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US20070117178A1 - Continuous polymer synthesizer - Google Patents

Continuous polymer synthesizer Download PDF

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Publication number
US20070117178A1
US20070117178A1 US11/521,574 US52157406A US2007117178A1 US 20070117178 A1 US20070117178 A1 US 20070117178A1 US 52157406 A US52157406 A US 52157406A US 2007117178 A1 US2007117178 A1 US 2007117178A1
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Prior art keywords
reaction
stations
reaction sites
plate
dispensing
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US11/521,574
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English (en)
Inventor
David Heiner
Aaron Jones
Steven Fambro
Mark Nibbe
Steven Burgett
Brett Ellman
Michal Lebl
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Illumina Inc
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Illumina Inc
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Priority to US11/521,574 priority Critical patent/US20070117178A1/en
Assigned to ILLUMINA, INC. reassignment ILLUMINA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FAMBRO, STEVEN P., BURGETT, STEVE R., HEINER, DAVID L., JONES, AARON C., LEBL, MICHAL, NIBBE, MARK J., ELLMAN, BRETT M.
Publication of US20070117178A1 publication Critical patent/US20070117178A1/en
Abandoned legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00281—Individual reactor vessels
    • B01J2219/00283—Reactor vessels with top opening
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315—Microtiter plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00324—Reactor vessels in a multiple arrangement the reactor vessels or wells being arranged in plates moving in parallel to each other
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    • B01J2219/0036—Nozzles
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    • B01J2219/00423—Means for dispensing and evacuation of reagents using filtration, e.g. through porous frits
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00585—Parallel processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00596—Solid-phase processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00612—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports the surface being inorganic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00675—In-situ synthesis on the substrate
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00693—Means for quality control
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00722—Nucleotides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00725—Peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
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    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/11—Automated chemical analysis
    • Y10T436/115831—Condition or time responsive
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/12—Condition responsive control

Definitions

  • FIG. 5E is a cross-sectional view of a plate holder mounted onto a plate module taken across the line 5 E- 5 E of FIG. 5A .
  • oligonucleotides contained in microtiter plates on the circular table can each be extended by addition of a single nucleotide if the order of the stations, spacing between the stations and rate of passage for each plate corresponds to the order of reagent delivery and reaction time for a complete monomer addition reaction cycle.
  • the reaction sites may be wells of a conventional microtiter plate, and the dispensing station may be configured to dispense reaction solutions to the wells of an entire row or column of the microtiter plate at the same time or in fast succession.
  • a linear arrangement of valves can be instructed by the computer control system to dispense reagents sequentially and in a way that coincides with the arcuate trajectory of the microtiter plate.
  • a synthesizer of the present embodiments can further include dispensing nozzles having localized reservoirs.
  • Reagents for a synthetic reaction can be maintained in large storage tanks that are in fluid contact with appropriate dispensing nozzles.
  • the local reservoirs allow rapid delivery of reagents and replacement of bulk reagents in the large storage tanks during the course of continuous synthesis.
  • Another embodiment relates to an imaging system that is configured to take a digital image of reaction sites after a reaction solution has been dispensed or removed, and then process that image to determine if reaction solutions were dispensed to or removed from the appropriate sites. If a quality control module within the system determines that a particular site did not properly receive or evacuate a reaction solution, it can be marked with an error flag to indicate that further steps of the reaction at that site should be discontinued or that the reaction site should be removed from the system.
  • An advantage of the imaging stations is that they can provide real-time confirmation that the upstream dispensers are functional and that evacuation of the plates was successful, resulting in the ability to pause the synthesis cycle and conduct maintenance without sacrificing downstream reactions.
  • the system includes a series of dispensing stations around the circumference of the device, and proximal to one or more of the dispensing stations is a digital camera that is configured to take an image of the reaction sites after a reaction solution has been dispensed into the reaction vessel.
  • the imaging system is preferably programmed to determine whether a particular reaction site was supposed to have received a reaction solution, and if so, then determine if the reaction site has such a solution within the vessel.
  • a system in one embodiment, includes an oligonucleotide synthesizer having a circular array of reaction sites. In this embodiment, each time the array of reaction sites completes a rotation, one nucleotide base is added to the oligonucleotide at each site.
  • there may be a plurality of reaction solution dispensing stations wherein a first station dispenses adenosine, a second station dispenses thymidine, a third station dispenses cytidine and a fourth station dispenses guanosine.
  • dispensing stations located along the outer perimeter of the circular array can be configured to dispense other reaction solutions that are necessary in order to synthesize oligonucleotides.
  • the dispensing stations can dispense reaction solutions for detrytilation, coupling, capping and oxidation, in accordance with the steps for synthesizing an oligonucleotide chain.
  • the synthesizer can be configured to dispense reaction solutions that will synthesize polypeptides.
  • the process of peptide synthesis on solid supports generally involves building a peptide from the carboxyl-terminal end.
  • the peptide is attached to a solid support via its carboxy-terminal amino acid and further includes a protecting group on the amino-terminal ⁇ -amino group. The protecting group is then cleaved off of the peptide to form a deprotected peptide.
  • each dispenser of a synthesizer of the present embodiments can be configured to dispense a wash solution, deprotection reagent, amino acid, or activation reagent.
  • the relative placement of the array of stations, relative placement of the array of reaction sites and the schedule by which the arrays communicate with each other can be correlated in accordance with the teachings herein and the known reaction schemes for peptide synthesis including, for example, those described in Goodman et al. (Eds.). Synthesis of Peptides and Peptidomimetics , Vol. E22a. Georg Thieme Verlag, Stuttgart (2002).
  • a stage can move reaction sites in a path having a linear shape or a curved shape that corresponds to all or a portion of a circle, ellipse or other shape.
  • a stage used in the present embodiments is configured to accept an array of reaction sites such that the sites are placed in a fixed order and fixed intervals relative to each other.
  • the array of reaction sites can be moved such that the relative positions of the reaction sites in the array are not altered.
  • a stage used in the present embodiments can be configured to allow movement of individual reaction sites such that the relative positions of the sites in the array can be altered.
  • a stage need not move and can be static, for example, in embodiments where an array of stations is moved instead.
  • the term “continuous,” when used in reference to synthesis of a plurality of molecules, means that the order of steps and time interval between steps for synthesis of each molecule occurs according to a reaction schedule and the schedule is unaltered by manipulations occurring for the other molecules.
  • the manipulations can include steps occurring according to a reaction schedule; steps utilized to initiate or terminate a synthetic reaction, such as addition of a reaction vessel to a synthetic device or removal of a reaction vessel from a synthetic device; passive steps such as maintaining reagents at a reaction site during an incubation step; or steps that differ from a reaction schedule such as premature removal of a reaction vessel for a failed synthetic reaction.
  • a continuous synthesizer may, for example, stop moving as a rotary table changes direction and may do so while continuous synthesis occurs at multi-well plates on the rotary table.
  • embodiments provide systems and methods wherein an array of reaction sites or an array of stations move on a schedule for sequential communication of the reaction sites with the stations, wherein the relative locations of the stations and the schedule correlate with the order and duration of the sequential steps of a particular reaction.
  • steps of a reaction means manipulations carried out or allowed to occur for a chemical transformation or change.
  • reaction schedule means a pre-defined order and duration of manipulations to be carried out for a chemical transformation or change.
  • the plate modules 500 which include plate holders (not shown) that are removably mounted to the rotary table 20 , also rotate along the outer circumference of the rotary table 20 .
  • Fixed in position, and mounted to the top of the synthesizer 10 are a series of dispensers 35 A-F and cameras 38 A-E. This will be described more completely with reference to FIG. 2 .
  • each of the plate modules 500 progressively move beneath the dispensers, also termed “dispensing stations” so that reaction solutions can be dispensed into the microtiter plates.
  • a feedback mechanism can be used that determines the position of the rotary table in relation to the dispenser valves. Such a determination can be made continually throughout operation or at specific times such as following an adjustment made to the system.
  • a sensor is used that determines the position of a fiducial on a microtiter plate or other reaction site. Once the sensor has determined the position of the rotary table, this location information is fed back to the system that controls the rotor and the timing of the valves in the dispenser nozzles.
  • the fiducial is a plastic structure, such as a rib or edge of a well, in the microtiter plate.
  • a detectable device or material can be temporarily used in place of a reaction site, for example, being temporarily placed in a plate module on rotary table 20 during a calibration step.
  • the exemplary system shown in FIGS. 1 and 2 moves in a net clockwise direction.
  • the system can be configured to move in a counterclockwise direction as well.
  • reaction solutions can be dispensed into a microtiter plate from a particular dispensing station while the rotary table moves in a clockwise direction.
  • the direction of movement for the rotary table can then be changed from clockwise to counterclockwise direction.
  • the counterclockwise distance traveled by the table can be such that the microtiter plate is placed in position to be imaged by one of the imaging stations 38 A-E.
  • the direction of the rotary table can again be changed whereby the microtiter plate that was imaged is moved in a clockwise direction past the particular dispensing station to the next dispensing station.
  • an imaging station can be placed such that it is either before or after a particular dispensing station in the net path of movement for a system.
  • An imaging station can be placed relative to the location of one or more of the dispensing stations and relative to the movement of the system so that an image of each reaction site can be taken after one or more reaction solutions has been dispensed.
  • imaging stations useful in the present embodiments will be described in more detail below.
  • an imaging station useful in the present embodiments can be configured to detect any of a variety of detectable characteristics of a reaction site such as an optical property including, without limitation, absorbance, fluorescence, chemiluminescence, polarization, circular dichroism, fluorescence resonance energy transfer (FRET), light scattering or the like.
  • an optical detection device such as those set forth herein can be modified or replaced with any of a variety of known detection devices appropriate for monitoring such optical properties.
  • the present embodiments can be used to detect changes in optical properties that occur in one or more range of the electromagnetic spectrum including, without limitation, infrared, visible, ultraviolet, x-ray, microwave, sub-regions thereof such as red, blue or yellow sub-regions of the visible region, combinations of these regions or sub-regions, or other regions of the spectrum.
  • An imaging station useful in the present embodiments can include a camera device such as a charge couple device (CCD) camera of the type including, but not limited to, the AXIS 2100 Network Camera provided by AXIS Communications, Inc. of Lund, Sweden.
  • CCD charge couple device
  • a camera used in the present embodiments can be any device that converts a detectable optical property into a signal in a location dependent manner.
  • exemplary cameras useful in the present embodiments include, for example, a complementary metal oxide semiconductor (CMOS) camera, video camera, internet camera, or other imaging device capable of converting a picture into a digital image.
  • CMOS complementary metal oxide semiconductor
  • Other imaging devices known in the art can also be used including, for example, those described in U.S. patent application Pub. No. 2004/0219063.
  • the present embodiments include a synthesizer that is capable of continuing to synthesize polymers within a multi-well plate, even if one well within that plate has been determined to be bad. For example, if the imaging system determines that one well of a multi-well plate did not have a reaction solution added to it, then the entire multi-well plate need not be marked as bad. Rather the specific well can be indicated as a failed synthesis. Thus, the system can continue to deliver solutions to other wells of the multi-well plate in order to synthesize polymers therein while delivery of solutions to the failed well is discontinued to avoid waste of reagents.
  • the plate module enters below the wash station dispenser 35 A.
  • the valves within the dispenser 35 A output a wash solution into the microtiter wells.
  • the dispenser includes 24 individually controlled valves which are configured to dispense wash solution into 24 wells of a microtiter plate.
  • the dispensing nozzles can be configured to match the pattern of wells in one or more rows or columns of a 384 well microtiter plate 515 .
  • each valve is timed to release a predetermined quantity of wash solution into each well of the microtiter plate.
  • the wash solution is an acetonitrile (ACN) wash solution.
  • ACN acetonitrile
  • the number of dispensing nozzles utilized at a wash station or other solution dispensing station can be fewer than the number of reaction sites.
  • the system exemplified above as having 24 valves can deliver solution to all of the 384 wells of the microtiter plate if each of the 24 valves fires 16 times, thereby filling all 16 rows of the microtiter plate.
  • a dispensing station can have a single linear arrangement of valves, for example, corresponding to a single row or column of a microtiter plate, or multiple linear arrangements of valves that form a matrix of rows and columns corresponding to all or a portion of the wells in a microtiter plate.
  • the plate modules can move to a position under the deblock dispenser 35 B.
  • This dispenser is configured to dispense a deblocking solution containing, in one embodiment, trichloroacetic acid that reacts with the growing oligonucleotide to remove a dimethoxytrityl (DMT) group from the last nucleotide.
  • DMT dimethoxytrityl
  • the plate module travels under the coupling dispenser 35 E wherein the appropriate nucleotide is added to each of the wells.
  • the dispenser 35 E would dispense a solution of adenosine into the well.
  • the dispenser 35 E is configured to dispense the proper nucleotide into each of the wells of the microtiter plate within the plate module.
  • the system can be configured so that there are multiple dispensers, wherein each dispenser is configured to provide a different nucleotide to each well.
  • microtiter plate communicates with different stations set forth above is provided for purposes of illustration.
  • the order in which a reaction site communicates with separate stations, direction of relative movement between a reaction site and array of stations, and duration between reaction site manipulations can be selected to suit a particular reaction or application of the present embodiments and can, therefore, differ from that exemplified above.
  • one embodiment is a system for continuously synthesizing molecules, whereby the molecules are synthesized by performing sequential steps of a reaction.
  • the molecules are oligonucleotides or polypeptides.
  • the system includes a stage configured to accept an array of reaction sites.
  • a reaction site may be, for example, a filter bottom microtiter plate, a tube, or any other means for holding reaction solutions.
  • the system also includes an array of different stations. One set of stations are reagent dispensing stations, such as the dispensers 35 . These stations are configured to separately and sequentially provide synthesis reaction solutions to the reaction sites for carrying out the sequential reaction steps.
  • the array of stations can be configured in a fixed spatial relationship corresponding to the order of the sequential steps of the reaction
  • Another set of stations that can be included in an array of stations includes imaging stations that are configured to obtain images of the reaction sites either after reactions solutions have been dispensed, or after the solutions have been evacuated.
  • the system can also include a control system, as discussed below, that is configured to move the stage or the array of stations so that the reaction sites sequentially communicate with the dispensing stations and the imaging stations. This allows the dispensing stations to dispense reaction solutions to the sites, and the imaging stations to image the sites.
  • the control system is further configured to allow replacement of a first reaction site, such as a microtiter plate, from the array of reaction sites with a second reaction site while the system continuously synthesizes molecules at other reaction sites of the array of reaction sites.
  • the system can also monitor the quality or yield of a synthesis reaction, and not just whether or not the reaction has occurred.
  • the continuous synthesizer can be configured for use in monitoring parallel chemical reactions and is particularly suited for real-time monitoring of polymer synthesis such as oligonucleotide synthesis or peptide synthesis.
  • the synthesizer is also particularly suited for providing a quality control (QC) measure for oligonucleotide, peptide or other polymer productions.
  • the chemical reaction monitor is an automated DMT monitoring system used to track the yield, quality and general state of oligonucleotides being synthesized at any one time.
  • a method or system of the present embodiments can be used for simultaneous synthesis of a large number of reactions.
  • the system exemplified in FIG. 2 includes 36 plates each having 96 or 384 wells, thereby being capable of simultaneously carrying out 3,456 or 13,828 individual reactions, respectively, at any given time.
  • the system can be configured to carry out larger numbers of simultaneous reactions, for example, by increasing the number of multi-well plates used or the number of wells in each plate or both.
  • a system of the present embodiments can be configured to carry out fewer simultaneous reactions, for example, by using fewer multi-well plates or fewer wells per plate.
  • a system or method of the present embodiments can be configured for continuously carrying out at least about 100, 1 ⁇ 10 3 , 1 ⁇ 10 4 , 1 ⁇ 10 5 or 1 ⁇ 10 6 reactions simultaneously.
  • Continuous synthesis using a system or method of the present embodiments provides for high-throughput production of desired products.
  • the system exemplified in FIG. 2 can operate at a rate that allows each 384-well plate to complete one lap in 9 minutes.
  • the present embodiments can be used to complete a synthetic cycle, such as addition of monomeric units to growing polymer, in at least about 1, 5, 7, 8, 9, 10, 11, 12, 15, 20, 30, or 60 minutes.
  • throughput using the present embodiments, depending upon reaction conditions selected can be, for example, at least about 100, 500, 1 ⁇ 10 3 , 5 ⁇ 10 3 , 1 ⁇ 10 4 , 5 ⁇ 10 4 , 1 ⁇ 10 5 , 5 ⁇ 10 5 or 1 ⁇ 10 6 reactions or reaction cycles completed per hour.
  • FIG. 3 is a block diagram of an exemplary continuous polymer synthesis system 100 that includes the continuous synthesizer 10 linked through an electronic connection 105 to a servo controller system 110 .
  • the servo controller system 110 controls the servo 108 that is mounted below the rotary table 20 and controls the precise position of the rotary table 20 with respect to the dispensers and cameras.
  • a feedback line 112 keeps the servo controller system 110 in constant communication with the synthesizer 10 so that it maintains the position of the rotary table in real-time.
  • a position sensor 115 detects the position of the microtiter plates as they move around the rotary table, and provides electronic feedback to the servo controller system 100 .
  • the servo controller system 110 provides instructions to the servo 108 to move the rotary table 20 to a particular position.
  • the sensor is a single beam sensor such as the Keyence LV-21A, LV-H35F sensor.
  • the position sensor 115 is configured to read markings on the microtiter plates, or other portions of the rotary table, in order to confirm that the table moves to its expected position.
  • FIG. 6 provides an image of a microtiter plate 120 and shows a set of alignment ribs 122 A, B and C. These ribs are standard structures within a microtiter plate 120 , and are therefore at the same position relative to microtiter wells 124 within each microtiter plate in the system.
  • sensors 115 A,B can be used to determine the position of the microtiter plate, and thereby the wells, as they rotate around the synthesizer based on the location of the alignment ribs.
  • Each sensor 115 A,B can be configured to detect when one of the ribs passes by the sensor as the microtiter plate 120 moves on the rotary plate. This information can be used to send feedback signals though the feedback line 112 of FIG. 3 .
  • Such alignment can include change in physical location or adjustment in the timing of solution delivery from one or more dispensing nozzles
  • the controller 110 is linked to an embedded control layer (TwinCat 130 ) that includes a programmable soft PLC running on a Windows XP compatible PC architecture.
  • This system provides deterministic control over the synthesizer hardware via the DeviceNet module 120 and LightBus control networks.
  • the Soft PLC communicates with and controls the servo controller via the DeviceNet network.
  • the control system 150 contains software modules that communicate with the synthesizer 10 and provide instructions concerning which well to add a particular nucleotide into, and which well should be given a modified base. As can be understood, the control system 150 includes data representing the proper oligonucleotides to be manufactured by the synthesizer 10 . These instructions are provided to the synthesizer 10 so that it can properly actuate the dispensers at the proper time as each well of a microtiter plate passes under a dispenser. This allows the system to manufacture different oligonucleotides within each well of a microtiter plate.
  • the control system 150 includes a storage device that stores oligonucleotide orders which specify the sequence of oligonucleotides to be manufactured.
  • a storage device that stores oligonucleotide orders which specify the sequence of oligonucleotides to be manufactured.
  • the control system notes the bar code number of that plate and then associates that bar code with a particular order stored within the control system.
  • the selected plate is then assigned oligonucleotide sequences that are to be synthesized within each well.
  • the control system tracks each microtiter plate on the synthesizer, and controls the nucleoside bases which are deposited into each well during synthesis.
  • some of the wells may receive a “C” base, whereas other wells may receive an “A”, “T”, “G” or specially modified base depending on the sequence of the oligonucleotide that is to be synthesized within each well.
  • Control system 150 can provide instructions to dispenser stations 35 A-F via the TwinCat control layer in the form of a firing table that is derived from a correlation of desired nucleotide sequences with the synthesizer protocol.
  • Nucleotide sequences can be imported into the control system in the form of batch files listing the sequence for the oligonucleotide to be synthesized in each well. Batch files can be obtained from a variety of sources including, for example, direct input from a user via a graphical user interface or via importation from a customer order system such as the oligonucleotide ordering systems described in U.S. Provisional App. No. 60/634,164, which is hereby incorporated by reference in its entirety.
  • Each well in a batch file can be identified according to a barcode for a particular plate and according to the location of the well in the plate (i.e. row and column).
  • the synthesizer protocol includes the location of each multi-well plate 30 on the rotary table 20 , the location of the dispenser stations 35 A-F and the rotation schedule of the rotary table 20 .
  • the schedule can be represented as a series of “tics”, whereby each tic represents movement of the rotary table 20 a discrete distance. Accordingly, a different set of wells will pass under a dispensing station during each tic.
  • the control system provides a different firing table based on the identity of the wells and the sequences of the oligonucleotides to be synthesized in the wells.
  • the firing table will be described in further detail with reference to the screen shot provided in FIG. 10 .
  • the screen shot represents a user interface for creating or modifying a firing table.
  • input options available for each well are listed in columns.
  • the input options listed include activated nucleotides (A, C, T and G), modification reagents (AmC6, HMDA and Phos), wash solutions (ACN, ACN Em, initial wash, and prebase) and various other reaction solutions (CAP, Deblock and Oxidizer).
  • Output reagents are listed in rows under the Delivery Parameters window.
  • the numbers in the table correspond to the volumes of each reagent to be delivered by the output device to satisfy the input option selected.
  • an alias acts as a place holder representing several different sets of instructions, wherein each set is based on the specific reagents to be added for a particular synthesis cycle.
  • an alias for the initial wash step can represent a first set of instructions to be used in a synthesis cycle when a first modification reagent is to be used and a different set of instructions when a second modification is to be used.
  • appropriate initial wash instructions can be included in a firing table based on the identification of a specific well and identification of the modification to be made to the oligonucleotide assigned to the well.
  • the firing table can be sent to the initial wash dispenser 35 A in response to the tic that brings the specific well into communication with dispenser 35 A at the cycle in which the modification is to be made to the oligonucleotide.
  • Two or more input options can be organized into groups.
  • groups are listed in the lower left window of the screen shot in FIG. 10 including Activator and Mods, Bases and Bulk ACN.
  • the Activator and Mods group is selected and includes the AmC6, HMDA and Phos input options.
  • Organization of input options into groups provides the advantage of convenient construction or modification of firing tables. For example, a global change to be made for several input options can be readily made and/or visualized when the input options are organized into a group.
  • any of a variety of polymers or other products of repetitive reaction cycles can be synthesized using a firing table listing reactive solutions suitable for the particular reaction of interest.
  • aspects of the present embodiments also include assays such as determining the sequence of polymers.
  • the sequence of DNA or proteins can be determined.
  • the control system exemplified for a rotary table-based instrument can be readily adapted to other instruments such as those described elsewhere herein.
  • instructions can be provided in other formats besides a firing table including for example, an electronic spreadsheet (for example, EXCELTM spreadsheet from Microsoft) a database table or any of a variety of formats that can represent text in an electronic file.
  • each camera device is a charge couple device (CCD) camera of the type including, but not limited to, the AXIS 2100 Network Camera provided by AXIS Communications, Inc. of Lund Sweden.
  • CCD charge couple device
  • a camera used in the present embodiments can be any device that converts a detectable optical property into a signal in a location dependent manner.
  • exemplary cameras useful in the present embodiments include, for example, a complementary metal oxide semiconductor (CMOS) camera, video camera, internet camera, or other imaging devices capable of converting a picture into a digital image such as those set forth previously herein and in U.S. patent application Pub. No. 2004/0219063.
  • CMOS complementary metal oxide semiconductor
  • each camera can be positioned on the synthesizer 10 over a multi-well plate or other plurality of wells such that it is capable of obtaining an image which includes all of the wells of a multi-well, or microtiter plate.
  • the multi-well plate generally includes 96 or 384 wells, however, one should appreciate that the multi-well plate may include other numbers of wells such as more than 384 wells.
  • the camera device not only allows observation of the multi-well plate as a whole, but also allows observation of each well individually.
  • the camera incorporates an optical filtering stage rendering the detector capable of spectral measurements and tunable to specific chemicals that exhibit specific absorptivities in the spectrum.
  • An optical filter useful in the present embodiments can be any device for selectively passing or rejecting passage of radiation in a wavelength, polarization or frequency dependent manner.
  • the camera can transfer an image electronically to a storage location, such as the image servers 160 A,B.
  • the control system 150 is configured to control each of the cameras.
  • image control software may be configured to signal the camera device, via the central network, when to take an image of a multi-well plate of the oligonucleotide synthesizer 10 .
  • the image may be transferred to the image process servers 160 A,B in the form of a JPEG, TIFF, BMP file or other suitable file format.
  • An exemplary example of an image of a microtiter plate is shown in FIG. 6 .
  • the image files are named according to batch number, plate number, or cycle number within the synthesis protocol that the synthesis process is at when the image is taken.
  • cycle refers to the complete cycle of steps for the addition of each base to the growing DNA chain including, without limitation, the deprotection, coupling, capping, and oxidation steps. It will be understood that an operation can be performed one or several times within the same cycle. Any of the steps set forth herein or otherwise useful in the present embodiments can be carried out as one or more repetitions of the particular step. For example, the deprotection step may repeat two or three times within the same cycle whereby a repetition designation can be used to differentiate the particular deprotection operation within a cycle.
  • FIG. 9 is a flow diagram showing one embodiment of a method 1000 for continuously synthesizing molecules.
  • the method 1000 begins at a start state 1002 and then moves to a state 1004 wherein reagents are dispensed from dispensing valves into a microtiter plate as the plate rotates on a rotary table. After all wells of the microtiter plate have passed under the dispenser valve, the microtiter plate moves below a camera so that an image is taken at a state 1006 .
  • the microtiter plate can be illuminated with a light source such as an LED array.
  • the camera can be placed directly above the rotary table and the LED array can be placed to cast light in a direction towards the light path between the plate and camera such that the two light paths intersect.
  • a beam splitter can be placed between the camera and plate at the intersection point and in a configuration, whereby light emitted from the LED is reflected to the plate by the reflective side of the beam splitter and whereby the camera obtains an image of the lighted plate through the transparent side of the mirror.
  • One exemplary image can be found with reference to FIG. 6 . Further description of imaging systems useful in the present embodiments and appropriate configurations are described in U.S. patent application Pub. No. 2004/0219063.
  • a file contained in the database and used for the comparison can include an expected property for a well based on the presence or absence of a particular volume of liquid.
  • the file can provide a numerical scale ranging from an arbitrary dark value (for example, 4096) to an arbitrary bright value (for example, 0).
  • the values can be assigned for a well based on one or more calibration images obtained for a plate that has been evacuated of solution, that contains an optically clear solution and/or that contains an optically dense solution.
  • an evacuated well can have a value or range of values near 4096
  • a well containing trityl can have a value or range of values near 0
  • a well containing an optically clear solution can have a value or range of values between those for the emptied or trityl containing well.
  • the ranges of values can be contiguous or alternatively can have gaps between them.
  • the optical density can be measured for a plate during synthesis and its optical density compared to the numerical scale to determine if it falls in the range of an empty, full, or trityl containing well.
  • the comparison results in a desired range, for example, an evacuated well has an optical density in the range near 4096, then synthesis for the well is allowed to proceed. If the comparison results in a range that is outside of the desired range, for example, occurring in a gap or in the range near 0, an error can be indicated and synthesis to the well discontinued.
  • the optical densities can be determined for the center of a well or for a specific portion of a well such as a central region of the well.
  • the location of wells is registered such that any image used for determining optical density excludes the edges of wells.
  • individual wells are typically calibrated and compared on an individual basis to compensate for different lighting effects at different parts of the plate.
  • image comparison is described above with respect to optical density, it will be understood that other values can be used in a comparison file in place of optical density such as the standard deviation for the distribution of optical densities measured in a region of a well or the skew for the distribution.
  • the process 1000 then moves to a decision state 1012 wherein a determination is made whether any errors occurred following comparison of the image to the database. Such an error may be that a well that was supposed to have received a reagent is not found to have a reagent within that well. Another error may be that a well that is supposed to be empty is found to be filled with a reagent solution. If an error has been found then process 1000 moves to a state 1016 wherein the error is reported back to the main system for further processing. The further processing may be, for example, that this well is marked as bad and thus does not receive further reaction solutions while the remaining wells in the microtiter plate are completed.
  • the entire microtiter plate can be marked as bad and the system thereafter instructed to load a new microtiter plate onto the continuous synthesizer in order to carry out the reactions that were to occur in the bad microtiter plate.
  • a written or displayed report can also be produced for the user of the system in order to notify the user that such an error has occurred.
  • the process 1000 evacuates the microtiter plate at a state 1024 and thereafter takes another image at a state 1026 in order to determine whether each well has been properly evacuated.
  • the image taken of the evacuated multi-well plate is compared to a database.
  • the process 1000 determines whether any errors occurred at a decision state 1030 and if an error did occur the process returns to the error reporting state 1016 . However, if no errors occurred then the process moves to a decision state 1032 to determine whether the synthesis reactions within the plate have been completed. If they have been completed then the process terminates at the end state 1020 . However if the synthesis reactions within the plate have not been completed at the decision state 1032 the process 1000 returns to the state 1004 to dispense additional reagents into the plate in order to continue the synthesis reactions.
  • FIG. 4 is a flow diagram illustrating an exemplary method 400 for synthesizing oligonucleotides.
  • the method begins at a state 410 wherein a universal support is provided which is used as the anchor for the oligonucleotide.
  • the universal support is a universal controlled pore glass (CPG) substrate that is configured to be used to initially anchor any nucleoside.
  • CPG universal controlled pore glass
  • One such universal CPG is available from Proligo Reagents (Boulder, Colo.).
  • ACN acetonitrile
  • Each well is then evacuated at a state 414 such that wash solution is removed while the universal support is retained in the well.
  • a deblocking solution, containing trichloroacetic acid is then delivered to each of the wells at a state 418 .
  • the process 400 loads any nucleotide modifications at a state 440 and then delivers those nucleotide bases to the reaction sites at a state 442 .
  • an oligonucleotide is to be modified to include an amino group at the 5′ end then monomethoxytritylaminohexyl phosphoramidite (MMT 5′ C6 Amino linker available as cat. #C-1001 from Trilink, San Diego Calif.) can be loaded and delivered.
  • FIG. 5A illustrates an exemplary plate module system 500 that includes an overflow tray 505 configured to hold a plate holder 510 .
  • the plate holder 510 is designed to hold a microtiter plate 515 so that it can be easily loaded and unloaded from the synthesizer 10 .
  • the overflow tray 505 is generally rectangular in shape and includes a front edge 512 , a rear edge 514 , a left edge 516 and a right edge 518 .
  • a central surface 520 of the overflow tray 505 is configured to hold the plate holder 510 .
  • the overflow tray 505 is mounted to the rotary table 20 and provides the means by which the plate holder 510 is loaded and unloaded onto the synthesizer.
  • the plate holder is deposited or removed from the plate module while the rotary table is turning. This allows the synthesizer to continuously synthesize even as the plate holders are being loaded and unloaded from the synthesizer
  • a filter-bottom microtiter plate is first secured into a plate holder.
  • the plate holder is then manually, or automatically, loaded onto the synthesizer by placing the plate holder into an overflow tray.
  • the plate module which is fixed to the rotary table, then rotates around the synthesizer as the rotary table turns.
  • the plate holder 510 rests in the central surface 520 of the overflow tray 505 .
  • the configuration of the plate holder 510 will be explained more completely with reference to FIG. 5B .
  • a vacuum line 525 and a nitrogen line 528 enter the overflow tray 505 through the rear edge 514 .
  • the vacuum line 525 runs inside the overflow tray 505 and communicates with a vacuum interface 530 in the central surface 520 of the plate module.
  • the vacuum interface 530 provides a source of vacuum for removing reaction solutions such as wash solutions or reagent containing solutions from the filter-bottom microtiter plate that is housed within the plate holder 510 .
  • the synthesizer outputs nitrogen gas at the same time that the vacuum is actuated, thus pulling nitrogen gas into each well of the microtiter plate during the evacuation process.
  • nitrogen is an inert gas, it is much less likely to cause a reaction with reaction products such as polymeric molecules being synthesized within each well of the microtiter plate.
  • the present embodiments are not limited to only using nitrogen gas to overlay the microtiter plate. Any type of gas, preferably inert gas, such as argon or helium, is also within the scope of the present embodiments.
  • a device similar to the quarantine devices described above can be used for delivery of a reactive gas to a reaction site in a system of the present embodiments.
  • Gas either inert or reactive
  • Gas can also be provided by one or more stationary stations, such as dispensing stations or imaging stations such that when the plates are evacuated they ingest this gas preferentially over ambient air or pollutants.
  • imaging stations 38 A-F can include a plenum between an upper window for the detector and a microtiter plate below. The plenum can be purged with nitrogen such that gas flows in a direction that is substantially normal to the microtiter plate. The flow of nitrogen gas can provide the advantages of removing moisture and debris from the window as well as displacing harmful vapors to reduce unwanted contact of these vapors with reaction products when the microtiter plate is vacuum evacuated at the imaging station.
  • the plate holder 510 includes an upper frame 550 which is configured to lock with a lower portion 552 of the plate holder 510 .
  • a recessed opening 556 which is sized to hold the microtiter plate 515 .
  • a set of locks 558 A,B reversibly lock the frame 550 against the lower portion 552 .
  • a circular vacuum interface 560 is located in the recessed opening 556 and provides a through-hole to the vacuum source within the plate module 505 .
  • the vacuum section bellow 575 reversibly mounts within the vacuum interface 560 so that the vacuum line 525 can evacuate reaction solutions from within the microtiter plate 515 .
  • the vacuum suction bellow 575 is preferably a flexible polymeric material, such as silicon or rubber, and is configured to provide a quick and efficient reversible seal with the vacuum interface 560 .
  • the vacuum suction bellows 575 includes compressible portions 580 which are adapted to compress or expand as the plate holder 510 is placed on top of the bellow 575 .
  • a module system of the present embodiments can be configured to provide the non-limiting advantages of (1) convenient addition and removal of a first reaction site without interrupting synthesis occurring for a second reaction site, (2) providing a continuously available solution removal device such as a valve attenuated vacuum source, and/or (3) providing a continuously available quarantine device such as a valve attenuated gas knife.
  • a similar module system can be used to hold a substrate for reaction sites having other configurations including, for example, a multi-well plate having a shape or number of wells that differs from the microtiter plate exemplified above.
  • a module system of the present embodiments can be configured for use with other reaction site substrates such as those described elsewhere herein. In embodiments including vacuum based removal of solutions, filter based substrates are particularly useful.
  • FIG. 7 a diagram of an exemplary system 700 for providing reaction solutions to the dispenser 35 A is illustrated.
  • a local reservoir 710 that hold the reaction solutions that are to be dispensed by the dispenser 35 A.
  • a set of level detectors 715 are used to measure the level of the local reservoir and determine when it is time to pump more reaction solution from a storage tank 720 .
  • the storage tank 720 is connected to a helium source 722 which is used to pressurize the storage tank 720 .
  • the helium pressure can be adjusted, for example, under computer control to force additional reaction solution to the local reservoir 710 when the level detectors 715 indicate that the local reservoir 710 is below a predetermined threshold.
  • the system can provide smoother and more reliable dispensing because the liquids do not have to travel through long lines to reach each valve. Any gas pockets or other small changes in pressure within one of such lines can lead to undesirable dispensing conditions, especially when the volumes to be dispensed are very small.
  • use of a hydraulically coupled local reservoir can provide the advantage of eliminating pressure variations that typically occur across a manifold that is connected to multiple dispenser valves, such as the pressure variance that arises due to differences in the number of valves that are open at any given time and the pressure variances that are caused by the opening and closing of valves. Elimination of such effects using, for example, hydraulically coupled local reservoirs provides for staggered firing of individual dispenser nozzles wherein any number of valves can be actuated at any time, as set forth below.
  • a system can be configured for staggered dispenser valve actuation such that staggered liquid dispensing occurs from a set of dispenser nozzles.
  • solenoid valves can control reagent dispensing.
  • Each reagent dispensing station can use multiple solenoid valves that are fired one at a time or in groups depending on the size of the power supply utilized. The number of simultaneous valve actuations per reagent can be constrained in order to limit the electrical current demand and therefore the size of the power supplies, if desired.
  • a dispensing station can be configured to deliver a different volume of fluid from different dispenser nozzles if desired.
  • each dispenser nozzle can be controlled to deliver fluid at different start times, for example, as set forth above.
  • the ability to dispense different volumes of fluid and to do so at different start times provides advantages over typical fixed volume or positive displacement type dispensers by allowing a high level of control over reagent utilization during a synthetic operation.
  • a valve dispenser useful in the present embodiments can be controlled using a hardware abstraction layer (HAL) that fires valves and manages the filling and pressurization of local reservoirs.
  • HAL hardware abstraction layer
  • Discrete logic can be used, for example, via a complex programmable logic device (CPLD), to implement a finite state machine for the local reservoir filling and to generate spike and hold signals that control the valves.
  • CPLD complex programmable logic device
  • the discrete logic for each spike and hold circuit for each valve is typically separate and independent of one another. This allows all valves to be fired simultaneously, slightly staggered, or selectively such that one or more are fired and others are not during a finite time period.
  • a hardware abstraction layer to control a multi nozzle dispenser provides advantages over the use of a microprocessor because a HAL can be scaled to the use of larger numbers of nozzles without increases in cost and computation time that can occur when a microprocessor is used.
  • a microprocessor can be used in the present embodiments, for example, in cases where a relatively small number of nozzles is to be controlled.
  • the HAL can receive four different inputs including inputs 901 , 902 , 903 and 904 .
  • Input 901 is configured to receive a logic “high” signal received from an I/O interface and controls the valve in response to signals generated from a firing table.
  • the signal from input 901 is processed in accordance with the activities of other inputs via OR gate 905 and multiplexer 907 .
  • the timing for the outputs is controlled by passage of the signal from OR gate 905 through an NAND gate 908 , flip flops 909 , 910 and 913 , then OR gate 912 and back to OR gate 908 .
  • the clock cycle is selected to control duration of the spike and hold outputs. For example, in the HAL diagram of FIG.
  • the spike output 915 has a duration of 1 millisecond which corresponds to two clock cycles.
  • Input 902 is configured to allow manual firing of a valve, for example, via a switch that is connected to all valves in a dispenser device.
  • Input 903 is configured to allow a signal to be sent to the HAL for the purpose of turning valve indicator LED's on or off to make a desired pattern, for example to communicate a message to a user.
  • Input 904 receives signals from a clock. Circuitry such as that shown in the diagram can be replicated ad-infinitum for as many valves as necessary.
  • enough current to source the spike of all of the valves can be stored locally.
  • Any of a variety of capacitors known in the art can be used to store the current. Local storage of current reduces the instantaneous demand for current on the power supply used for the dispenser, thereby providing advantages of reducing the cost of the power supply and reducing the amount of space required to house the power supply.
  • the HAL is typically configured to store at least an amount of energy sufficient to fire all of the valves simultaneously.
  • FIG. 8A shows a diagram of one embodiment of a dispenser 35 A as it is outputting solutions to a microtiter plate 515 simultaneously with movement of the microtiter plate via the rotary table 20 .
  • a series of linear valve arrangements 805 , 810 , 815 , 820 , 825 , 830 and 835 are shown within the dispenser 35 A.
  • Each linear arrangement of valves is fluidly connected to the same reagent solution reservoir and a different reservoir delivers solution to each linear arrangement of valves.
  • the valve column 805 is connected to a modified nucleoside.
  • Valve column 810 is connected to an adenosine solution
  • column 815 is connected to a cytidine solution
  • column 820 is connected to a guanosine solution
  • column 825 is connected to a thymidine solution.
  • the sugar moiety for the nucleosides is typically a deoxyribose for synthesis of DNA.
  • monomers can contain other moieties such as ribose sugars useful for synthesizing RNA or moieties used for synthesizing nucleic acids having alternative backbones such as peptide nucleic acids (PNA).
  • Columns 830 and 835 can be connected to, for example, ACN wash solutions, deblocking solutions or capping solutions depending on their position in the synthesizer.
  • valve-reservoir connections used in the present embodiments can be altered from those exemplified above to suit a particular application.
  • each dispenser may have only one valve column, or any other number of valve columns without departing from the spirit of the present embodiments.
  • the valve columns are removable and interchangeable so that a particular dispenser can be outfitted with any number of valve columns to dispense the correct solutions for synthesizing a polymer.

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080182757A1 (en) * 2007-01-26 2008-07-31 Illumina, Inc. Image data efficient genetic sequencing method and system
US20100137166A1 (en) * 2007-01-26 2010-06-03 Illumina, Inc. Independently removable nucleic acid sequencing system and method
US10040048B1 (en) 2014-09-25 2018-08-07 Synthego Corporation Automated modular system and method for production of biopolymers
US12337291B2 (en) 2017-09-11 2025-06-24 Synthego Corporation Guide RNA synthesis system and method
US12421546B2 (en) 2007-01-26 2025-09-23 Illumina, Inc. Nucleic acid sequencing system

Families Citing this family (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2238235A1 (fr) * 2008-01-23 2010-10-13 CSEM Centre Suisse d'Electronique et de Microtechnique SA - Recherche et Développement Appareil et procédé de micro-injection
WO2011090949A2 (fr) 2010-01-19 2011-07-28 Illumina, Inc. Procédés et compositions pour le traitement de réactions chimiques
US8612072B2 (en) * 2010-02-11 2013-12-17 Teleflex Canada, Inc. System for automatically instancing marine engines
US9029103B2 (en) 2010-08-27 2015-05-12 Illumina Cambridge Limited Methods for sequencing polynucleotides
JP5650970B2 (ja) * 2010-09-28 2015-01-07 富士フイルム株式会社 検査装置およびその制御方法、並びに検査用反応容器
US8575071B2 (en) 2010-11-03 2013-11-05 Illumina, Inc. Reducing adapter dimer formation
US20120297997A1 (en) * 2011-05-25 2012-11-29 Michael Novick Image forming apparatuses and methods thereof
WO2013117595A2 (fr) 2012-02-07 2013-08-15 Illumina Cambridge Limited Enrichissement et amplification ciblés d'acides nucléiques sur un support
JP2014219623A (ja) * 2013-05-10 2014-11-20 ソニー株式会社 観測システム、観測プログラム及び観測方法
EP4610368A3 (fr) 2013-08-05 2025-11-05 Twist Bioscience Corporation Banques de gènes synthétisés de novo
US10570447B2 (en) 2014-05-16 2020-02-25 Illumina, Inc. Nucleic acid synthesis techniques
TWI611173B (zh) 2014-07-28 2018-01-11 賽諾菲巴斯德維思設計公司 用於確定抗體結合活性之方法及系統
HK1245346A1 (zh) 2014-12-05 2018-08-24 Amyris, Inc. 多核苷酸的高通量测序
WO2016126882A1 (fr) 2015-02-04 2016-08-11 Twist Bioscience Corporation Procédés et dispositifs pour assemblage de novo d'acide oligonucléique
WO2016172377A1 (fr) 2015-04-21 2016-10-27 Twist Bioscience Corporation Dispositifs et procédés pour la synthèse de banques d'acides oligonucléiques
JP6982362B2 (ja) 2015-09-18 2021-12-17 ツイスト バイオサイエンス コーポレーション オリゴ核酸変異体ライブラリーとその合成
KR20250053972A (ko) 2015-09-22 2025-04-22 트위스트 바이오사이언스 코포레이션 핵산 합성을 위한 가요성 기판
WO2017165630A1 (fr) * 2016-03-23 2017-09-28 Truvian Sciences, Inc. Systèmes et procédés de détection d'analytes multiples
US10417457B2 (en) 2016-09-21 2019-09-17 Twist Bioscience Corporation Nucleic acid based data storage
AU2018284227B2 (en) 2017-06-12 2024-05-02 Twist Bioscience Corporation Methods for seamless nucleic acid assembly
WO2018231864A1 (fr) 2017-06-12 2018-12-20 Twist Bioscience Corporation Méthodes d'assemblage d'acides nucléiques continus
JP2020536504A (ja) 2017-09-11 2020-12-17 ツイスト バイオサイエンス コーポレーション Ｇｐｃｒ結合タンパク質およびその合成
TWI738328B (zh) * 2017-09-28 2021-09-01 美商伊路米納有限公司 流體施配器總成與用於將流體施配至流體匣中的方法
US10894242B2 (en) 2017-10-20 2021-01-19 Twist Bioscience Corporation Heated nanowells for polynucleotide synthesis
EP3495038B1 (fr) 2017-12-11 2020-06-10 The Institute of Organic Chemistry and Biochemistry AV CR Dispositif de synthèse d'oligomères parallèles, procédé de synthèse d'oligomères parallèles et son utilisation
CN120485344A (zh) 2018-01-04 2025-08-15 特韦斯特生物科学公司 基于dna的数字信息存储
US11932842B2 (en) 2018-02-09 2024-03-19 Global Life Sciences Solutions Usa Llc Bioprocessing apparatus
US12077743B2 (en) 2018-02-09 2024-09-03 Global Life Sciences Solutions Usa Llc Apparatus for fluid line management in a bioprocessing system
US11920119B2 (en) 2018-02-09 2024-03-05 Global Life Sciences Solutions Usa Llc Systems and methods for bioprocessing
JP7322041B2 (ja) * 2018-02-09 2023-08-07 グローバル・ライフ・サイエンシズ・ソリューションズ・ユーエスエー・エルエルシー バイオプロセッシング装置
US12252682B2 (en) 2018-02-09 2025-03-18 Global Life Sciences Solutions Usa Llc System and method for fluid flow management in a bioprocessing system
WO2019158007A1 (fr) * 2018-02-13 2019-08-22 深圳华大生命科学研究院 Procédé et système de synthèse d'oligonucléotides
JP2021526366A (ja) 2018-05-18 2021-10-07 ツイスト バイオサイエンス コーポレーション 核酸ハイブリダイゼーションのためのポリヌクレオチド、試薬、および方法
GB2606472A (en) * 2018-07-05 2022-11-09 Synthego Corp Automated modular system and method for production of biopolymers
WO2020037194A1 (fr) * 2018-08-17 2020-02-20 Sierra Biosystems, Inc. Synthèse d'oligonucléotides indépendante de la rangée
JP7542444B2 (ja) 2018-12-14 2024-08-30 イルミナ ケンブリッジ リミテッド 配列決定の間のアンラベル化ヌクレオチドによるフェージング減少
WO2020126595A1 (fr) 2018-12-17 2020-06-25 Illumina Cambridge Limited Oligonucléotide d'amorce pour le séquençage
EP3899040B8 (fr) 2018-12-17 2025-06-11 Illumina Cambridge Limited Procédé de séquençage de polynucléotides
WO2020139871A1 (fr) 2018-12-26 2020-07-02 Twist Bioscience Corporation Synthèse de novo polynucléotidique hautement précise
SG11202109322TA (en) 2019-02-26 2021-09-29 Twist Bioscience Corp Variant nucleic acid libraries for glp1 receptor
WO2020176680A1 (fr) 2019-02-26 2020-09-03 Twist Bioscience Corporation Banques d'acides nucléiques variants pour l'optimisation d'anticorps
US12239950B2 (en) 2019-04-10 2025-03-04 Nitto Denko Avecia, Inc. Process and apparatus for sequential synthesis of biological polymers
CA3144644A1 (fr) 2019-06-21 2020-12-24 Twist Bioscience Corporation Assemblage de sequences d'acide nucleique base sur des code-barres
CA3155630A1 (fr) 2019-09-23 2021-04-01 Twist Bioscience Corporation Bibliotheques d'acides nucleiques variants pour des anticorps a domaine unique
AU2020356471A1 (en) 2019-09-23 2022-04-21 Twist Bioscience Corporation Variant nucleic acid libraries for CRTH2
JP2021065810A (ja) * 2019-10-18 2021-04-30 ヤマト科学株式会社 制御装置、プログラム、及び固相合成装置
IL297701A (en) 2020-04-27 2022-12-01 Twist Bioscience Corp Variable libraries of nucleic acids for the coronavirus
KR20230074151A (ko) 2020-08-26 2023-05-26 트위스트 바이오사이언스 코포레이션 Glp1r 변이체에 관한 방법 및 조성물
US11970697B2 (en) 2020-10-19 2024-04-30 Twist Bioscience Corporation Methods of synthesizing oligonucleotides using tethered nucleotides
CA3206018A1 (fr) 2021-01-21 2022-07-28 Twist Bioscience Corporation Methodes et compositions se rapportant a des recepteurs d'adenosine
AU2022245985A1 (en) 2021-03-22 2023-09-21 Illumina Cambridge Limited Methods for improving nucleic acid cluster clonality
US12258406B2 (en) 2021-03-24 2025-03-25 Twist Bioscience Corporation Antibodies that bind CD3 Epsilon
WO2022271884A2 (fr) 2021-06-22 2022-12-29 Twist Bioscience Corporation Méthodes et compositions se rapportant à des épitopes d'anticorps contre le covid
US12480157B2 (en) 2021-09-30 2025-11-25 Illumina, Inc. Polynucleotide sequencing
AU2022424380A1 (en) 2021-12-29 2024-01-18 Illumina, Inc. Methods of nucleic acid sequencing using surface-bound primers
WO2023130123A2 (fr) 2022-01-03 2023-07-06 Twist Bioscience Corporation Anticorps bispécifiques du sars-cov-2 et procédés d'utilisation
WO2024249591A1 (fr) 2023-05-31 2024-12-05 Illumina, Inc. Procédés de séquençage double brin par synthèse
WO2025144626A1 (fr) 2023-12-28 2025-07-03 Illumina, Inc. Séquençage avec protéines de liaison simple brin

Citations (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1241539A (en) * 1913-07-08 1917-10-02 Max Meirowsky Making mica plates.
US3586484A (en) * 1969-05-23 1971-06-22 Atomic Energy Commission Multistation analytical photometer and method of use
US3712535A (en) * 1970-04-29 1973-01-23 Becton Dickinson Co Centrifuge rotor and sample holder with agitating means
US3722789A (en) * 1972-01-31 1973-03-27 American Hospital Supply Corp Centrifuge and self positioning tube holder therefor
US4042338A (en) * 1975-09-13 1977-08-16 Bodenseewerk Perkin-Elmer & Co. Gmbh Automatic sample preparation device
US4236666A (en) * 1978-03-13 1980-12-02 Dr. Molter Gmbh Laboratory centrifuge
US4244694A (en) * 1978-03-31 1981-01-13 Union Carbide Corporation Reactor/separator device for use in automated solid phase immunoassay
US4285463A (en) * 1979-11-01 1981-08-25 American Hospital Supply Corporation Decanting centrifuge
US4287154A (en) * 1980-05-07 1981-09-01 Sommers Philip B Specimen transfer rack
US4412973A (en) * 1980-12-15 1983-11-01 Jean Guigan Autonomous simultaneous analysis apparatus and a method of using it
US4808380A (en) * 1986-02-21 1989-02-28 Kabushiki Kaisha Toshiba Automatic chemical analyzing apparatus
US4844868A (en) * 1985-06-18 1989-07-04 Kabushiki Kaisha Toshiba Automatic chemical analysis reagent distribution and analysis apparatus
US4862932A (en) * 1988-04-20 1989-09-05 Bio-Rad Laboratories, Inc. Fraction collector
US4906433A (en) * 1986-06-24 1990-03-06 Kabushiki Kaisha Toshiba Automatic chemical analyzer
US5045047A (en) * 1989-07-17 1991-09-03 Zymark Corporation Automated centrifuge
US5084242A (en) * 1987-08-14 1992-01-28 Kabushiki Kaisha Toshiba Distribution nozzle apparatus for automatic chemical analyzer
US5089417A (en) * 1987-07-01 1992-02-18 Miles Inc. Fluid separation and processing device
US5105305A (en) * 1991-01-10 1992-04-14 At&T Bell Laboratories Near-field scanning optical microscope using a fluorescent probe
US5178602A (en) * 1990-02-07 1993-01-12 Wells John R Automatic decanting centrifuge
US5202418A (en) * 1990-02-02 1993-04-13 Ceskoslovenska Akademie Ved Method of performing multiple synthesis of peptides on solid carrier
US5434083A (en) * 1989-07-17 1995-07-18 Hitachi, Ltd. Method and apparatus for automatically analyzing a plurality of test items
US5472672A (en) * 1993-10-22 1995-12-05 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and method for polymer synthesis using arrays
US5501984A (en) * 1989-07-19 1996-03-26 Boehringer Mannheim Gmbh Analyser unit for heterogeneous immunological tests
US5514789A (en) * 1994-04-21 1996-05-07 Barrskogen, Inc. Recovery of oligonucleotides by gas phase cleavage
US5585068A (en) * 1990-02-20 1996-12-17 Biochemical Diagnostics, Inc. Apparatus for automatically separating a compound from a plurality of discrete liquid specimens
US5614608A (en) * 1995-01-20 1997-03-25 Selectide Corporation Apparatus and method for multiple synthesis of organic compounds on polymer support
US5633972A (en) * 1995-11-29 1997-05-27 Trustees Of Tufts College Superresolution imaging fiber for subwavelength light energy generation and near-field optical microscopy
US5707331A (en) * 1995-05-05 1998-01-13 John R. Wells Automatic multiple-decanting centrifuge
US5888723A (en) * 1992-02-18 1999-03-30 Johnson & Johnson Clinical Diagnostics, Inc. Method for nucleic acid amplification and detection using adhered probes
US6045760A (en) * 1995-12-05 2000-04-04 Hitachi Koki Co., Ltd. Micro-plate adapter
US6045755A (en) * 1997-03-10 2000-04-04 Trega Biosciences,, Inc. Apparatus and method for combinatorial chemistry synthesis
US6121054A (en) * 1997-11-19 2000-09-19 Trega Biosciences, Inc. Method for separation of liquid and solid phases for solid phase organic syntheses
US6130046A (en) * 1998-05-04 2000-10-10 Affymetrix, Inc. Techniques for synthesis integrity evaluation utilizing cycle fidelity probes
US6264891B1 (en) * 1998-12-22 2001-07-24 Eos Biotechnology, Inc. Apparatus and method for concurrent chemical synthesis
US6357907B1 (en) * 1999-06-15 2002-03-19 V & P Scientific, Inc. Magnetic levitation stirring devices and machines for mixing in vessels
US20020044894A1 (en) * 1999-12-13 2002-04-18 Michal Lebl Oligonucleotide synthesizer
US6375898B1 (en) * 1998-02-20 2002-04-23 Start Diagnostics Gmbh Analysis system
US6663832B2 (en) * 1999-12-13 2003-12-16 Illumina, Inc. Oligonucleotide synthesizer
US20040219063A1 (en) * 2003-01-21 2004-11-04 Heiner David Louis Chemical reaction monitor
US6846460B1 (en) * 1999-01-29 2005-01-25 Illumina, Inc. Apparatus and method for separation of liquid phases of different density and for fluorous phase organic syntheses

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61139756A (ja) 1984-12-12 1986-06-27 Hitachi Koki Co Ltd 遠心式自動反応装置
EP0569115A3 (fr) 1992-05-05 1994-01-05 General Atomics Système d'élaboration d'ADN à grand débit
US6071748A (en) 1997-07-16 2000-06-06 Ljl Biosystems, Inc. Light detection device
US6270730B1 (en) * 1998-06-16 2001-08-07 Northwest Engineering Inc. Multi-well rotary synthesizer
CA2361223A1 (fr) 1999-01-29 2000-08-03 Illumina, Inc. Appareil et procede destines a la separation de phases liquides de differentes densites et a la synthese organique en phase fluoree
DE19919607A1 (de) * 1999-04-29 2000-11-16 Mets Ion Gmbh Ges Fuer Angewan Verfahren und Vorrichtung zur parallelen Herstellung von wenigstens 4n Oligonukleotiden
US6558623B1 (en) 2000-07-06 2003-05-06 Robodesign International, Inc. Microarray dispensing with real-time verification and inspection
US6587579B1 (en) 2000-01-26 2003-07-01 Agilent Technologies Inc. Feature quality in array fabrication
US6692972B1 (en) 2000-08-24 2004-02-17 University Of Chicago Device for producing microscopic arrays of molecules, a method for producing microscopic arrays of molecules

Patent Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1241539A (en) * 1913-07-08 1917-10-02 Max Meirowsky Making mica plates.
US3586484A (en) * 1969-05-23 1971-06-22 Atomic Energy Commission Multistation analytical photometer and method of use
US3712535A (en) * 1970-04-29 1973-01-23 Becton Dickinson Co Centrifuge rotor and sample holder with agitating means
US3722789A (en) * 1972-01-31 1973-03-27 American Hospital Supply Corp Centrifuge and self positioning tube holder therefor
US4042338A (en) * 1975-09-13 1977-08-16 Bodenseewerk Perkin-Elmer & Co. Gmbh Automatic sample preparation device
US4236666A (en) * 1978-03-13 1980-12-02 Dr. Molter Gmbh Laboratory centrifuge
US4244694A (en) * 1978-03-31 1981-01-13 Union Carbide Corporation Reactor/separator device for use in automated solid phase immunoassay
US4285463A (en) * 1979-11-01 1981-08-25 American Hospital Supply Corporation Decanting centrifuge
US4287154A (en) * 1980-05-07 1981-09-01 Sommers Philip B Specimen transfer rack
US4412973A (en) * 1980-12-15 1983-11-01 Jean Guigan Autonomous simultaneous analysis apparatus and a method of using it
US4844868A (en) * 1985-06-18 1989-07-04 Kabushiki Kaisha Toshiba Automatic chemical analysis reagent distribution and analysis apparatus
US4808380A (en) * 1986-02-21 1989-02-28 Kabushiki Kaisha Toshiba Automatic chemical analyzing apparatus
US4906433A (en) * 1986-06-24 1990-03-06 Kabushiki Kaisha Toshiba Automatic chemical analyzer
US5089417A (en) * 1987-07-01 1992-02-18 Miles Inc. Fluid separation and processing device
US5084242A (en) * 1987-08-14 1992-01-28 Kabushiki Kaisha Toshiba Distribution nozzle apparatus for automatic chemical analyzer
US4862932A (en) * 1988-04-20 1989-09-05 Bio-Rad Laboratories, Inc. Fraction collector
US5434083A (en) * 1989-07-17 1995-07-18 Hitachi, Ltd. Method and apparatus for automatically analyzing a plurality of test items
US5045047A (en) * 1989-07-17 1991-09-03 Zymark Corporation Automated centrifuge
US5501984A (en) * 1989-07-19 1996-03-26 Boehringer Mannheim Gmbh Analyser unit for heterogeneous immunological tests
US5202418A (en) * 1990-02-02 1993-04-13 Ceskoslovenska Akademie Ved Method of performing multiple synthesis of peptides on solid carrier
US5338831A (en) * 1990-02-02 1994-08-16 Academy Of Sciences Of The Czech Republic Changed From Ceskoslovenska Akademie Ved Method of making multiple synthesis of peptides on solid support
US5342585A (en) * 1990-02-02 1994-08-30 Academy Of Sciences Of The Czech Republic Apparatus for making multiple synthesis of peptides on solid support
US5178602A (en) * 1990-02-07 1993-01-12 Wells John R Automatic decanting centrifuge
US5585068A (en) * 1990-02-20 1996-12-17 Biochemical Diagnostics, Inc. Apparatus for automatically separating a compound from a plurality of discrete liquid specimens
US5105305A (en) * 1991-01-10 1992-04-14 At&T Bell Laboratories Near-field scanning optical microscope using a fluorescent probe
US5888723A (en) * 1992-02-18 1999-03-30 Johnson & Johnson Clinical Diagnostics, Inc. Method for nucleic acid amplification and detection using adhered probes
US5472672A (en) * 1993-10-22 1995-12-05 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and method for polymer synthesis using arrays
US5529756A (en) * 1993-10-22 1996-06-25 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and method for polymer synthesis using arrays
US5514789A (en) * 1994-04-21 1996-05-07 Barrskogen, Inc. Recovery of oligonucleotides by gas phase cleavage
US5614608A (en) * 1995-01-20 1997-03-25 Selectide Corporation Apparatus and method for multiple synthesis of organic compounds on polymer support
US5707331A (en) * 1995-05-05 1998-01-13 John R. Wells Automatic multiple-decanting centrifuge
US5633972A (en) * 1995-11-29 1997-05-27 Trustees Of Tufts College Superresolution imaging fiber for subwavelength light energy generation and near-field optical microscopy
US6045760A (en) * 1995-12-05 2000-04-04 Hitachi Koki Co., Ltd. Micro-plate adapter
US6045755A (en) * 1997-03-10 2000-04-04 Trega Biosciences,, Inc. Apparatus and method for combinatorial chemistry synthesis
US6121054A (en) * 1997-11-19 2000-09-19 Trega Biosciences, Inc. Method for separation of liquid and solid phases for solid phase organic syntheses
US6375898B1 (en) * 1998-02-20 2002-04-23 Start Diagnostics Gmbh Analysis system
US6130046A (en) * 1998-05-04 2000-10-10 Affymetrix, Inc. Techniques for synthesis integrity evaluation utilizing cycle fidelity probes
US6264891B1 (en) * 1998-12-22 2001-07-24 Eos Biotechnology, Inc. Apparatus and method for concurrent chemical synthesis
US20020031833A1 (en) * 1998-12-22 2002-03-14 Herbert Heyneker Apparatus and method for concurrent chemical synthesis
US6846460B1 (en) * 1999-01-29 2005-01-25 Illumina, Inc. Apparatus and method for separation of liquid phases of different density and for fluorous phase organic syntheses
US6357907B1 (en) * 1999-06-15 2002-03-19 V & P Scientific, Inc. Magnetic levitation stirring devices and machines for mixing in vessels
US20020044894A1 (en) * 1999-12-13 2002-04-18 Michal Lebl Oligonucleotide synthesizer
US6663832B2 (en) * 1999-12-13 2003-12-16 Illumina, Inc. Oligonucleotide synthesizer
US20040219063A1 (en) * 2003-01-21 2004-11-04 Heiner David Louis Chemical reaction monitor

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8914241B2 (en) 2007-01-26 2014-12-16 Illumina, Inc. Nucleic acid sequencing system and method
US9121063B2 (en) 2007-01-26 2015-09-01 Illumina, Inc. Independently removable nucleic acid sequencing system and method
US20100137166A1 (en) * 2007-01-26 2010-06-03 Illumina, Inc. Independently removable nucleic acid sequencing system and method
US7835871B2 (en) 2007-01-26 2010-11-16 Illumina, Inc. Nucleic acid sequencing system and method
US20110009296A1 (en) * 2007-01-26 2011-01-13 Illumina, Inc. Nucleic acid sequencing system and method
US20110009278A1 (en) * 2007-01-26 2011-01-13 Illumina, Inc. Nucleic acid sequencing system and method
US8244479B2 (en) 2007-01-26 2012-08-14 Illumina, Inc. Nucleic acid sequencing system and method using a subset of sites of a substrate
US8315817B2 (en) 2007-01-26 2012-11-20 Illumina, Inc. Independently removable nucleic acid sequencing system and method
US8412467B2 (en) 2007-01-26 2013-04-02 Illumina, Inc. Nucleic acid sequencing system and method
US9797012B2 (en) 2007-01-26 2017-10-24 Illumina, Inc. Nucleic acid sequencing system and method
US20100138162A1 (en) * 2007-01-26 2010-06-03 Illumina, Inc. Nucleic acid sequencing system and method using a subset of sites of a substrate
US20080182757A1 (en) * 2007-01-26 2008-07-31 Illumina, Inc. Image data efficient genetic sequencing method and system
US8725425B2 (en) 2007-01-26 2014-05-13 Illumina, Inc. Image data efficient genetic sequencing method and system
US12435371B2 (en) 2007-01-26 2025-10-07 Illumina, Inc. Nucleic acid sequencing system
US10053730B2 (en) 2007-01-26 2018-08-21 Illumina, Inc. Independently removable nucleic acid sequencing system and method
US12421546B2 (en) 2007-01-26 2025-09-23 Illumina, Inc. Nucleic acid sequencing system
US11499191B2 (en) 2007-01-26 2022-11-15 Illumina, Inc. Independently removable nucleic acid sequencing system and method
US11439971B2 (en) 2014-09-25 2022-09-13 Synthego Corporation Automated modular system and method for production of biopolymers
US10814300B2 (en) 2014-09-25 2020-10-27 Synthego Corporation Automated modular system and method for production of biopolymers
US10569249B2 (en) 2014-09-25 2020-02-25 Synthego Corporation Automated modular system and method for production of biopolymers
US10040048B1 (en) 2014-09-25 2018-08-07 Synthego Corporation Automated modular system and method for production of biopolymers
US12337291B2 (en) 2017-09-11 2025-06-24 Synthego Corporation Guide RNA synthesis system and method

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US20070110638A1 (en) 2007-05-17

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