layers of the tissue in a plurality of volumes of the tissue in the region of interest, sectioning the portion of the tissue and imaging a second plurality of layers of the tissue in a second plurality of volumes of the tissue in the region of interest, detecting a fluorescence image of the tissue due to said excitation light; and processing three-dimensional data that is collected to create a three-dimensional image of the region of interest.

The method includes a multi-photon microscope. The penetration depth of the multi-photon microscope is in the range of approximately 200-500 .mu.m. The step of sectioning further includes a microtome system integral with the microscope. The speed of the step of imaging includes at least 5 frames per second. The step of scanning further includes video rate scanning (approximately 30 frames per second). The method further includes providing a depth resolution of approximately 0.1 .mu.m or higher. In a preferred embodiment the depth resolution is between a range of 0.1 and 2 .mu.m.

In accordance with another aspect of the invention, a system for providing a three-dimensional image of a region of interest, includes a light source for producing excitation light and providing at least two photons into a region of interest, a scanning microscope optically coupled to the light source, a tissue sectioning device such as, for example, but not limited to, a rotating blade, vibratome or microtome mechanically coupled to the microscope, an x-y scanner to scan the region of interest, an image sensor that detects a plurality of images of the region of interest; and a data processor that processes the plurality of images to produce a processed three-dimensional image of the region of interest.

The system can include a multi-photon microscope. The microscope can be a confocal microscope. The light source is preferably a Titanium-Sapphire laser or a picosecond or femtosecond laser. The system can include a rotating polygonal mirror that provides a fast scanning axis and a galvanometer driven mirror that provides a slow scanning axis and. The system also includes a piezoelectric-driven lens translator that provides a depth axis. The system has at least one diode to generate a reference signal. The image sensor can be a charge coupled device (CCD), an avalanche photodiode or a photomultiplier tube (PMT). The excitation light is in the range of 650-1200 nm and preferably in the range of 700-1100 nm for two photon excitation.

In another embodiment, a method of imaging tissue, includes the steps of mounting the tissue in a multi-photon microscope, directing at least two photons onto a region of interest, scanning a plurality of layers of the tissue in the region of interest and to limit the region of excitation, imaging a plurality of layers in the region of interest in the tissue, detecting a fluorescence image of the tissue due to said excitation light in the region of interest, processing the detected fluorescence image including the steps of sequentially storing a plurality of portions of a three-dimensional image data set, enhancing the image data set, registering individual three-dimensional data sets to generate a large three-dimensional data set, and displaying the three-dimensional data set of the region of interest.

The step of processing can further include compressing the three-dimensional data set, identifying and quantifying features of the region of interest. The step of processing further includes analyzing the three-dimensional data set. The step of imaging includes, for example, imaging mitotic recombination in tissues in transgenic animals wherein recombination events give rise to a fluorescent signal.

In accordance with another aspect of the present invention, a method of imaging tissue includes initially scanning a plurality of layers of tissue at a lower resolution, optically or spectrally or using a combination of both, followed by imaging a certain identified region of interest using a higher resolution imaging mode as described herein before.

The foregoing and other features and advantages of the systems and methods for volumetric tissue scanning microscopy will be apparent from the following more particular description of preferred embodiments of the system and method as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

 

Example 2. Composite Sensor Membrane, Approved in 2008.

United States Patent 7,344,678
Date March 18, 2008
Title Composite sensor membrane
Abstract A sensor may include a membrane to deflect in response to a change in surface stress, where a layer on the membrane is to couple one or more probe molecules with the membrane. The membrane may deflect when a target molecule reacts with one or more probe molecules.
Inventors Majumdar; Arun (Orinda, CA), Satyanarayana; Srinath (Berkeley, CA), Yue; Min (Albany, CA)
Assignee The Regents of the University of California (Oakland, CA)
Appl. No.: 10/420,661
Government Support R21 CA86132-01 awarded by the National Institutes of Health/National Cancer Institute and Contract No. DE-FG03-98ER14870 awarded by the United States Department of Energy
Summary of the Invention In general, in one aspect, a sensor may include a membrane to deflect in response to a change in surface stress. A layer on the membrane may be provided to couple one or more probe molecules with the membrane. The membrane may deflect when a target molecule reacts with one or more probe molecules. The membrane may be fixed to a substrate at a first portion and a second different portion, and may span a well in the substrate.

The membrane may include a flexible material, such as a polymer. Polymers such as polyimide and parylene, or other polymers may be used. The layer may include a material to couple probe molecules to the membrane. For example, the layer may include gold. The layer may cover a portion of a first side of the membrane. The portion may be between about 5% and about 90%, or between about 10% and about 70%.

A system may include a substrate and one or more membranes coupled with the substrate. For example, the system may include a membrane spanning a well, where the membrane may have a layer to couple probe molecules to the membrane. The system may also include another membrane spanning another well, where the another membrane has a layer to couple probe molecules with the membrane. The system may include a cover to enclose the well and the another well. The system may include channels to provide fluid to the membranes.

In general, in another aspect, a method may include introducing fluid into a region proximate to a membrane, the fluid including one or more target molecules to be sensed. At least some of the target molecules may interact with the probe molecules and cause the membrane to deflect. The method may include measuring the deflection of the membrane. The deflection may be measured using optical detection methods and/or electrical detection methods.

The details of one or more implementations are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings, and from the claims.

 

Example 3. Spectral Imaging of Deep Tissue, Approved in 2008.

United States Patent 7,321,791
Date January 22, 2008
Title Spectral imaging of deep tissue
Abstract Apparatus and methods are provided for the imaging of structures in deep tissue within biological specimens, using spectral imaging to provide highly sensitive detection. By acquiring data that provide a plurality of images of the sample with different spectral weightings, along with subsequent spectral analysis, light emission from a target compound is separated from autofluorescence in the sample. With the autofluorescence reduced or eliminated, an improved measurement of the target compound is obtained.
Inventors Levenson; Richard (Brighton, MA), Cronin; Paul J. (Charlestown, MA)
Assignee Cambridge Research and Instrumentation, Inc. (Woburn, MA)
Appl. No.: 10/669,101

 

Example 4. Method for Determining Differences in Molecular Interactions and for Screening a Combinatorial Library, Approved in 2007.

United States Patent 7,291,456
Date November 6, 2007
Title Method for determining differences in molecular interactions and for screening a combinatorial library
Abstract The invention includes a method for determining the differences between the molecular interactions of two different mixtures of molecules and identifying ligands specific for molecules in one mixture. The method utilizes a combinatorial library to compare the molecular interactions of the two mixtures and eliminates those interactions that are common to both mixtures and those that are unique to the first mixture, such that interactions essentially unique to the target mixture are identified. Ligands specific for molecules in the target mixture can then be identified. The invention also includes a method of screening a combinatorial library to distinguish between true positive beads and false positive beads and to provide for the identification of ligands specific for target molecules.
Inventors Lam; Kit S. (Davis, CA), Lehman; Alan L. (Sacramento, CA)
Assignee The Regents of the University of California (Oakland, CA)
Appl. No.: 10/057,178
Government Support Grant Nos. R21 CA78909 and R33 CA86364, awarded by the National Institutes of Health/National Cancer Institute
Summary of the Invention The present invention is directed to a quick and efficient method for comparing and determining the differences between the molecular interactions of two different mixtures of molecules and of identifying ligands specific for molecules in one of the mixtures, the target mixture. The method compares the molecular interactions of the two mixtures and eliminates those interactions that are common to both mixtures and those that are unique to the first mixture, such that the interactions essentially unique to the target mixture are identified. Then, ligands specific for molecules in the target mixture can be identified.

The method comprises: preparing first and second mixtures of molecules with a tag or label, where the second mixture is the target mixture; introducing the first mixture to a combinatorial library of solid phase supports; incubating the library with the first mixture of molecules; performing a first marking step to mark the solid phase supports that have molecules of the first mixture bound to them; introducing the target mixture to the library; incubating the library with the target mixture of molecules; immobilizing the library; obtaining a first image, referred to as image “A,” before the marking of any solid phase supports that have molecules of the target mixture bound to them, showing as marked only those solid phase supports that were marked in the first marking step; performing a second marking step to mark the solid phase supports that have molecules of the target mixture bound to them; obtaining a second image, referred to as image “B,” showing as marked those solid phase supports that were marked in the first marking step and those that were marked in the second marking step; performing image analysis on the first and second images to create a third image referred to as “C,” showing, for each solid phase support, (B-A)/A, such that image “C” identifies the solid phase supports that were marked only in the second marking step; isolating a solid phase support identified in image “C”; and determining the chemical structure of the compound on that solid phase support.

The invention is also directed to a method for screening a combinatorial bead library that quickly and accurately distinguishes between a small number of true positive beads and a large number of false positive beads and provides for the identification of ligands specific for a target molecule.

 

Example 5. Method for Screening Combinational Bead Library; Ligands for Cancer Cells, Approved in 2007.

United States Patent 7,262,269
Date August 28, 2007
Title Method for screening combinational bead library; ligands for cancer cells
Abstract The invention includes a cell-growth-on-bead assay for screening a one-bead-one-compound combinatorial bead library to identify synthetic ligands for cell attachment and growth or proliferation of epithelial and non-epithelial cells. Cells are incubated with a compound bead library for 24 to 72-hours, allowing them to attach and grow on the beads. Those beads with cells growing are removed, and the ligand on the bead is identified. Also provided are ligands specific for cancer cells.
Inventors Lam; Kit S. (Davis, CA), Lau; Derick H. (Gold River, CA)
Assignee The Regents of the University of California (Oakland, CA)
Appl. No.: 10/682,659
Government Support R33 CA89706 awarded by the National Cancer Institute and the National Institutes of Health
Summary of the Invention The present invention is directed to a method for screening a combinatorial bead library for ligands that promote the attachment and growth or proliferation of epithelial and non-epithelial cells. The method satisfies the need for an assay that is specific and sensitive, that can be used to detect cell surface receptors susceptible to trypsin, and that can identify ligands that promote cell growth and proliferation. The method comprises introducing a suspension of live cells to a combinatorial library of small molecules, peptides, or other types of molecules, incubating the cells with the library for about 24 to 72 hours, identifying a solid phase support of the library with cells growing on the support, isolating the solid phase support, and determining the chemical structure of the compound attached to that solid phase support.

The invention also includes ligands specific for cell attachment and growth or proliferation of epithelial and non-epithelial cancer cells.

 

Example 6. Ultrasound-Mediated High-Speed Biological Reaction and Tissue Processing, Approved in 2008.

United States Patent 7,262,022
Date August 28, 2008
Title Ultrasound-mediated high-speed biological reaction and tissue processing
Abstract Methods of fixing and processing tissue and samples on a membrane by using ultrasound radiation as a part of the method are presented. Ultrasound of a frequency in the range of 0.1-50 MHz is used and the sample or tissue receives 0.1-200 W/cm2 of ultrasound intensity. The use of ultrasound allows much shorter times in the methods. Also presented are apparati comprising transducers of one or of multiple heads for producing the ultrasound radiation and further comprising a central processing unit and optionally comprising one or more sensors. Sensors can include those to measure and monitor ultrasound and temperature. This monitoring system allows one to achieve accurate and optimum tissue fixation and processing without overfixation and tissue damage. The system also allows the performance of antigen-antibody reactions or nucleic acid hybridizations to be completed in a very short time while being highly specific and with a very low or no background.
Inventors Chu; Wei-Sing (Silver Spring, MD)
Assignee American Registry of Pathology (Washington, DC)
Appl. No.: 09/901,013

Example 7

 

Example 7. Methods for Rapid Screening of Polymorphisms, Mutations, and Methylation, Approved in 2008.

United States Patent 7,247,428
Date July 24, 2008
Title Methods for rapid screening of polymorphisms, mutations and methylation
Abstract The present method is directed to methods of detecting mismatches, polymorphisms, and methylation in multiple genes or the same gene in multiple individuals.
Inventors Makrigiorgos; Gerrasimos M. (Brookline, MA)
Assignee Dana-Farber Cancer Institute, Inc. (Boston, MA)
Appl. No.: 10/179,053

 

Example 8. Allelic Imbalance in the Diagnosis and Prognosis of Cancer. Approved in 2008.

United States Patent 20080108057
Date May 8, 2008
Title Allelic imbalance in the diagnosis and prognosis of cancer
Abstract Methods for assessing the extent of allelic imbalance in a genomic nucleic acid sample. Methods for diagnosing cancer and determining the prognosis of a patient with cancer, including breast or prostate cancer, by assessing the extent of allelic imbalance in a genomic nucleic acid sample.
Inventors Griffith; Jeffrey K; (Cedar Crest, NM)
Assignee Mueting, Raasch & Gebhardt, P.A. (Minneapolis, MN)
Appl. No.: 435/6

 

Return on Investment: Patents Awarded Per Dollar Spent on IMAT

The number of patent applications citing the IMAT Program has steadily increased since the program’s inception (see patent trends). Approximately 101 patents have been filed or received by the program since 2001, with 7 additional patents approved between 2007 and the first half of 2008. All patent analyses were performed only on applications and patents in USPTO databases that specifically cited an IMAT grant number, which assumes that all inventors acknowledged this information and that they entered the grant number using 1 of 4 possible iterations in the Government Interest field. Based on these parameters, the average approximate program expenditure per patent over the course of the program’s lifespan is approximately $343,353, or roughly the size of a large R21.