By Electrophoresis Patents (Class 356/344)
  • Patent number: 5754291
    Abstract: The present invention features two flat-field, telecentric, infinite conjugate, achromatic objectives each of which has an external pupil lying in a common plane located equidistant from the two objectives, defining a mechanically accessible central pupil of an imaging system centered in the common plane. Each of the objectives are afocal in the common plane, with one of the lenses forming a focal plane proximate to a sample. The lenses are adapted to provide varying levels of magnification while keeping constant the number of resolvable points in the field of view. An array detector is positioned proximate to a focal plane formed of the remaining objective lens. The double objective lens assembly is described as being included in transillumination and epi-illumination systems.
    Type: Grant
    Filed: September 19, 1996
    Date of Patent: May 19, 1998
    Assignee: Molecular Dynamics, Inc.
    Inventor: Robert C. Kain
  • Patent number: 5712476
    Abstract: An improved electrophoresis and fluorescence detection apparatus has an electromagnetic radiation sensor juxtaposed with a sensing region. The output signal from the electromagnetic radiation sensor is a current signal, and the current signal is converted to a voltage signal. The voltage signal is summed with a programmable offset generated by an inexpensive eight-bit D/A converter. The offset signal is selected to establish a lower starting point for the dynamic range of the A/D conversion, and is selected to null some or all of the background electromagnetic radiation level. The summed signal is amplified and integrated in an integrator. The integrator is switchable under program control. The integrator is switched on for long and short intervals. The short intervals permit sensing over a dynamic range accommodating very high levels of fluorescence; very high peaks may be measured and features of the peaks distinguished.
    Type: Grant
    Filed: March 27, 1996
    Date of Patent: January 27, 1998
    Assignee: Visible Genetics Inc.
    Inventors: John A. Renfrew, James W. Cassidy
  • Patent number: 5710628
    Abstract: Improved detection methods and apparatus which may be used individually or in various combinations enhance the ability of the electrophoresis apparatus to detect fluorophore-labeled materials in short periods of time.
    Type: Grant
    Filed: December 12, 1994
    Date of Patent: January 20, 1998
    Assignee: Visible Genetics Inc.
    Inventors: Paul Waterhouse, John A. Renfrew, John K. Stevens
  • Patent number: 5699157
    Abstract: The present invention provides a microfluidic system for fast, accurate and low cost electrophoretic analysis of materials in the fields of chemistry, biochemistry, biotechnology, molecular biology and numerous other fields. Light from periodically spaced regions along a channel in the microfluidic system are received by a photodetector. The intensity of light received by the photodetector is modulated by the movement of species bands through the channel under electrophoretic forces. By Fourier analysis, the velocity of each species band is determined and the identification of the species is made by its electrophoretic mobility in the channel.
    Type: Grant
    Filed: July 16, 1996
    Date of Patent: December 16, 1997
    Assignee: Caliper Technologies Corp.
    Inventor: J. Wallace Parce
  • Patent number: 5627643
    Abstract: The present invention comprises a method Of detecting and quantifying components separated by capillary electrophoresis or other techniques using thin capillaries in the separation. The method of the present invention comprises irradiating the whole or large parts of the capillary at short time intervals and detecting the fluorescence originating from the sample components, preferably by a CCD detector (charge coupled device). Thereby, an instantaneous image of the progress of the separation process is obtained. The present invention further comprises an apparatus for performing this detection.
    Type: Grant
    Filed: October 7, 1994
    Date of Patent: May 6, 1997
    Inventors: Staffan Birnbaum, Jonas Johansson, Per-Olof Larsson, Akiyoshi Miyabayashi, Klaus Mosbach, Staffan Nilsson, Sune Svanberg, Karl-Gustav Wahlund
  • Patent number: 5584982
    Abstract: A multiple capillary analyzer allows detection of light from multiple capillaries with a reduced number of interfaces through which light must pass in detecting light emitted from a sample being analyzed, using a modified sheath flow cuvette. A linear or rectangular array of capillaries is introduced into a rectangular flow chamber. Sheath fluid draws individual sample streams through the cuvette. The capillaries are closely and evenly spaced and held by a transparent retainer in a fixed position in relation to an optical detection system. Collimated sample excitation radiation is applied simultaneously across the ends of the capillaries in the retainer. Light emitted from the excited sample is detected by the optical detection system. The retainer is provided by a transparent chamber having inward slanting end walls. The capillaries are wedged into the chamber.
    Type: Grant
    Filed: March 29, 1995
    Date of Patent: December 17, 1996
    Assignee: The Governors of the University of Alberta
    Inventors: Norman J. Dovichi, Jian Z. Zhang
  • Patent number: 5578460
    Abstract: The present invention sorts microorganism populations from a mixture which contains more than one microorganism population. Microorganisms of different types vary in size, shape, and surface charge characteristics. These characteristics we believe contribute to the rate of migration for microorganisms under the influence of an electric field. Microorganisms of the same population (genus and species) will migrate similarly. By applying an electric field in a direction opposite the direction of fluid flow, separation is enhanced.
    Type: Grant
    Filed: April 18, 1995
    Date of Patent: November 26, 1996
    Assignee: E. I. Du Pont de Nemours and Company
    Inventors: Richard C. Ebersole, John G. DeCarolis, Randy M. McCormick
  • Patent number: 5556529
    Abstract: The improved DNA base sequencer has a flat plate type gel electrophoretic unit that has multiple tracks for electrophoresing DNA fragments and which is held in a vertical position, a light exciting laser light applying unit that applies laser light to the respective tracks in the electrophoretic unit from one lateral side thereof in such a way that it crosses the tracks at right angles, and a fluorescence detecting unit that detects the fluorescence as generated from the DNA fragments illuminated with the laser light and which converts the detected fluorescence to an electric signal. The sequencer is characterized in that the fluorescence detecting unit comprises a fluorescence condensing lens, a fluorescence filtering unit and a solid-state imaging device, (e.g., a CCD line sensor), the fluorescence filtering unit being composed of at least two filters that selectively transmit fluorescences having different wavelengths and that are staggered with each other along a common longitudinal axis.
    Type: Grant
    Filed: July 10, 1995
    Date of Patent: September 17, 1996
    Assignee: Hitachi Electronics Engineering Co., Ltd.
    Inventor: Ryozi Nemoto
  • Patent number: 5552322
    Abstract: The improved DNA base sequencer comprises a flat plate type gel electrophoretic means that has a multiple of tracks for electrophoresing DNA fragments and which is held in a vertical position, a light exciting laser light applying means that applies laser light to the respective tracks in said electrophoretic means from one lateral side thereof in such a way that it crosses said tracks at right angles, and a fluorescence detecting means that detects the fluorescence as generated from the DNA fragments illuminated with the laser light and which converts the detected fluorescence to an electric signal, and it is characterized in that the fluorescence detecting means comprises an index-distributed lens array, a filter and a solid-state imaging device such as a CCD line sensor. This apparatus uses light-receiving optics that does not include a large and expensive optical device such as an image intensifier and which yet is capable of efficient fluorescence detection without "smiling" and other adverse effects.
    Type: Grant
    Filed: September 28, 1994
    Date of Patent: September 3, 1996
    Assignee: Hitachi Electronics Engineering Co., Ltd.
    Inventors: Ryozi Nemoto, Yoshinori Mishina
  • Patent number: 5549805
    Abstract: To sequence DNA automatically, fluorescently marked DNA are electrophoresed in a plurality of channels through a gel electrophoresis slab; wherein the DNA samples are resolved in accordance with the size of DNA fragments in the gel electrophoresis slab into fluorescently marked DNA bands. The separated samples are scanned photoelectrically with a laser and a sensor, wherein the laser scans with scanning light at a scanning light frequency within the absorbance spectrum of said fluorescently marked DNA samples and light is sensed at the emission frequency of the marked DNA. The light is modulated from said laser at a predetermined modulation frequency and fluorescent light emitted by said DNA bands at said modulation frequency is detected, whereby background noise from the medium through which the light is transmitted is discriminated against.
    Type: Grant
    Filed: August 11, 1994
    Date of Patent: August 27, 1996
    Assignee: The Board of Regents of the University of Nebraska
    Inventors: Lyle R. Middendorf, John A. Brumbaugh, Gi Y. Jang
  • Patent number: 5545901
    Abstract: An apparatus and method are set for determining the centers of capillaries in a multicapillary electrophoresis array for subsequent rapid and efficient laser induced fluorescence interrogation. A galvometric scanner reflects the laser beam to scan the array during an alignment pre-scan. The beam interacts with the array to produce an intensity pattern indicative of the capillary centers. The scanner positions corresponding to the capillary centers determined during the pre-scan is recalled to direct the beam during the interrogation scan to the column centers.
    Type: Grant
    Filed: August 23, 1995
    Date of Patent: August 13, 1996
    Assignee: Beckman Instruments, Inc.
    Inventors: Stephen L. Pentoney, Jr., Clarence Y. Lew, David Rakestraw
  • Patent number: 5543018
    Abstract: Changes in polarized light incident on a detection zone within a separation matrix are used to detect optically active molecules within the separation matrix. The separation and detection of optically active molecules within the detection zone is done by loading a sample containing optically active molecules onto a separation matrix; applying a motive force to cause the sample to migrate through the separation matrix and to separate into a plurality of subgroups of optically active molecules; directing an incident beam of polarized radiation to the detection zone; processing the collected exiting beam with an optical component which discriminates between radiation having the same polarization as the incident beam and radiation having a different polarization from the incident beam; and measuring the intensity of the processed exiting beam.
    Type: Grant
    Filed: February 13, 1995
    Date of Patent: August 6, 1996
    Assignee: Visible Genetics Inc.
    Inventors: John K. Stevens, Alexandre M. Ismailov
  • Patent number: 5540825
    Abstract: A noise-suppressing capillary separation system for detecting the real-time presence or concentration of an analyte in a sample is provided. The system contains a capillary separation means through which the analyte is moved, a coherent light source that generates a beam which is split into a reference beam and a sample beam that irradiate the capillary, and a detector for detecting the reference beam and the sample beam light that transmits through the capillary. The laser beam is of a wavelength effective to be absorbed by a chromophore in the capillary. The system includes a noise suppressing system to improve performance and accuracy without signal averaging or multiple scans.
    Type: Grant
    Filed: March 20, 1995
    Date of Patent: July 30, 1996
    Assignee: Iowa State University Research Foundation, Inc.
    Inventors: Edward S. Yeung, Yongjun Xue
  • Patent number: 5538613
    Abstract: An apparatus for detecting fluorescently-labeled molecules moving in an electrophoretic separation medium. The apparatus utilizes a scanning detection system in which multiple fluorophores are efficiently and simultaneously detected using dichroic mirrors to allow simultaneous detection of fluorescently-labeled molecules in ultrathin gels labeled with several fluorophores and to permit operation at speeds ten times faster than prior art gel separations. The apparatus also utilizes a detection system where lightweight collection optics are in motion while detection optics are fixed in a remote location, thereby allowing exceptionally high-speed scanning.
    Type: Grant
    Filed: October 19, 1995
    Date of Patent: July 23, 1996
    Assignee: GeneSys Technologies, Inc.
    Inventors: Robert L. Brumley, John A. Luckey
  • Patent number: 5534703
    Abstract: An electrophoresis analyzer includes a light detector for detecting images of a linear fluorescence emitting region, the linear fluorescence emitting region including a plurality of fluorescence emitting points disposed along a straight line, each of the fluorescence emitting points being a point at which samples emit light including a plurality of wavelengths, the light detector including a line sensor, the line sensor including a plurality of photopixels disposed along a straight line, the photopixels constituting a detection surface of the line sensor, an image forming unit for receiving the light emitted by the samples at the fluorescence emitting points and forming a plurality of images of each of the fluorescence emitting points on the detection surface of the line sensor at mutually different positions disposed at a predetermined interval along the straight line along which the photopixels are disposed, and a filter unit disposed between the linear fluorescence emitting region and the light detector fo
    Type: Grant
    Filed: March 30, 1994
    Date of Patent: July 9, 1996
    Assignee: Hitachi, Ltd.
    Inventors: Hideki Kambara, Takashi Anazawa, Satoshi Takahashi, Katsuhiko Murakami
  • Patent number: 5529679
    Abstract: An electrophoresis apparatus includes a plurality of first capillaries containing a separation medium, such as a gel, and an optical cell in which one end of each of the first capillaries is disposed. Samples labeled with fluorophores are introduced into the first capillaries, and an electric field is applied to the first capillaries to cause the samples to migrate through the first capillaries into the optical cell. A light source excites the fluorophores with light when the samples are in the optical cell, causing the fluorophores to emit fluorescence, and a photodetecting system detects the fluorescence emitted by the fluorophores. The ends of the first capillaries in the optical cell may be arranged in a straight line. The light source may include a He-Ne laser emitting light having a wavelength of 594 nm, and the fluorophores may include either sulforhodamine or a derivative of sulforhodamine.
    Type: Grant
    Filed: November 7, 1994
    Date of Patent: June 25, 1996
    Assignee: Hitachi, Ltd.
    Inventors: Satoshi Takahashi, Hideki Kambara
  • Patent number: 5528366
    Abstract: This invention describes a method by which the precision of the reported molecular weights and radii of chromatographically separated molecules may be estimated. By suitably analyzing both the baseline and peak regions of a chromatogram, one may determine standard deviations of the signals from the various chromatographic detectors used in the analysis. This procedure yields standard deviations of the calculated values of molecular weight and root mean square radius of the separated molecules, as well as standard deviations of the calculated moments of the distribution of molecules. These standard deviations provide an estimate of the precision of the measurements.
    Type: Grant
    Filed: October 20, 1994
    Date of Patent: June 18, 1996
    Assignee: Wyatt Technology Corporation
    Inventor: David W. Shortt
  • Patent number: 5527680
    Abstract: A flow-through receptacle is disclosed, one end of which is designed to hold multiple plugs of gel material, containing solutes such as macromolecules, excised from electrophoretic separations, and the other end of which is capable of insertion into a recipient matrix that lies between the plates of a slab gel enclosure in an electrophoresis apparatus. The receptacle is used to place the gel plugs, containing the macromolecules or solutes, into electrophoretic contact with a recipient matrix and allows for electrophoretic transfer of the solutes from the plugs into a single concentrated zone in the recipient matrix. The concentrated macromolecules or solutes can then be further processed in the recipient gel or excised and used for procedures requiring greater amounts and concentrations of the solute than are available in the original plugs.
    Type: Grant
    Filed: March 15, 1995
    Date of Patent: June 18, 1996
    Assignee: The Regents of the University of California
    Inventors: Huu M. Tran, Diana M. Smith, Lois B. Epstein
  • Patent number: 5515169
    Abstract: A spectral wavelength discrimination system and method for using are provided which allows the wavelength of a beam of radiation to be accurately determined using compact inexpensive optics and electronics. The system is particularly useful for identifying the emission wavelength of a multi-component marker system which includes a plurality of components having different wavelength ranges. The system comprises a wavelength selective beamsplitter, termed a Linear Wavelength Filter, that directs predetermined fractions of the beam at each wavelength into each of two output beams. The intensities of these output beams are measured. The measurements and selected system parameters, including the beamsplitter spectral characteristics and the detector sensitivity characteristics are used in a special algorithm for performing Fourier based wavelength-dispersive analysis. The unique solution of the Fourier based analysis is the wavelength of the beam of radiation.
    Type: Grant
    Filed: October 13, 1993
    Date of Patent: May 7, 1996
    Assignees: Labintelligence Inc., Optical Coating Laboratory, Inc.
    Inventors: Robert L. Cargill, Erich Gombocz, Claudio I. Zanelli, Basil Swaby
  • Patent number: 5503994
    Abstract: In many separation techniques, such as field flow fractionation, liquid chromatography and electro-phoresis, chemical species form bands that migrate at different velocities. If the data-digitization rate and excitation intensity are both set to be optimal for the fastest migrating band, to compensate for different band velocities, both the data-digitization rate and the excitation intensity are decreased as a function of time by a factor equal to the migration time of the fastest migrating band to the separation time.
    Type: Grant
    Filed: October 8, 1993
    Date of Patent: April 2, 1996
    Assignee: The Board of Trustees of the Leland Stanford Junior University
    Inventors: Jason B. Shear, Rajeev Dadoo, Harvey A. Fishman, Neil Shafer, Richard N. Zare
  • Patent number: 5498324
    Abstract: A fluorescence detection system for capillary electrophoresis is provided wherein the detection system can simultaneously excite fluorescence and substantially simultaneously monitor separations in multiple capillaries. This multiplexing approach involves laser irradiation of a sample in a plurality of capillaries through optical fibers that are coupled individually with the capillaries. The array is imaged orthogonally through a microscope onto a charge-coupled device camera for signal analysis.
    Type: Grant
    Filed: April 6, 1994
    Date of Patent: March 12, 1996
    Assignee: Iowa State University Research Foundation, Inc.
    Inventors: Edward S. Yeung, John A. Taylor
  • Patent number: 5482608
    Abstract: A system for controlling the bulk flow rate in capillary electrophoresis employs pressure to increase velocity without unacceptably increasing plate height. Thus, the system controls bulk flow over a range of velocities, independent of the chemistry of the system. Additionally, the use of pressure under certain conditions may decrease plate height and improve resolution.
    Type: Grant
    Filed: January 19, 1993
    Date of Patent: January 9, 1996
    Assignee: Hewlett Packard Company
    Inventors: Catherine A. Keely, Douglass McManigill, Robert R. Holloway
  • Patent number: 5483075
    Abstract: A rotary scanning apparatus for scanning a plurality of separation lanes where the separation lanes are disposed in a nonplanar array. The scanning apparatus includes an optical detection system for detecting radiation emanating from the separation lanes, the optical detection system including collection optics for collecting and focusing the radiation, a detector for measuring the intensity of the radiation, and a rotary scanner for providing relative movement between the collection optics and the separation lanes.
    Type: Grant
    Filed: November 1, 1994
    Date of Patent: January 9, 1996
    Assignee: Perkin-Elmer Corporation
    Inventors: Douglas H. Smith, Charels R. Connell
  • Patent number: 5439578
    Abstract: A multiple capillary analyzer allows detection of light from multiple capillaries with a reduced number of interfaces through which light must pass in detecting light emitted from a sample being analyzed, using a modified sheath flow cuvette. A linear or rectangular array of capillaries is introduced into a rectangular flow chamber. Sheath fluid draws individual sample streams through the cuvette. The capillaries are closely and evenly spaced and held by a transparent retainer in a fixed position in relation to an optical detection system. Collimated sample excitation radiation is applied simultaneously across the ends of the capillaries in the retainer. Light emitted from the excited sample is detected by the optical detection system. The retainer is provided by a transparent chamber having inward slanting end walls. The capillaries are wedged into the chamber.
    Type: Grant
    Filed: June 3, 1993
    Date of Patent: August 8, 1995
    Assignee: The Governors of the University of Alberta
    Inventors: Norman J. Dovichi, Jian Z. Zhang
  • Patent number: 5414508
    Abstract: An optical cell or an optical detection system, of a simple structure having a small light path length, such as, for example, an optical cell having a light path length equal to that of a capillary. Light incidence and exit surfaces of the optical cell are each formed by a half transmitting mirror, and light is made incident on the optical cell in a direction perpendicular to the cell. The reflectance of the half transmitting mirror formed at the incidence surface is set smaller than that of the half transmitting mirror formed at the exit surface. The said optical cell or optical detection system is used as an optical detector portion of a sample separation and detection system which is for separation and detection of a sample using a liquid chromatography system or an electrophoresis system.
    Type: Grant
    Filed: March 2, 1993
    Date of Patent: May 9, 1995
    Assignee: Hitachi, Ltd.
    Inventors: Satoshi Takahashi, Hideki Kambara
  • Patent number: 5366601
    Abstract: A technique for separating, identifying and measuring ions in solution by capillary zone electrophoresis is described, which provides improved sensitivity and resolution of anionic species. The method involves introducing a sample containing the ionic species into a narrow bore capillary filled with a carrier electrolyte containing a selected light-absorbing anion. An electrical potential is applied across the capillary column causing the ions to elute according to their ionic mobility. Both UV absorbing and UV-transparent ions can be detected and quantitated by UV/visible photometric monitoring.
    Type: Grant
    Filed: October 20, 1992
    Date of Patent: November 22, 1994
    Assignee: Millipore Corporation
    Inventors: William R. Jones, Petr Jandik
  • Patent number: 5366603
    Abstract: To sequence DNA automatically, DNA marked with near infrared fluorescent dyes are electrophoresed in a plurality of channels through a gel electrophoresis slab wherein the DNA samples are resolved in accordance with the size of DNA fragments in the gel electrophoresis slab into fluorescently marked DNA bands. The separated samples are scanned photoelectrically with a laser diode and a sensor, wherein the laser scans with scanning light at a scanning light frequency within the absorbance spectrum of said fluorescently marked DNA samples and light is sensed at the emission frequency of the marked DNA. The light is modulated from said laser at a predetermined modulation frequency and fluorescent light emitted by said DNA bands at said modulation frequency is detected, whereby background noise from the medium through which the light is transmitted is discriminated against.
    Type: Grant
    Filed: March 30, 1992
    Date of Patent: November 22, 1994
    Assignee: Li-Cor, Inc.
    Inventors: Lyle R. Middendorf, Gabor Patonay
  • Patent number: 5360523
    Abstract: To sequence DNA, DNA samples marked with fluorescent infrared dye are applied at a plurality of locations for electrophoresing in a plurality of channels through a gel electrophoresis slab. The channels are scanned with a laser and a sensor, that include a microscope focused on the gel slab. The focal point and slab are adjusted with respect to each other so that the focal point of the microscope remains on the gel slab during a scan. The data from the scan is directly used to amplitude modulate density readings on a display, and the scan is displayed in a horizontal sweep of a cathode ray tube, whereby said cathode ray tube provides intensity displays of bands representing DNA. Different sizes of glass gel sandwiches may be mounted to the same console for different sequencing tasks.
    Type: Grant
    Filed: February 17, 1993
    Date of Patent: November 1, 1994
    Assignee: Li-Cor, Inc.
    Inventors: Lyle R. Middendorf, Robert C. Bruce, Robert D. Eckles
  • Patent number: 5354440
    Abstract: To detect bands in an electrophoresis capillary tube having a liquid separating medium, a light source and a light detector of a monitor are positioned on opposite sides of the capillary tube with the light source transmitting light through a first slit and light passing to the detector through a second slit after it has passed through the capillary tube. The first and second slits are aligned with the direction of motion of bands, have a maximum length of less than 500 micrometers and a maximum width of less than 200 micrometers. There are no vertical lengths in the capillary tube having a dimension greater than one third of its length between a sample injecting end and a detecting end of the capillary tube.
    Type: Grant
    Filed: November 29, 1988
    Date of Patent: October 11, 1994
    Assignee: Isco, Inc.
    Inventor: Robert W. Allington
  • Patent number: 5324401
    Abstract: A fluorescence detection system for capillary electrophoresis is provided wherein the detection system can simultaneously excite fluorescence and substantially simultaneously monitor separations in multiple capillaries. This multiplexing approach involves laser irradiation of a sample in a plurality of capillaries through optical fibers that are coupled individually with the capillaries. The array is imaged orthogonally through a microscope onto a charge-coupled device camera for signal analysis.
    Type: Grant
    Filed: February 5, 1993
    Date of Patent: June 28, 1994
    Assignee: Iowa State University Research Foundation, Inc.
    Inventors: Edward S. Yeung, John A. Taylor
  • Patent number: 5318686
    Abstract: A cartridge for high performance capillary electrophoresis is constructed to accommodate a capillary with a flexible length of tubing surrounding it for the passage of a liquid coolant. Connections and fittings in the cartridge permit quick insertion and removal of the capillary and coolant tube so that capillaries of different lengths can be used with the same cartridge. Apertures in the cartridge body permit the capillary and tubing to be looped outside the cartridge so that different lengths can be connected without the need to coil the capillary inside the cartridge body. A removable capillary aligning device is also disclosed, which fits in the cartridge in a fixed orientation and holds the capillary in alignment with lenses if used and a light beam passing through the cartridge.
    Type: Grant
    Filed: August 5, 1993
    Date of Patent: June 7, 1994
    Assignee: Bio-Rad Laboratories, Inc.
    Inventors: Rand Dill, Christopher J. Siebert
  • Patent number: 5314602
    Abstract: In a DNA detecting method wherein the fluorescence detection type electrophoresis apparatus is used, Texas Red is employed as a fluorophor which labels a DNA fragment, an He-Ne laser having an emission wavelength of 594 nm is used as an excitation light, the excitation light irradiates a line portion of the gel plate simultaneously, and the resulting linear fluorescent image is collected by a cylindrical lens and photodetected thereby providing an apparatus featuring a higher sensitivity, a smaller size and a lighter weight than conventional apparatuses.
    Type: Grant
    Filed: March 5, 1993
    Date of Patent: May 24, 1994
    Assignee: Hitachi, Ltd.
    Inventors: Hideki Kambara, Keiichi Nagai
  • Patent number: 5312535
    Abstract: Detecting light in a capillary electrophoresis optical system includes input and output windows in the outside surface of a capillary tube. The width of the windows is not substantially greater than the bore of the tube. A fiber optic input is spaced from the capillary tube so that the light is directed to the tube and is matched to the window width. The light output from the tube is matched to be received by a fiber optic output spaced from the capillary tube. The optical light envelop from the fiber input through the tube and to the fiber output is governed by the LaGrange Invariant. The matching is effected in accordance with the Numerical Aperture of the fiber optics.
    Type: Grant
    Filed: July 17, 1992
    Date of Patent: May 17, 1994
    Assignee: Beckman Instruments, Inc.
    Inventors: Frank L. Waska, Gerald L. Klein, Wayne S. Johnson
  • Patent number: 5306618
    Abstract: A DNA sequencing system and method are described to detect the presence of radiant energy emitted from different excited reporter dye-labeled species (DNA fragments) following separation in time and/or space, and the identity of the species which emit radiant energy closely spaced in wavelength. Functions of the emitted energy are obtained which vary over the wavelengths of the closely spaced spectra in different senses and the functions ratioed, whereby the ratio is indicative of the identity of the DNA fragments.The emitting portion of the reporter-labeled DNA fragment is preferably one of a family of fluorescent dyes based on 9-carboxyethyl-6-hydroxy-3-oxo-3H-xanthene. These xanthene dyes are covalently attached to the DNA fragments through the carboxylic acid functionality, preferably via an amide linkage. The dyes may be protected by including an alkoxy group at the 9-position. A spacer may be inserted between the dye and the amine.
    Type: Grant
    Filed: January 16, 1992
    Date of Patent: April 26, 1994
    Assignee: E. I. Du Pont de Nemours and Company
    Inventors: James M. Prober, Rudy J. Dam, Charles W. Robertson, Jr., Frank W. Hobbs, Jr., George L. Trainor
  • Patent number: 5307148
    Abstract: A multicolor fluorescence detection type electrophoresis apparatus comprises an electrophoretic device having migration lanes in which fragment groups specifically labeled by fluorophores of different light emission peak wavelengths are mixed, added, and migrated. It identifies and detects the fragment groups. It uses laser beams of different wavelengths for exciting the fluorophores in the migration lanes. The laser beams are irradiated to separate positions on the migration lanes for detection of a few kinds of fluorophores at irradiation positions. For the purpose, multicolor optical filters are arranged near the irradiation positions to identify and detect lights emitted from the fluorophores excited by wavelength at every irradiation position.
    Type: Grant
    Filed: April 12, 1991
    Date of Patent: April 26, 1994
    Assignee: Hitachi, Ltd.
    Inventors: Hideki Kambara, Keiichi Nagai, Tamotu Simada, Tetsuo Nishikawa, Tomoaki Sumitani
  • Patent number: 5306404
    Abstract: A process for preparing a polyacrylamide gel plate for electrophoresis with any desired concentrations, which comprises mixing a high concentration acrylamide monomer solution, a low concentration peroxide solution, and a low concentration reducing solution at an arbitrary ratio, and introducing the mixture into a gel supporter. The process enables preparation of a large quantity of high quality polyacrylamide gel plates for electrophoresis which is useful for analysis of high molecular weight in vivo components typified by proteins with a good reproducibility. It also contributes to the production of various gels having a plurality of gel concentrations or having a specified concentration gradient, and serves for improving the productivity of multi-products manufacturing of such gel plates.
    Type: Grant
    Filed: January 26, 1993
    Date of Patent: April 26, 1994
    Assignee: Daiichi Pure Chemicals Co., Ltd.
    Inventors: Kazuaki Notsu, Nobuyoshi Ebata, Akiko Udagawa, Mieko Shiratori
  • Patent number: 5302272
    Abstract: A capillary electrophoresis detector assembly including a separation column in which the components of a mixed sample are separated; an exit column which completes the connection to the terminal buffer reservoir; and a support sleeve which includes precisely positioned radial bores therethrough to allow insertion of optical fibers in the form of an input fiber which transmits the incoming radiation from an illumination source and an exit fiber which receives the radiation and relays same to a detector.In fabricating the assembly, a precision wire is partially inserted into the output end of the separation column. The column/wire combination is inserted into one end of the sleeve. The exit column is threaded onto the precision wire and also inserted into the opposite end of the sleeve. The input and exit fibers are inserted into the radial bores in the sleeve until they touch the precision wire in opposition.
    Type: Grant
    Filed: March 5, 1992
    Date of Patent: April 12, 1994
    Assignee: Beckman Instruments, Inc.
    Inventor: Gerald L. Klein
  • Patent number: 5294323
    Abstract: In an apparatus for gel electrophoresis in which a sample of fluorophore-labelled DNA fragments is caused to migrate by electrophoresis through a gel electrolyte layer in an electrophoresis plate from top to bottom, thereby separating the sample into individual DNA fragments, and a laser beam is launched horizontally into said electrolyte layer from one side of the electrophoresis plate in a direction perpendicular to the longitudinal axis of said electrophoresis plate, with the emitted fluorescences being detected to determine the base sequences of the respective DNAS, a mirror for reflecting fluorescences is provided at the back of the electrophoresis plate in such a way that it is parallel to the direction of laser beam application, and the fluorescences reflected by this mirror are received by a fluorescence detector such as a CCD sensor or MOS linear image sensor. In one embodiment, the mirror is inclined by an angle of 45.degree.
    Type: Grant
    Filed: June 1, 1993
    Date of Patent: March 15, 1994
    Assignees: Hitachi, Ltd., Hitachi Electronics Engineering Co., Ltd.
    Inventors: Teruo Togusari, Kazuyuki Irisawa, Hideki Kambara
  • Patent number: 5290419
    Abstract: In the multi-color fluorescence detection type electrophoresis apparatus provided with the electrophoresis gel plate, excitation laser source, means to separate the fluorescence images according to each emission wavelength, and the detector of the fluorescence subjected to wavelength selection, two or more laser sources are provided, each of laser lights is irradiated on the sample on a time-sharing basis, and the filter which cuts off the scattered light of each the laser synchronous with the laser beam is installed in front of the wavelength separation means thereby providing simultaneous, quick and real-time analysis of a great number of samples such as DNA and RNA labeled by many types of fluorophores, without overlapping the wavelengths of the excitation light and the fluorescence.
    Type: Grant
    Filed: April 12, 1993
    Date of Patent: March 1, 1994
    Assignees: Hitachi, Ltd., Hitachi Electronics Engineering Co., Ltd., Hitachi Software Engineering Co.
    Inventors: Hideki Kambara, Takashi Anazawa, Keiichi Nagai, Hiroaki Machida, Hisanori Nasu
  • Patent number: 5286356
    Abstract: A method for performing capillary electrophoresis with improved regularity of migration time of the analytes is disclosed. A capillary electrophoresis system includes a fused silica capillary, a high voltage power supply, electrolyte reservoirs at both ends of the capillary, means for injecting a sample, and a detector. After separation, analytes within the sample are identified by comparing their migration time with the migration time of internal or external standards. Since migration times are dependent on the concentration of the injected sample, identification of unknown analytes can often be difficult or subject to error without the use of such standards. These problems associated with concentration dependent migration time are substantially eliminated by using a combination of high voltage power supply running modes (i.e. constant current, constant voltage or constant power) during the course of the analysis.
    Type: Grant
    Filed: January 21, 1993
    Date of Patent: February 15, 1994
    Assignee: Millipore Corporation
    Inventors: William R. Jones, Martin Fuchs, Michael Merion
  • Patent number: 5273633
    Abstract: The present invention features a system for detecting a substance in a fluid sample. A capillary is provided with a longitudinal axis and a channel is formed in it for receiving a fluid sample. The channel is disposed parallel to the longitudinal axis. A reflecting surface surrounds the outer surface of the capillary for reflecting electromagnetic energy. The reflecting surface has an incident window for allowing the electromagnetic energy to enter the capillary and an exit window for allowing the electromagnetic energy to exit the capillary. The exit window is disposed downstream of the incident window with respect to the longitudinal axis, so that the electromagnetic energy that enters the capillary is internally reflected more than once by the reflecting surface.
    Type: Grant
    Filed: July 10, 1992
    Date of Patent: December 28, 1993
    Inventor: Tiansong Wang
  • Patent number: 5268080
    Abstract: In a DNA detecting method wherein the fluorescence detection type electrophoresis apparatus is used, Texas Red is employed as a fluorophor which labels a DNA fragment, the He-Ne laser having an emission wavelength of 594 nm is used as an excitation light, the excitation light irradiates the line portion of the gel plate simultaneously, and a resulting linear fluorescent image is collected by a cylindrical lens and photodetected, thereby providing an apparatus featuring a higher sensitivity, a smaller size and a lighter weight than conventional apparatuses.
    Type: Grant
    Filed: February 28, 1992
    Date of Patent: December 7, 1993
    Assignee: Hitachi, Ltd.
    Inventors: Hideki Kambara, Keiichi Nagai
  • Patent number: 5268568
    Abstract: A device for detecting the marker dye band which is used to monitor the progression of biological macromolecules in gel electrophoresis. This device mounts external to the gel box, and utilizes a single light detector and a pair of AC activated light sources. The light sources produce reflected or transmitted light signals which, when balanced at the detector, cancel. When marker dye is absent the light signals are balanced, and no signal is detected. When marker dye is present at a specific detection point within the gel, the light reflected (or transmitted) is no longer balanced and a signal is detected.
    Type: Grant
    Filed: November 30, 1992
    Date of Patent: December 7, 1993
    Inventor: Thomas E. Lee
  • Patent number: 5242567
    Abstract: A fluorescence pattern reading apparatus for reading a fluorescence pattern by exciting a fluorescence substance labeled on a sample developed into an electrophoresis pattern by electrophoresis of the sample has optical scanning mechanisms, a light-receiving unit, a photoelectric converting unit, and amplifiers. The mechanisms are to irradiate the gel in the direction of thickness of the gel by scanning the irradiation light for exciting the fluorescent substance of the fluorescence patter. The light-receiving unit is to receive the fluorescence by separating the fluorescence from the light scattered on the reading surface of the gel due to a spatial position relationship of a light-receiving path in which the light-receiving surface is set to exist in the direction different from the axis of the irradiation light. The photoelectric converting unit is to generate electric signals by converting light signals received by the light-receiving unit.
    Type: Grant
    Filed: May 22, 1991
    Date of Patent: September 7, 1993
    Assignee: Hitachi Software Engineering Co., Ltd.
    Inventors: Hitoshi Fujimiya, Hiromichi Mishima, Toshitaka Ishikawa, Kouji Yuda, Hisanori Nasu
  • Patent number: 5239360
    Abstract: An apparatus for enhancing signal to noise ratio in the detection of electromagnetic radiation traversing a capillary tube includes a ball lens and a holding element for holding the ball lens and the capillary tube, the holding element having an aperture so that the aperature and the lens together define an optic axis. The holding element is configured to hold the capillary tube such that the center of the capillary tube traverses the optic axis. The lens has a focal length and is held at such a position relative to that focal length by the holding element such that electromagnetic radiation incident on the aperature is focussed to pass radially through the capillary tube. Thus, the effective path length is 100% of the inside diameter of the capillary tube.
    Type: Grant
    Filed: July 31, 1990
    Date of Patent: August 24, 1993
    Assignee: Applied Biosystems, Inc.
    Inventors: Stephen E. Moring, Dennis E. Mead
  • Patent number: 5221454
    Abstract: An electrophoresis-based assay system for detection of one or more target substances, i.e. an analyte tagged with fluorescent binding agents. The analyte is reacted with an excess amount of fluorescently tagged binding agent. The reaction mixture is subjected to electrophoresis and the migration of bound and free fluorescent substances are timed at a location where there is a spatial and optical differentiation of the two substances. An optical detector supplies signals corresponding to fluorescent amplitudes of the two substances. The free fluorescent substance arrives at a time expected from calibration runs. This optical signal is a marker for a second time, either earlier or later, when the bound substance should have arrived. Recorded data is searched to establish the relation between free and bound dye among the recorded optical signals. An absence of a bound dye signal infers the absence of target analyte in a sample.
    Type: Grant
    Filed: June 25, 1992
    Date of Patent: June 22, 1993
    Assignee: Biometric Imaging Inc.
    Inventors: Bala S. Manian, Vartan Ghazarossian
  • Patent number: 5215883
    Abstract: A process and apparatus for detecting the mobility of fluorescently labeled molecules in response to a force is disclosed. The fluorescently labeled molecules are placed in a fluid medium such as an electrophoretic gel in a capillary tube. An electric field is applied to induce the movement of the molecules. A region of the labeled molecules is photobleached leaving a geometrically defined region which has not been photobleached. The region which has not been photobleached is excited by a reading beam. The reading and the photobleaching beams can be generated by focusing a laser through a diffraction grading. The intensity produced by the interaction of the reading beam in the geometrically defined region of the molecule is detected by a photo detector. In detecting more than one spThis invention was partially made with Government support under the polymers program of the National Science Foundation DMR8617820. The Government has certain rights in the invention.
    Type: Grant
    Filed: July 9, 1990
    Date of Patent: June 1, 1993
    Assignee: The Research Foundation
    Inventor: Benjamin Chu
  • Patent number: 5213673
    Abstract: A multi-colored electrophoresis pattern reading apparatus is capable of labelling each of plural samples separately with each of plural fluorescent substances having different fluorescence wavelengths, by electrophoresing the plural samples to develop a pattern, exciting the fluorescent substances labelled on the samples to emit fluorescence, and reading a fluorescent pattern emitting the fluorescence.
    Type: Grant
    Filed: November 29, 1991
    Date of Patent: May 25, 1993
    Assignee: Hitachi Software Engineering Co., Ltd.
    Inventors: Hitoshi Fujimiya, Hisanori Nasu
  • Patent number: 5190632
    Abstract: The multi-colored electrophoresis pattern reading system compares the patterns of electrophoresis without a warp to be caused upon electrophoresis by reading the patterns of electrophoresis which is carried out concurrently for plural samples and by labelling the samples with fluorescent substances having different fluorescent wavelengths. The patterns of electrophoresis are read by allowing fluorescence to emit from the plural samples. In reading the fluorescent patterns, optical signals are received by the light receiving section and then the fluorescence having a predetermined wavelength is separated by the fluorescent-wavelength separating section from the optical signals with the aid of an optical filter capable of controlling an angle of incidence relative to the optical axis of the optical filter.
    Type: Grant
    Filed: March 20, 1992
    Date of Patent: March 2, 1993
    Assignee: Hitachi Software Engineering Co., Ltd.
    Inventors: Hitoshi Fujimiya, Hisanori Nasu
  • Patent number: 5141609
    Abstract: This invention relates to a detection method and apparatus useful in capillary electrophoresis and capillary chromatography that employs an array of solid state detector such as a charge-coupled device operating in the time-delayed integration mode which allows more exposure time of the moving analyte zones. The CCD is synchronized so that after a normal exposure of the CCD, the charge information in every row of the CCD is shifted toward one end of the CCD and the charge/signal information in the last row is quantified. Applying the CCD and the time-delayed integration method in effect increases the effective sampling volume of the flow cell without introducing band broadening. Use of the CCD as a fluorescence detection in capillary electrophoresis separations allows analytes to be differentiated both in migration time and fluorescence emission, yielding detection limits for fluorophores in the 1-8.times.10.sup.-20 mole range.
    Type: Grant
    Filed: November 16, 1990
    Date of Patent: August 25, 1992
    Assignee: The Trustees of the Leland Stanford Junior University
    Inventors: Jonathan V. Sweedler, Jason B. Shear, Richard N. Zare