system and method to perform molecular diagnostic tests on several samples in parallel and simultane

专利摘要:
EQUIPMENT FOR PERFORMING REAL-TIME AMPLIFICATION AND DETECTION OF NUCLEIC ACID, SYSTEM AND METHODS IMPLEMENTED IN ONE OR MORE COMPUTER PROCESSORS TO OPTIMIZE PROTOCOLS FOR THE SIMULTANEOUS PLURALITY OF THERMAL AND CYCLE REALITY REVIEWS AND REALIZATION. PCR REACTION CAMERAS AND NON-TRANSITIONAL MEDIA READABLE BY COMPUTER. Systems and methods for the simultaneous performance of nucleic acid amplification and detection. The systems and methods comprise methods for managing a plurality of protocols in conjunction with directing an array of sensors through each of a plurality of reaction chambers. In certain embodiments, the protocols comprise thermocycling profiles and the methods can deviate and extend the duration of the thermocycling profiles to achieve more efficient detection behavior.
公开号:BR112013026451B1
申请号:R112013026451-9
申请日:2012-04-13
公开日:2021-02-09
发明作者:Thomas Catalino Gubatayao；Kalyan Handique；Karthik Ganesan；Daniel M. Drummond
申请人:Becton, Dickinson And Company；
IPC主号:

专利说明:

REMISSIVE REFERENCE TO RELATED ORDERS
[001] This Order claims the benefit in 35 USC Section 119 (e) of United States Provisional Patent Application for Serial No. 61 / 476,175, filed on April 15, 2011, entitled “SOFTWARE CONTROL PROCESS TO SYNCHRONIZE TERMOCYCLING AND SCANNING OPTICAL DETECTION ”and United States Provisional Patent Application for Serial No. 61 / 476,167, filed on April 15, 2011, entitled“ 6-COLOR SCANNING REAL-TIME MICROFLUIDIC THERMOCYCLER ”whose applications are incorporated by reference here in their entirety. TECHNICAL FIELD
[002] The systems and methods described here generally refer to the automated execution of nucleic acid amplification assays, such as Polymerase Chain Reaction (PCR), and in some cases real-time PCR, in a plurality of reaction chambers microfluidic in a microfluidic cartridge. The system can subsequently detect target nucleic acids, for example, target amplicons, within each of the reaction chambers. BACKGROUND OF THE INVENTION
[003] The medical diagnostics industry is a critical element of today's health infrastructure. Currently, however, in vitro diagnostic analyzes, no matter what routine, have become a bottleneck in patient care. There are several reasons for this. First, many diagnostic tests can be done only with highly specialized equipment that is both expensive and only operable by trained doctors. Such equipment can be found only in a few locations --- often just one in any given urban area. This requires hospitals to send samples for analysis to these locations, thereby incurring shipping costs and shipping delays, and possibly even the loss or misuse of the sample. Second, the equipment in question is typically not available “on demand”, however, instead it runs in batches, thereby slowing down the processing time for many samples since they must wait for a machine to reach capacity before can be performed.
[004] Understanding that diagnostic tests on biological samples can be divided into several main steps, it is generally desirable to automate one or more steps. For example, a biological sample, such as those obtained from a patient, can be used in nucleic acid amplification assays, to amplify a target nucleic acid (for example, DNA, RNA or the like) of interest. Once amplified, the presence of a target nucleic acid or amplification product from a target nucleic acid reactor (eg, a target amplicon) can be detected, with the presence of a target nucleic acid and / or target amplicon being used to identify and / or quantify the presence of a target (for example, a target microorganism or similar). Generally, nucleic acid amplification assays involve multiple steps, which can include nucleic acid extraction, nucleic acid amplification, and detection. It is desirable to automate certain steps in these processes.
[005] There is a need for a method and mechanism for performing molecular diagnostic assays on multiple samples in parallel, with or without the amplification of target nucleic acids, and detection in a prepared biological sample. The system can be configured for high performance, and operation in a commercial reference laboratory or at the service point, thereby eliminating the need to send the sample to a specialized center. SUMMARY OF THE INVENTION
[006] The modalities described here refer to the methods and devices for the simultaneous testing of multiple samples. Certain modalities include a mechanism to carry out the detection and amplification of nucleic acid in real time. The mechanism may include a detector head comprising a plurality of light source and photodetector pairs. The detector head can be mounted on a rail, the pairs of light source and detector being aligned in a first row and a second row. The mechanism can include a receptacle for a microfluidic cartridge that has a plurality of independent reaction chambers aligned in adjacent columns of a first row and a second row. The mechanism may also include a perforated plate that is configured to be positioned over the microfluidic cartridge when the cartridge is present in the receptacle. The perforated plate may include a plurality of openings that are each aligned with each of the plurality of reaction chambers while the receptacle is holding the microfluidic cartridge. The detector head can be located on the perforated plate, and be movable along the rail, such that each of the plurality of photodetectors and light source pairs in the first row can be positioned over each opening in the first row of the perforated plate, and each of the plurality of photodetectors and light source pairs in the second row may be positioned over each opening in the second row of the perforated plate.
[007] In some embodiments, the mechanism also includes a second detector head that has a plurality of photodetectors and light source pairs aligned in a first row and a second row. The second detector head can be mounted on the rail. The mechanism may also include a second receptacle for a microfluidic cartridge including a plurality of independent reaction chambers aligned on adjacent columns of a first row and a second row. The mechanism may also include a second perforated plate configured to be positioned over the second microfluidic cartridge when the second cartridge is present in the second receptacle, and which may include a plurality of openings that are each aligned in each of the plurality of the reaction chambers of the second microfluidic cartridge while the second receptacle is holding the second microfluidic cartridge. The second detector head can be located on the perforated plate, and can be movable along the rail such that each of the plurality of photodetectors and light source pairs in the first row of the second detector head can be positioned over each opening in the first row of the second perforated plate, and each of the plurality of photodetectors and light source pairs in the second row of the second detector head may be positioned over each opening in the second row of the second perforated plate.
[008] In some embodiments, photodetectors and light source pairs may include at least six different photodetectors and light source pairs operating at six different wavelengths. In some embodiments, the six different wavelengths comprise a light source emitting a green light, a light source emitting a yellow light, a light source emitting an orange light, a light source emitting a green light. red colored light, and a light source emitting crimson colored light. In some embodiments, the detector head includes at least N rows of photodetectors and light source pairs, and the detector is configured to move to at least the M + N-1 positions on a perforated plate comprising the M opening rows .
[009] In some embodiments, the perforated plate comprises steel, aluminum, nickel or a combination thereof. In some embodiments, the perforated plate may be approximately 0.64 centimeter (0.25 inch) thick. In some embodiments, at least part of the perforated plate is electrochemically oxidized to make it darker than when the perforated plate is not electrochemically oxidized. In some embodiments, the perforated plate provides substantially uniform pressure across the area of the microfluidic cartridge, when the cartridge is present within the receptacle. In some embodiments, a perforated plate comprises at least one of aluminum, zinc or nickel, the perforated plate also comprising a dye.
[0010] In some embodiments, the mechanism also comprises a heating plate, the heating plate being positioned under the microfluidic cartridge when a cartridge is present in the receptacle. In some embodiments, the heating plate comprises at least one of glass or quartz. In some embodiments, the perforated plate provides substantially uniform pressure through the microfluidic cartridge area when a cartridge is present in the receptacle. The substantially uniform pressure can facilitate the substantially uniform thermal contact between the microfluidic reaction chambers and the heating plate. As such, in some embodiments, the perforated plate provides uniform pressure that can ensure that each of the plurality of reactors or reaction chambers in the microfluidic cartridge are in uniform thermal contact or communication with a respective plurality of heating elements located within the heating plate. .
[0011] In some embodiments, the mechanism also comprises a photodetector, the photodetectors located on the perforated plate, and the microfluidic chamber is configured to receive light at an angle of view from a light source relative to the photodetectors. In some embodiments, the heating plate comprises a plurality of heating elements, each of the plurality of heating elements being positioned such that when the microfluidic cartridge is present in the receptacle, the plurality of heating elements is in thermal connection with each of the plurality of reaction chambers, respectively.
[0012] Certain modalities include a method implemented in one or more computer processors to optimize protocols, such as Polymerase Chain Reaction (PCR) or similar protocols, to simultaneously perform a plurality of thermal cycling reactions, each of which The thermal cycling reaction comprises one or more detection steps, and the thermal cycling reactions are carried out in a plurality of reactors. The method may include the steps of determining or providing a detection cycle time for each of the pluralities of reactor; receiving or accessing a protocol step, the step associated with a step duration, the step comprising a time for detection; and determining a first adjustment to the step such that the duration of the step is a multiple of the detection cycle time.
[0013] In some modalities the method also comprises determining a second adjustment for the step, the detection time being a multiple of the detection cycle time when the step is adjusted by the first adjustment and the second adjustment. In some embodiments, the method also comprises determining an initial compensation adjustment based on a reaction chamber position associated with the protocol. In some embodiments, the detection cycle time comprises the amount of time required for a detector head to perform a predetermined plurality of detections for a reactor. In some embodiments, the detection cycle time includes a time required for the movement of the detector head for each of a plurality of reactor and movement of the detector head to the starting position. In some modalities, the method also comprises starting the protocol.
[0014] Certain modalities include a non-transient computer-readable medium comprising instructions, instructions configured to make one or more processors perform the following steps: determine or provide or access a detection cycle time; receive or access a step in the protocol, the step being associated with a step duration, and the step includes a time for detection; and determining a first adjustment for the step such that the duration of the step is a multiple of the detection cycle time.
[0015] In some embodiments, the protocol step is associated with a protocol of a plurality of protocols. Each protocol plurality can be associated with at least one of a plurality of thermal cycling reactions, such as Polymerase Chain Reaction (PCR) protocols, with each thermal cycling reaction comprising one or more detection steps, and the determination of a first adjustment being based at least in part on a time of one or more detection steps associated with thermal cycling reactions of at least two or more of the protocol pluralities when the two or more of the pluralities of protocol are executed simultaneously. In some embodiments, the method also includes the step of determining a second adjustment for the step, the detection time being a multiple of the detection cycle time when the step is adjusted by the first adjustment and the second adjustment. In some embodiments, the method also includes the step of determining an initial compensation adjustment based on a position of a reaction chamber associated with the protocol. In some embodiments, the detection cycle time includes an amount of time required for a detector head to perform a predetermined plurality of detections for a reaction chamber. In some embodiments, the detection cycle time also includes a time required for the movement of the detector head for each of a plurality of detection positions of the reaction chamber and movement of the detector head to an initial position. In some modalities, the method also comprises starting the protocol.
[0016] Certain modalities include a system to optimize the protocols for a plurality of reaction chambers. The system may include a processor configured to do the following: determine or provide or access a detection cycle time; receive or access a protocol step, the step being associated with a step duration, and the step includes a time for detection; and determining a first adjustment for the step such that the duration of the step is a multiple of the detection cycle time.
[0017] In some embodiments, the protocol step is associated with a protocol of a plurality of protocols. Each of the plurality of protocols can be associated with at least one of a plurality of thermal cycling reactions, such as a Polymerase Chain Reaction (PCR) protocol, with each thermal cycling reaction comprising one or more detection steps, and the determination of a first adjustment is based at least in part on a time of one or more detection steps associated with thermal cycling reactions of at least two or more of the pluralities of protocol when the two or more of the pluralities of protocol are simultaneously executed. In some embodiments, the processor is also configured to determine a second setting for the step, the detection time being a multiple of the detection cycle time when the step is adjusted by the first setting and the second setting. In some embodiments, the processor is also configured to determine an initial compensation setting based on a position in a reaction chamber associated with the protocol. In some embodiments, the detection cycle time includes an amount of time required for a detector head to perform a predetermined plurality of detections for a reaction chamber. In some embodiments, the detection cycle time also includes a time required for the movement of the detector head for each of a plurality of detection positions of the reaction chamber and movement of the detector head to the starting position. In some embodiments, the processor is also configured to start the protocol.
[0018] Certain modalities contemplate a method to simultaneously perform real-time PCR in a plurality of PCR reaction chambers, comprising: (a) providing sufficient scanning time for a detector assembly to perform a scanning cycle during which it can scan each of the plurality of PCR reaction chambers for at least one detectable signal and become ready to repeat the scan; (b) provide a reaction protocol for each of the PCR reaction chambers that includes multiple cycles, each cycle comprising a cycle time that includes at least one heating step, at least one cooling step, and at least one level of temperature that includes a reading cycle period during which the detector assembly is to scan the reaction chamber for at least one detectable signal; (c) determine, using a processor, whether the cycle time for this reaction chamber is the same or an integer multiple of the scan time, and if not, adjust the scan time or cycle time so that the cycle time is the same or an integer multiple of the scan time; (d) perform at least steps (b) and (c) for the reaction protocol for each of the pluralities of PCR reaction chambers so that the cycle time for each reaction protocol is the same or a multiple integer scan time; and (e) under the direction of a processor, perform real-time PCR in each of the reaction chambers using the reaction protocol for each of the reaction chambers, including conducting multiple scanning cycles with the detector assembly, each chamber being PCR reaction is scanned by the detector assembly during each period of the reading cycle for that reaction chamber.
[0019] In some modalities the method also comprises the phase of adjustment of the cycle time of the reaction protocol for at least one of the reaction chambers. In some embodiments, at least one said reaction protocol is different from the other said reaction protocol. In some embodiments, at least one cycle time in one reaction protocol is different from the cycle time in another reaction protocol. BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1A is a front plan view of a diagnostic mechanism as used in certain modalities.
[0021] FIG. IB is a perspective view of the upper part of the diagnostic mechanism in Figure 1A showing certain internal components of the mechanism.
[0022] FIG. 2 illustrates an internal view of the diagnostic mechanism of Figures 1A and 1B.
[0023] FIG. 3A illustrates a top plan view of a possible microfluidic arrangement in certain embodiments of a microfluidic cartridge as described here.
[0024] FIG. 3B illustrates the layout of a heating substrate in relation to the reaction chamber of certain modalities.
[0025] FIG. 4A illustrates an external view of the optical module including the detector head of certain modalities described here.
[0026] FIG. 4B illustrates a view of the optical module of Figure 4A with a side cover removed.
[0027] FIG. 4C illustrates a basic view of the optical module of Figure 4A.
[0028] FIG. 5 illustrates the detector head used in the optical module of certain modalities along line 13 of Figure 4B.
[0029] FIG. 6 describes the layout of the light sources and optical detectors as used in certain embodiments of the detector head described here.
[0030] FIG. 7 is a graph of fluorescence versus time of using real-time PCR of target nucleic acids performed in a mechanism of certain modalities as described here.
[0031] FIG. 8 is an abstract description of certain chambers, opening, and heating layers found in certain embodiments as described here.
[0032] FIGS. 9A-H illustrate various perspectives of a perforated plate embodiment.
[0033] FIG. 10 illustrates various dimensions of the perspective of the perforated plate of Figures 9A-H.
[0034] FIG. 11 is a plot of part of a thermal profile for a possible protocol implemented in certain modalities.
[0035] FIG. 12 is a flowchart describing a process for determining protocol durations, tradeoffs, and detection times, for optimizing and organizing the efficiency of the detector.
[0036] FIG. 13 illustrates a part of a user interface for selecting the durations of certain protocol steps and sub-steps and determining the accompanying intra-cycle adjustment.
[0037] FIG. 14 is a plot of a thermal profile comprising an inter-cycle adjustment.
[0038] FIGS. 15A-C plot a plurality of thermal profiles for a plurality of protocols implemented in certain modalities. Figures 15A and 15B illustrate the character of the protocol profiles before the initial compensation adjustment. Figure 15C illustrates the plurality of protocol profiles relative to one another after applying the initial compensation adjustments.
[0039] FIG. 16 is a plot of a thermal profile under active cooling when implemented in certain modalities. DETAILED DESCRIPTION
[0040] Certain modalities present include a mechanism, referred to here as a thermocycler, which can consistently heat and analyze the microfluidic chambers. Polynucleotide amplification, such as by real-time PCR, can be performed in fluidic chambers. In some embodiments, the thermocycler can be configured to carry out the detection and individual thermocycling protocols in a plurality of microfluidic reaction chambers in a microfluidic cartridge. Thermocycling can be used to amplify nucleic acids, for example, DNA, RNA or the like, for example, by real-time PCR or other nucleic acid amplification protocols described here, inside the microfluidic reaction chambers. The thermal cycler may comprise a detector head, comprising a plurality of pairs of detectors, for example, six or more pairs of detector heads, each pair of detectors comprising a light emitting source, for example, an LED or the like , and a cognate photodiode. In some embodiments, each pair of individual detectors is configured to generate and detect the light emitted from a fluorescent fraction, for example, a fluorescent probe, to indicate the presence of a target polynucleotide.
[0041] As used here, the term "microfluidic" refers to volumes of less than 1 ml, preferably less than 0.9 ml, for example. 0.8 ml, 0.7 ml, 0.6 ml, 0.5 ml, 0.4 ml, 0.3 ml, 0.2 ml, 0.1 ml, 90 μL, 80 μL, 70 μL, 60 μL, 50 μL, 40 μL, 30 μL, 20 μL, 10 μL, 5 μL, 4 μ1.3 μL, 2 μL, 1 μL or less or any amount in between. It should be understood that, unless specifically stated otherwise, where the term PCR is used here, any variant of PCR including, without limitation, real-time and quantitative PCR, and any other form of polynucleotide amplification is intended be covered.
[0042] The detection process used in the assay can also be multiplexed to allow multiple concurrent measurements in multiple reactions concurrently. In some embodiments, these measurements can be taken from separate reaction chambers. Certain of these modalities perform a plurality of PCR reactions simultaneously in a single PCR reaction chamber, for example, multiplex PCR. A PCR protocol can comprise standards for performing the successive annealing and denaturation of the polynucleotides in the reaction chamber before detection. Such standards, comprising a time profile for heating the chamber, can be referred to as a “protocol”. Certain of the described modalities facilitate consistent heating and / or cooling through a plurality of reaction chambers performing PCR, while facilitating detection using a set of sensors. In certain embodiments, the mechanism may comprise a perforated plate that facilitates consistent heating and cooling of the reaction chambers by applying pressure to a cartridge containing a plurality of PCR reaction chambers. Certain details and methods for processing polynucleotides can be found in, for example, United States Patent Application Publication 2009-0131650 and United States Patent Application Publication 2010-0009351, incorporated herein by reference.
[0043] The skilled technician will appreciate that the modalities described here are useful for various types of nucleic acid amplification reactions. For example, nucleic acid amplification methods in conjunction with the modalities described here may include, but are not limited to: Polymerase Chain Reaction (PCR), filament displacement amplification (SDA), for example, multiple displacement amplification (MDA), loop-mediated isothermal amplification (LAMP), ligase chain reaction (LCR), immuno-amplification, and a variety of transcription-based amplification procedures, including transcription-mediated amplification (TMA), based amplification nucleic acid sequence (NASBA), self-sustained sequence replication (3SR), and rotating circle amplification. See, for example, Mullis, “Process for Amplifying, Detecting, and / or Cloning Nucleic Acid Sequences,” United States Patent No. 4,683,195; Walker, “Strand Displacement Amplification”, United States Patent No. 5,455,166; Dean et al., "Multiple Displacement Amplification", United States Patent No. 6,977,148; Notomi et al., "Process for Synthesizing Nucleic Acid", United States Patent No. 6,410,278; Landegren and others. United States Patent No. 4,988,617 "Method of detecting a nucleotide change in nucleic acids"; Birkenmeyer, “Amplification of Target Nucleic Acid Using Gap Filling ligase Chain Reaction”, United States Patent No. 5,427,930; Cashman, "Blocked-Polymerase Polynucleotid Immunoassay Method and Kit", United States Patent No. 5,849,478; Kacian et al., “Nucleic Acid Sequence Amplification Methods”, United States Patent No. 5,399,491; Malek et al., "Enhanced Nucleic Acid Amplification Process", United States Patent No. 5,130,238; Lizardi et al., BioTechnology, 6: 1 197 (1988); Lizardi et al., United States Patent No. 5,854,033 “Rolling circle replication reporter systems”.
[0044] In some embodiments described here, the target nucleic acid, for example, the target amplicon, can be detected using an oligonucleotide probe. Preferably, the probes include one or more detectable fractions that can be detected by the systems described herein. The skilled technician will appreciate that several probe technologies are useful in the modalities described here. For example, the modalities described here can be used with TAQMAN® probes, molecular beacon probes, SCORPION ™ probes and the like.
[0045] TaqMan® assays are homogeneous assays to detect polynucleotides (see, United States Patent No. 5,723,591). In the TAQMAN® assays, two PCR primers flank a central TAQMAN® probe oligonucleotide. The probe oligonucleotide contains a fluorophore and extinguisher. During the polymerization step of the PCR process, the 5 'nucleasse activity of the polymerase cleaves the probe oligonucleotide, causing the fluorophore fraction to become physically separated from the extinguisher, which increases the fluorescence emission. The more PCR product is created, the emission intensity at the new wavelength increases.
[0046] Molecular beacons are an alternative to TAQMAN® probes for the detection of polynucleotides, and are described in, for example, United States Patent Nos. 6,277,607; 6,150,097; and 6,037,130. Molecular beacons are oligonucleotide clamps that undergo a conformational change when attached to a perfectly matched model. The conformational change of the oligonucleotide increases the physical distance between a fraction of fluorophore and a fraction of the extinguisher present in the oligonucleotide. This increase in physical distance causes the effect of the extinguisher to be reduced, thereby increasing the signal derived from the fluorophore.
[0047] The adjacent probe method amplifies the target sequence by Polymerase Chain Reaction in the presence of two nucleic acid probes that hybridize to adjacent regions of the target sequence, one of the probes being labeled with a fluorophore receptor and the other probe labeled with a fluorophore donating a fluorescence energy transfer pair. Upon hybridization of the two probes to the target sequence, the donor fluorophore interacts with the recipient fluorophore to generate a detectable signal. The sample is then stimulated with light at a wavelength absorbed by the donor fluorofluor and the fluorescent emission of the fluorescence energy transfer pair is detected to determine that target amount. United States Patent No. 6,174,670 describes such methods.
[0048] Sunrise primers use a hairpin structure similar to molecular beacons, however, attached to a target binding sequence that serves as an initiator. When the complementary filament of the initiator is synthesized, the hairpin structure is broken, thereby eliminating the extinction. These primers detect the amplified product and do not require the use of a polymerase with a 5 'exonuclease activity. Sunrise initiators are described by Nazarenko and others. (Nucleic acid Res. 25: 2516-21 (1997) and United States Patent No. 5,866,336.
[0049] SCORPION ™ probes combine a primer with an added hairpin structure, similar to Sunrise primers. However, the hairpin structure of SCORPION ™ probes is not opened by synthesis of the complementary filament, however, by hybridizing part of the hairpin structure with a part of the target that is downstream of the part that hybridizes to the primer.
[0050] DzyNA-PCR involves a primer containing the antisense sequence of a DNAzyme, an oligonucleotide capable of cleaving specific RNA phosphodiester bonds. The primer binds to a target sequence and conducts an amplification reaction producing an amplicon that contains the active DNAzyme. The active DNAzyme then cleaves a generic reporter substrate in the reaction mixture. The reporter substrate contains a fluorophore-extinguisher pair and the substrate cleavage produces a fluorescence signal that increases with the amplification of the target sequence. DNAzy-PCR is described in Todd et al., Clin. Chem. 46: 625-30 (2000) and United States Patent No. 6,140,055.
[0051] Fiandaca and others. describes a fluorogenic method for PCR analysis using an extinguisher-labeled peptide nucleic acid probe (Q-PNA) and a fluorophore-labeled oligonucleotide primer. Fiandaca and others. Genome Research. 11: 609- 613 (2001). The Q-PNA hybridizes to a label sequence at the 5 'end of the primer.
[0052] Li et al., Describe a double-stranded probe having an extinguisher and fluorophore in opposite oligonucleotide strands. Li and others. Nucleic Acids Research. 30 (2): e5, 1-9 (2002). When not attached to the target, the filaments hybridize to each other and the probe is extinguished. However, when a target is present at least one strand hybridizes to the target resulting in a fluorescent signal.
[0053] Fluorophore fractions and labels useful in the modalities described here include, without limitation, inks from the fluorescein family, the carboxyrodamine family, the cyanine family, and the rhodamine family. Other families of paints that can be used in the invention include, for example, paints from the polyalofluorescein family, paints from the hexachlorofluorescein family, paints from the coumarin family, paints from the oxazine family, paints from the thiazine family, paints from the squarain family , paints from the chelated lanthanide family, the family of paints available under the trade name Alexa Fluor J, from Molecular Probes, and the family of paints available under the trade name Bodipy J, from Invitrogen (Carlsbad, Calif). Inks of the fluorescein family include, for example, 6-carboxyfluorescein (FAM), 2 ', 4', 1,4, -tetrachlorofluorescein (TET), 2 ', 4', 5 ', 7', 1.4-hexachlorofluores- (HEX), 2 ', 7'-dimethoxy-4', 5'-dichloro-6-carboxyrodamine (JOE), phenyl-1,4-dichloro-6-carboxyfluorescein 2'-chloro-5'-fluor-7 ', 8'-fused (NED), 2'-chloro-7'-phenyl-1,4-dichloro-6-carboxyfluorescein (VIC), 6-carboxy-X-rhodamine (ROX), and 2', 4 ' , 5 ', 7'-tetrachlor-5-carboxy-fluorescein (ZOE). Inks from the carboxy-amine family include tetramethyl-6-carboxy-mine (TAMRA), tetrapropane-6-carboxy-amine (ROX), Texas Red, R110 and R6G. Inks from the cyanine family include Cy2, Cy3, Cy3.5, Cy5, Cy5.5, and Cy7. fluorophores are readily available commercially from, for example, Perkin-Elmer (Foster City, Calif.), Molecular Probes, Inc. (Eugene, Oreg.) and Amersham GE Healthcare (Piscataway, N.J.).
[0054] As described above, in some embodiments, probes useful in the embodiments described here may comprise an extinguisher. Extinguishers can be fluorescent or non-fluorescent extinguishers. Fluorescent extinguishers include, without limitation, TAMRA, ROX, DABCYL, DABSYL, cyanine inks including nitrothiazole blue (NTB), anthraquinone, malachite green, nitrothiazole compounds, and nitroimidazole. Exemplary non-fluorescent extinguishers that dissipate the absorbed energy of a fluorophore include those made available under the trade name Black Hole ™ from Biosearch Technologies, Inc. (Novato, Calif), those made available under the trade name Eclipse ™. Dark, by Epoch Biosciences (Bothell, Wash.), Those available under the trade name Qxl J, by Anaspec, Inc. (San Jose, Calif.), And those available under the Iowa Black ™ trademark of Integrated DNA Technologies (Coralville, Iowa ).
[0055] In some embodiments described above, a fluorophore and an extinguisher are used together, and can be the same or different oligonucleotides. When placed together, a fluorophore and fluorescent extinguisher can be referred to as a donor fluorophore and receptor fluorofluor, respectively. Various convenient fluorophore / extinguisher pairs are known in the art (see, for example, Glazer et al., Current Opinion in Biotechnology, 1997; 8: 94-102; Tyagi et al., 1998, Nat. Biotechnol., 16: 49-53 ) and are readily available commercially from, for example, Molecular Probes (Junction City, Oreg.), and Applied Biosystems (Foster City, Calif.). Examples of donor fluorophores that can be used with various receptor fluorophores include, but are not limited to, fluorescein, Lucifer Yellow, B-phycoerythrin, 9-acridine isothiocyanate, Yellow VS Lucifer, 4-acetamido-4'-isothio-cyanatostylbene-2 , 2'-disulfonic, 7-diethylamino-3- (4'-isothiocyanatophenyl) -4-methylcoumarin, succinimidyl 1-pyrenobutyrate and 4-acetamido-4'-isothiocyanatostilbene-2-, 2'-disulfonic acid derivatives . Receptor fluorofluors typically depend on the donor fluorofluor used. Examples of receptor fluorophores include, but are not limited to, LC-Red 640, LC-Red 705, Cy5, Cy5.5, lysamine rhodamine B sulfonyl chloride, tetramethyl rhodamine isothiocyanate, rhodamine x isothiocyanate, erythrosine isothiocyanate , fluorescein, diethylenetriamine pentaacetate or other chelates of Lanthanide ions (for example, Europium or Terbium). Donor and recipient fluorophores are readily available commercially from, for example, Molecular Probes or Sigma Chemical Co. (St. Louis, Mo.). Flouroforo / extinguisher pairs useful in the compositions and methods described here are well known in the art, and can be found, for example, described in S. Marras, “Selection of fluoroforo and Quencher Pairs for Fluorescent Nucleic Acid Hybridization Probes” available on the website world molecular-beacons.org/ download / marras, mmb06% 28335% 293.pdf (as of April 11, 2012).
[0056] The detection process used in the tests described here advantageously allows multiple concurrent measurements of multiple detectable fractions, for example, a plurality of probes containing different detectable fractions, etc. In some embodiments, these measurements can be taken from separate reaction chambers in a microfluidic cartridge, for example, comprising a layer of the chamber (the layer of the chamber referring here to that part of the microfluidic cartridge containing the reaction chambers). Certain of these modalities perform a plurality of amplification reactions simultaneously in a single reaction chamber, for example, multiplex PCR. A PCR protocol may comprise standards for performing successive denaturation and annealing of polynucleotides in the reaction chamber before detection. In certain embodiments, the mechanism is configured to facilitate consistent heating and / or cooling through a plurality of reaction chambers to perform nucleic acid amplification, and to facilitate the detection of target amplicons in individual reaction chambers, for example, detecting fluorescent emissions using a set of sensors.
[0057] In certain embodiments, the mechanism may comprise a perforated plate that facilitates consistent heating and cooling of the reaction chambers by applying pressure to a cartridge containing a plurality of reaction chambers through multiple independent optical pairs. The perforated plate is preferably configured to allow and facilitate the generation and detection of fluorescent probe signals in multiple independent reaction chambers. In some embodiments, the perforated plate is configured such that there is an individual opening (or windows), positioned over each of the individual reaction chambers in the microfluidic cartridge. Diagnostic Mechanism
[0058] Figures 1A and 1B show a diagnostic mechanism 10 for certain of the present modalities. In the embodiment illustrated in Figure 1A, the diagnostic mechanism includes a mechanism compartment 30. The compartment 30 can guarantee a controlled environment for the processing of microfluidic samples and to prevent unwanted light from entering the detection space. The compartment 30 may comprise a cover 16 which includes a cable 14 and a translucent window 12. The cover 16 can be lowered to close the opening in front of the diagnostic mechanism 10 when the diagnostic mechanism 10 is in operation.
[0059] As seen in the modalities of Figures 1A and 1B, the diagnostic mechanism 10 can accommodate two specimen shelves 24a, 24b at the front of the diagnostic mechanism 10. The skilled technician will appreciate, however, that the description of the diagnostic mechanism in Figures 1A and 1B it is exemplary only, and that in some embodiments, the mechanism can be configured to accommodate more than two specimen shelves, for example, three, four, five, six, seven, eight, nine, ten or more specimen shelves. Preferably, the mechanism is configured to accommodate the same number of specimen shelves, for example, two, as microfluidic cartridges.
[0060] In some embodiments, each specimen shelf 24a, 24b may include multiple cables 26. The cables 26 may include receptacles for holding diagnostic reagents, such as reagents for nucleic acid amplification, for example, PCR reagents or similar. Shelves 24 may also include specimen tubes (not shown) and mixing tubes (not shown) for preparing samples ready for diagnosis, such as samples ready for amplification. The mechanism can prepare the desired reagents on shelves 24a, 24b using dispenser 400. Another description of various fluid dispensers can be found in, for example, United States Patent Application Publication 20090130719 and United States Patent Application Publication 20090155123, incorporated herein by reference.
[0061] In some embodiments, the reaction chambers in the microfluidic cartridge (s) include one or more reagents, buffers etc., used in the nucleic amplification assay. For example, in some embodiments, the reaction chambers of the microfluidic cartridge may include, for example, amplification primers, probes, nucleotides, enzymes such as polymerase, buffering agents or the like. For example, in some embodiments, the reaction chambers may include lyophilized reagents, to which the processed biological sample (for example, a solution of extracted nucleic acids) is added. The prepared fluids can then be transferred to a microfluidic cartridge and inserted into the optical heater / module 500a, 500b for processing and analysis.
[0062] Figure 1A is a frontal plan view of the diagnostic mechanism 10 of certain modalities. As seen in Figure 1A, the diagnostic mechanism 10 can include a fluid, distributor 400, mounted on a side rail 20. The side rail 20 can be part of a motorized gantry 18, which can also include a front-rear rail 22 ( not shown). The front-rear rail 22 can be connected to the side rail 20 and mounted perpendicularly to the side rail 20 on the diagnostic mechanism 10.
[0063] Figure 1A also illustrates the cover 28 over the heater / optical module 500a, 500b. The receiving rails 520a and 520b can be located under or inside the heater / optical module 500a, 500b. The receiving rail 520a is illustrated in an open position, making it available to receive a microfluidic cartridge 200. The receiving rail 520b is illustrated in a closed position. Closing the rail not only puts the reagents in the proper position for processing, but it also additionally protects the interior of the heater / optical module from receiving any unwanted light. Where stray light has been introduced into the detection area, the system can identify erroneous fluorescent levels derived from light that is not emitted from the reaction chamber.
[0064] Figure IB is a perspective view of the diagnostic mechanism 10 showing certain internal components found in certain modalities. To better illustrate certain aspects, the mechanism compartment 30, the cover 16, and the heater / optical cover 28 found in Figure 1A have been removed from the view in Figure 1B. Shown in Figure 1B is gantry 18, including side rail 20, front-rear rail 22. Fluid distributor 400 can be mounted on side rail 20 and can slide laterally along the length of side rail 20. Side rail 20 can be connected to the front-rear rail 22 which can move in the front-rear direction. In this way, the fluid distributor 400 is available to move in the X, Y direction throughout the diagnostic device 10. As described below, the fluid distributor 400 may also be able to move up and down on the z plane. side rail 20, thereby giving the distributor 400 the ability to move in three directional degrees across the diagnostic device 10.
[0065] Also shown in Figure 1B are the heaters / optical modules 500a, 500b with the cover 28 of the heaters / optical modules of Figure 1A removed. The receiving rails 520a and 520b are described in the open position and are each holding the cartridges 200. In some embodiments, the receiving rails can each include a heating substrate 600 (not shown) below each of the microfluidic cartridges 200. The heaters / optical modules 500a, 500b can also each include a detector head 700 described in more detail below.
[0066] As will be described in more detail below, the diagnostic mechanism 10 may be able to conduct diagnostics in real time on one or more samples. The sample to be tested can first be placed in a specimen tube (not shown) on shelf 24a or 24b. The diagnostic reagents can be located on the cables 26 on the shelf 24a inside the diagnostic mechanism 10. The fluid dispenser 400 can mix and prepare the sample for the diagnostic test and can then release the prepared sample into the microfluidic cartridge 200 to thermal cycling and analyte detection in heaters / optical modules 500a, 500b. Alternatively, fluid dispenser 400 can release nucleic acid samples into the reaction chambers of the microfluidic cartridge, the reaction chambers of the microfluidic cartridge already containing reagents for an amplification reaction.
[0067] FIGURE 2 illustrates an interior view of the diagnostic mechanism 10, showing the shelf 24a that holds several sample tubes 32 and reagent cables 26, and a cartridge 200 located on the receiving rail 520a. The receiving rail 520a is in an open position that extends from the heater / optical module 500a which has the cover 28 attached. The receiving rail 520b is in a closed position. Advantageously, in some embodiments, the receiving rails 520a, b may allow easy placement of the microfluidic cartridge 200, by a user or by a self-loading device. Such a design can also accommodate multiplexed sample pipetting using the robotic fluid dispenser 400. Reception Tray
[0068] As illustrated in Figure 2, the recess bay 524 can be a "part" of the receiving rail 520 that is configured to selectively receive the microfluidic cartridge 200. For example, the recess bay 524 and the microfluidic cartridge 200 can have an edge 526 which is complementary in shape so that the microfluidic cartridge 200 is selectively received in, for example, a single orientation. For example, microfluidic cartridge 200 may have a registration member 202 that fits into a complementary aspect of the bay. The registration member 202 can be, for example, a cut in one edge of the cartridge 200 (as shown in Figure 3A) or one or more notches that are made on one or more of the sides. The skilled technician will easily appreciate that the complementarity between the cartridge and the receiving bay can be easily achieved using other suitable arrangements, for example, a pole or protrusion that fits into an opening. By selectively receiving cartridge 200, recess bay 524 can assist a user in placing cartridge 200 so that optical module 502 can properly operate on cartridge 200. In this way, error-free alignment of cartridges 200 can be obtained.
[0069] The receiving rail 520 can be aligned so that various components of the mechanism that can operate on the microfluidic cartridge 200 (such as heat sources, detectors, power members, and the like) are positioned to properly operate on the microfluidic cartridge 200 at the same time that the cartridge 200 is received in the recess bay 524 of the receiving rail 520. For example, the contact of the sources and heat in the heating substrate 600 may be positioned in the recess bay 524 in such a way that the sources of heat can be thermally coupled to the different locations in the microfluidic cartridge 200 that is received on the receiving rail 520. Microfluidic cartridge
[0070] Certain modalities include a microfluidic cartridge configured to perform the amplification, such as by PCR, of one or more polynucleotides from one or more samples. By cartridge is meant a unit that can be disposable or reusable in whole or in part, and that can be configured to be used in conjunction with some other mechanism that has been properly and complementarily configured to receive and operate (such as releasing energy for) in the cartridge.
[0071] By microfluidics, as used here, it is understood that the sample volumes, and / or reagent, and / or amplified polynucleotide are from about 0.1 μL to about 999 μL, such as from 1 -100 μL or 2-25 μL, as defined above. Similarly, when applied to a cartridge, the term microfluidic means that various components and channels of the cartridge, as also described here, are configured to accept, and / or retain, and / or facilitate the passage of the microfluidic volumes of the sample, reagent or polynucleotide amplified. Certain modalities here can also work with volumes of nanoliter (in the range of 10-500 nanoliters, such as 100 nanoliters).
[0072] Figure 3A is a top plan view of a microfluidic cartridge 200. The cartridge 200 can comprise a plurality of sample strips 1706a-c. The strips can lead to the 1703 PCR chambers located on the “left” and “right” sides (ie, rows) of the cartridge. As shown in Figure 3a, the strips can provide 1705 inlet holes in a convenient location close to the user. However, the strips to which the holes are connected can then take independent routes to separate chambers 1703a-c. In the modality of Figure 3a, for example, the first strip 1706a is in communication with the first chamber 1703a on the left side, the second strip 1706b is in communication with the first chamber on the right side 1703b, the third strip 1706c is in communication with second chamber 1703c on the left side etc. Each of the microfluidic strips may also comprise microfluidic valves 1702, 1704, microfluidic inlets, and microfluidic channels. These inlets and valves can be configured, for example, by thermal actuation, to facilitate the timed release and controlled diffusion of certain fluids in ranges 1706 of cartridge 200. The cartridge of this modality may comprise ventilation holes 1701 that prevent air from blocking the fluid passing through the cartridge. Another description of various cartridge components, such as valves, can be found in, for example, United States Patent Application Publication 2009-0130719, incorporated herein by reference.
[0073] The microfluidic cartridge 200 may include a registration member 202, for example, a cut, which corresponds to a complementary edge in the recess bay 524 of the receiving rail 520a, b of the heaters / optical modules 500a, 500b. The registration member 202 and the complementary edge 526 can allow the safe and correct placement of the microfluidic cartridge 200 on the receiving rail 520a, b.
[0074] In various embodiments, the components of a microfluidic network in the sample 1706 ranges of the cartridge 200 can be thermally heated by coupling them with the heaters on a heater substrate 600. The heater substrate 600 can be configured to heat a mixture of the sample comprising amplification reagents and a polynucleotide sample ready for amplification and causes it to undergo suitable thermal cycling conditions to create amplicons of the sample ready for amplification. The heating substrate 600 may be located in the cartridge 200 in some embodiments or in the recess bay 524.
[0075] The microfluidic network in each band can be configured to perform nucleic acid amplification, such as by PCR, in a sample ready for amplification, such as one containing nucleic acid extracted from a sample. A sample ready for amplification may comprise a mixture of amplification reagents and the extracted polynucleotide sample. The mixture may be suitable to undergo thermal cycling conditions to create amplicons from the extracted polynucleotide sample. For example, a sample ready for amplification, such as a sample ready for PCR, may include a mixture of PCR reagent comprising a polymerase enzyme, a positive control nucleic acid, a selective fluorgenic hybridization probe for at least part of the acid positive control nucleic and a plurality of nucleotides, and at least one probe that is selective for a target polynucleotide sequence. The microfluidic network can be configured to couple heat from an external heat source with the mixture comprising the PCR reagent and the polynucleotide sample extracted under suitable thermal cycling conditions to create PCR amplicons from the extracted polynucleotide sample.
[0076] In various embodiments, the reagent mixture may comprise fluorescent labels or other optically detectable labels for detecting the generation of a desired amplicon. In some embodiments, multiple sets of primers and multiple labels can be used in a multiplex assay format, for example, multiplexed PCR, where each of a plurality of different amplicons can be detected in a single reaction chamber, if present. For example, a test chamber could include nucleic acids model from a test sample, model nucleic acids from positive control, one or more pairs of primers for the amplification of specific target sequences, one or more probes for the detection of target amplicons, and one or more pairs of primers and a probe for detecting positive control amplicons. In addition, the skilled technician will appreciate that in some embodiments, the microfluidic cartridge accommodates a negative control polynucleotide that will not produce an amplicon with primer pairs used to amplify the positive or target control sequences.
[0077] In certain of the illustrated modalities, chambers 1703a-c respectively associated with each track 1706a-c of a multi-band cartridge 200 can perform independent amplification reactions. The results of the reactions for the first column of chambers (1703a, 1703b) for the first two bands (1706a, 1706b) can then be measured simultaneously and independently using a detector head comprising a pair of left and right light source-photodetectors . That is, each camera 1703a-b of each range 1706a-b can receive light from a separate light source and be observed by a separate photodetector simultaneously. In this way, a variety of reaction combinations can be performed on the cartridge effectively. For example, in some embodiments, a plurality of amplification assays for detecting a plurality of target nucleic acids can be performed in one band, a positive control and a negative control in two other bands; or one or more amplification assays for the detection of one or more target nucleic acids, respectively, in combination with an internal positive control in a range, with a negative control in a separate range. In a particular embodiment, 2, 3, 4, 5, 6 or more assays are multiplexed in a single range, with at least that number of fluorescently distinct fluorophores in the reaction chamber.
[0078] A microfluidic cartridge 200 can be constructed of several layers. Consequently, an aspect of the present technology relates to a micro fluidic cartridge that comprises a first, second, third, fourth and fifth layer with one or more layers defining a plurality of microfluidic networks, each network having several components configured to perform PCR in a sample in which the presence or absence of one or more polynucleotides must be determined. In another embodiment, the microfluidic cartridge 200 may comprise a plurality of strips, each including a reaction chamber, etched or molded in a single plane, such as on a molded plastic substrate, with each stripe being closed by a covering layer, such as as a layer of adhesive plastic film. Modes with 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 30 or more bands per cartridge are contemplated. For example, a suitable design is a single cartridge 200 having 24 reaction chambers, arranged in two rows of 12 reaction chambers, optionally having relatively aligned inlet holes. Another description of various cartridges and their components can be found in, for example, United States Patent Application Publication 2008-0182301 and United States Patent Application Publication 2009-0130719, incorporated herein by reference. Heater Substrate
[0079] Shown in Figure 3B is a plan view of the upper part of certain modalities of the heating substrate 600. Any type of heater can be used, including resistive, Peltier or mobile fluid heaters, with passive or active cooling contemplated. One of the many possible modalities includes a plurality of resistive heaters in thermal contact with each reaction chamber, preferably also including one or more temperature sensors. Because resistive heaters also exhibit some thermistor effect, that is, their resistance changes with temperature, resistive heaters alone can double as temperature sensors, allowing precise control of the temperature of each reaction chamber while simplifying the design of product. Although the heaters can be controlled together with each other, in some embodiments each reaction chamber may have one or more individual heaters in thermal contact between them, such that the heaters are separately controllable and each reaction chamber can be heated and allowed to cool independently of the other reaction chambers. This allows different tests to be carried out simultaneously in each of a plurality of reaction chambers. A particular resistive heater assembly for use with an individual reaction chamber is shown in Figure 3B. In the embodiment shown in Figure 3B, any combination of an upper sensor / sensor heater 1604, a base heater / sensor 1603, a side heater / sensor 1601 and a central heater / sensor 1602 can be used to heat the reaction chamber located above . For ease of understanding, a description of the PCR 1703 chamber of certain modalities is superimposed on the heating substrate. In certain embodiments, the heaters on the heater substrate 600 may be contact heaters. Such contact heaters may comprise (for example) a resistive heater (or network thereof), a radiator, a fluidic heat exchanger and a Peltier device. The contact heat source can be configured in the recess bay 524 to be thermally coupled to one or more locations other than the microfluidic cartridge 200 received on the receiving rail 520a, b through which the different locations are selectively heated. The contact heat sources can each be configured on the heating substrate 600 to be independently thermally coupled to a different distinct location on a microfluidic cartridge 200 received on the receiving rail 520a, b by which the distinct locations are independently heated. The contact heat sources can advantageously be configured to be in direct physical contact with locations other than a microfluidic cartridge 200 received on the receiving rail 520a, b. In various embodiments, each contact source heater can be configured to heat a distinct location having an average 2-dimensional diameter of about 1 millimeter (mm) to about 15 mm (typically about 1 mm to about 10 mm) or a distinct location having a surface area of between about 1 mm and about 225 mm (in some embodiments between about 1 mm and about 100 mm or in some embodiments between about 5 mm and about 50 mm).
[0080] The heater substrate 600 can be arranged in "bands" 1605a, b in parallel with the structure of the strips 1706a-c of the cartridge 200. In some embodiments, the heater substrate 600 may include 24 heater bands 1605a, 1605b corresponding to the sample strips 1706 of cartridge 200. When the microfluidic cartridge 200 is placed in the recess bay 524 of the receiving rail 520a, b, the cartridge components 200 can be aligned adjacent to, and above, the corresponding heaters on the heater substrate 600. When the microfluidic cartridge 200 is placed in the recess bay 524, the heaters may be in physical contact with the respective components. In some embodiments, the heaters remain thermally coupled to their respective components, for example, through one or more materials or intermediate layers, although not in direct physical contact. Another description of ranges can be found, for example, in United States Patent Application Publication 2009-0130719, incorporated herein by reference.
[0081] In some embodiments, the multiple heaters can be configured to simultaneously and uniformly activate to heat their respective cartridge components adjacent to the microfluidic network in the microfluidic cartridge 200. Each heater can be independently controlled by a processor and / or control circuit used in conjunction with the mechanism described here. Generally, the heating of microfluidic components (inlets, valves, chambers, etc.) in microfluidic cartridge 200, is controlled by passing currents through suitably configured microfabricated heaters. in proper circuit control, tracks 1706 of a multi-track cartridge can then be heated independently, and thereby independently controlled, from one another. In addition, as described in more detail below, individual heaters 1601-1604 can be heated independently, and thereby independently controlled, from each other. This can lead to greater control and energy efficiency of the mechanism, because not all heaters are heating at the same time, and a given heater is receiving current for only that fraction of time when heating is required.
[0082] The heating substrate 600 may also include one or more heat sensors. To reduce the required number of sensors or heaters to control heaters in a range of heaters 1605a, 1605b, heaters can be used to sense temperature as well as heat, and thereby avoid the need to have a separate dedicated sensor for each heater . For example, the impedance and / or resistance of some materials changes with the surrounding temperature. Consequently, the heater / sensor resistance 1601 -1604 can be used as an indication of temperature while the sensors are not being actively heated.
[0083] In some embodiments, the heaters on the heater substrate 600 may be designed to have sufficient voltage to allow the heaters to be grouped in series or in parallel to reduce the number of electronically controllable elements, thereby reducing the load on the associated electronic circuit . Heaters that are grouped together in this way would be operated in synchronized and substantially simultaneous control.
[0084] In some modalities, the reaction chamber heaters on opposite sides of the second stage heaters can be grouped and configured to operate in synchronized control. For example, in some embodiments, the 1601 -1602 PCR / amplification heaters can be grouped and configured to operate in synchronized control. Alternative settings and groupings can be applied to other heater groups in the 1601 -1604 PCR / amplification heaters. The PCR / amplification heaters 1601 -1604 can be configured to operate individually and independently or they can be configured to operate in groups of two (pairs), three (trios), four, five or six.
[0085] In some modalities, the heating can be controlled periodically by turning the current on and off for a respective heater with varying pulse width modulation (PWM), with the pulse width modulation referring to the on-time / time ratio off to the mains. The current can be supplied by connecting a micro heater manufactured to a high voltage source (for example, 30V), which can be blocked by the PWM signal. In some embodiments, the device may include 48 PWM signal generators. In some embodiments, there are two PWM signal generators associated with each reaction chamber. The operation of a PWM generator can include the generation of a signal with a chosen period, programmable (the final count) and granularity. For example, the signal can be 4000 us (microseconds) with a granularity of 1 us, in which case the PWM generator can maintain a counter starting at zero and advancing in 1 us increments until it reaches 4000 us, when it returns to zero . In this way, the amount of heat produced can be adjusted by adjusting the final count. A high final count corresponds to a longer duration of time during which the manufactured micro heater receives current and, therefore, a greater amount of heat is produced.
[0086] In several modalities, the operation of a PWM generator can also include a programmable initial count in addition to the aforementioned granularity and final count. In such embodiments, multiple PWM generators can produce signals that can be selectively non-overlapping (for example, by multiplexing the on time of the various heaters) such that the capacity of the high voltage current is not exceeded.
[0087] Multiple heaters can be controlled by different PWM signal generators with varying final and initial counts. The heaters can be divided into banks, whereby a bank defines a group of heaters of the same initial count. The control of heating elements, and cooling elements, if present, in certain modalities is described in further details below. Optical Module
[0088] Figures 4A-C illustrate the heater / optical module 500 of the detection mechanism 10 found in certain embodiments. The heater / optical module 500 may comprise an optical module 502 and a receiving rail 520 or a part of the receiving rail. Figure 4A shows a modality of the closed optical module 502 having a motor 504 externally attached to it to direct the movement of the detector head 700. The detector head 700 can be housed within the optical module 502. Figure 4A illustrates the receiving rail 520 coupled to a base side 506 of the optical module 502. The receiving rail 520 can receive a cartridge 200 comprising samples under which the detection must be carried out. After receiving the samples, the receiving rail 520 can be moved (for example, mechanically or manually) on the rails 522 to a position under the optical module 502. In some embodiments, described in more detail below, the receiving rail may comprise a self-loading device, which automatically aligns the cartridge once positioned under the optical module 502. In some embodiments, a recess bay 524 of the receiving rail 520 may contain a heating substrate 600. In some embodiments, the receiving rail it can subsequently be raised to bring the cartridge into contact with the optical module 502, such as in contact with a perforated plate 540 at the base of the optical module 502.
[0089] Figure 4B illustrates an embodiment of the optical module 502 with a front panel 508 removed to show the interior of the optical module 502. Shown in Figure 4B is the detector head 700. As described in detail below, the movement of the head of the detector detector 700 can be directed by the motor 504 to move laterally through the interior of the optical module 502 to provide detection and optical scanning on the cartridge 200 when the cartridge 200 is positioned below the optical module 502 on the receiving rail 520. Shown in Figure 4B is a perforated plate 540, positioned on the base side 506 of the optical module 502.
[0090] Figure 4C provides a plan view of the base of the optical module 502. Shown in Figure 4C is the perforated plate 540 and a normalizing plate 546 attached to the base of the 506 of the optical module 502. The standardizing plate can be used to calibrate the light source - pair of photodetectors of the detector head. The normalizing plate 546 preferably comprises one or more components having standard, known optical characteristics, and is configured to calibrate, standardize or confirm the proper operation of the detector head 700 and associated circuit. The normalizing plate 546 can extend on the optical module and the detector head 700 can be positioned on the normalizing plate. In some embodiments, before the start of optical measurements the detector head cartridge 700 is calibrated using the known properties of the normalizing plate 546. If the detector head 700 is not working properly, corrective action can be taken, such as including compensation measurements or notify the user of the error. In some embodiments, the normalizing plate may be made of optically transparent material such as polycarbonate mixed with a highly fluorescent paint or other standard chromophore or fluorophore. In one embodiment, the normalizing plate includes a chromophore or fluorophore standardized for each channel or color in the detector head 700.
[0091] As shown in Figure 4C, the perforated plate 540 contains the openings 557. The dimensions of the openings 557 are such that the light sources of the detector and photodetectors can have access to (optically excite or visualize) levels in the reaction chambers of the cartridge 200 when the detector is moved to a plurality of positions in the optical module 502. That is, when a pair of light source-detector photodetectors of the detector is located in a position on a particular aperture light it can travel from the light source and reach the reactor in the chamber through aperture 557. The fluorescent reagents in the reaction chamber can then be visible to the photodetectors through aperture 557. Detector Head
[0092] Figure 5 shows a profile of the detector head 700 taken along line 13 of Figure 4B. The detector head 700 can be configured to optically excite and / or monitor the fluorescence emitted in conjunction with the detection of one or more polynucleotides present in reaction chambers 1703. Note that a positive result (presence of a target amplicon) can be indicated by increased fluorescence or decreased fluorescence, depending on the design of the assay. For example, when the assay involves a fluorophore and an extinguisher, the extinguisher can extinguish fluorescence when the target is present or in other assay designs, when the target is absent. The system can comprise, for example, a plurality of pairs of detectors, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11. 12, 13, 14, 15, 16, 17, 18, 19, 20, 21. 22, 23, 24 or more, such as pair of detectors 726. Each pair of detectors 726 can be comprised of a light source 726a, such as a light emitting diode (LED), and a corresponding light detector 726b, such as a photodiode. The light source 726a can selectively emit light in an absorption band of a fluorescent probe. The light detector 726b can selectively detect light in an emission band of the fluorescent probe, the fluorescent probe being a polynucleotide probe or a fragment thereof. In certain embodiments, the light source 726a may comprise a bandwidth-filtered diode that selectively emits light in the absorption band of the fluorescent probe. The light detector 726b may comprise a band-pass filtered photodiode that selectively detects light in the emission band of a fluorescent fraction, for example, emission of a fluorescent probe. In certain embodiments, a filter 726al, such as a bandpass filter, can be applied to the light from the light source 726a. The light from the light source 726a passes through a filter before passing through the sample in the microfluidic channel (300g depth in certain modalities). In certain embodiments, the length of the optical pathway for the light from the reaction chamber to the light detector 726b may be very small. The incident light from the 726a light source generates fluorescence in the reaction chamber. The light from the reaction chamber then travels to the light detector 726b. Certain modalities seek to mitigate the entry of any unwanted light into the detector and thereby adversely affect the light signal from the reaction chamber.
[0093] In some embodiments, each of the plurality of pairs of detectors may be arranged along the length of the detector head 700 in the rows. That is, behind pairs 726 and 727 illustrated in Figure 5 there may be another column of pairs in a similar or equal orientation. For the sake of explanation, a collection of cartridges or pairs of detectors along the length of the cartridge is referred to as a "row" and those along the width as a "column". Thus, the vertical direction in Figures 3A and 6 indicates a “column” and the horizontal direction a “row”. Certain modalities include six or more columns such pairs of detectors. In these modalities, there are 12 pairs of detectors in total (two rows of six) with two pairs of detectors per column, allowing 12 separate and simultaneous detections.
[0094] Each light source, such as, for example, light source 726a, can be configured to produce light of a specific wavelength for a specific fluorescent fraction associated with, for example, a probe, contained in the reaction chambers . Each light detector, such as, for example, 726b, can be configured to detect the light emitted from the fluorescent probes associated with the light produced by the light emitter in the pair of detectors. The detector pairs can be configured to independently detect a plurality of fluorescent fractions, for example, different fluorescent probes, having different fluorescent emission spectra, and in each reaction chamber, the emission of each fluorescent probe is indicative of the presence or absence of a particular target polynucleotide or fragment thereof. Although folded light paths can be used, one modality uses a pair of detector and emitter where each is in direct optical contact with the reaction chamber, preferably simultaneously in such contact. Optionally, the detector and emitter of a pair are aligned with the reaction chamber along lines that substantially intersect at an acute angle in the reaction chamber. The angle can be, for example, between about 5 and 70 degrees, preferably between about 8 and 60 degrees, more preferably between about 10 and 50 degrees.
[0095] In some embodiments, the detector head includes two rows of pairs of photodetectors and light source that correspond to two rows of reaction chambers of microfluidic cartridges, when present in the mechanism. For example, the detector head may include a first or shallow row of six photodetectors and light source pairs, and a second or base row of photodetectors and light source pairs, which are configured to refer to the first and second rows of reaction chambers in a microfluidic cartridge, respectively.
[0096] Figure 6 illustrates a possible photodetector and light source layout implemented in certain detector modalities. The first column comprises ROX light emitters 201a, 201b and corresponding detectors 207a, 207b. The second column comprises HRM light emitters 201c, 201d and corresponding detectors 207c, 207d. The third column comprises CY5 light emitters 201e, 201f and corresponding detectors 207e, 207f. The fourth column comprises light emitters FAM 201g, 201h and corresponding detectors 207g, 207h. The fifth column comprises the light emitters Q705 201i, 201j and corresponding detectors 207i, 207j. The sixth column comprises VIC 201k, 2011 light emitters and corresponding detectors 207k, 207l. In some cases, detectors and emitters are selected with reference to the particular fluorophores to be used in an assay. In the embodiment illustrated in Figure 6, the pairs of detector and light source of the first or surface row comprise a plurality of pairs of photodetectors and light source, for example, emitters 201a, 201c, 201e, 201g, 201i, and 201k and detectors 207a, 207c, 207e, 207g, 207i and 207k. The detector pairs and light source of the second or base row comprise a plurality of pairs of photodetectors and light source, for example, emitters 201b, 201d, 201f, 201h, 201j, and 201l and detectors 207b, 207d, 207f, 207h, 207j and 207l. A summary of the properties of exemplary emitters and detectors is shown in Table 1 below. TABLE 1


[0097] The exemplary arrangement of photodetectors and light sources described in Figure 6 can inhibit the interference between the detection columns. That is, the wavelength range for each pair of transmitters and detectors can be selected to have minimal overlap with their neighboring pair of transmitter-detectors. Thus, for example, where the No. of CT refers to the column of a particular pair of emitter-detectors in a 6-column detector head, Ex is the excitation wavelength of a fluorophore and Em is the length of emission wave adjacent to the emission, it will be evident that wavelengths are not adjacent to each other in the detector head. That the row's HRM dye is nil merely indicates that a variety of dyes, not required for this particular example, can be used. In some modalities, HRM refers to a “High Resolution Fusion” and a corresponding light source for these photodetectors can comprise an LED operating in the ultraviolet spectrum. Someone will recognize that the columns can be arranged in alternative variations and that the alternative selections of light emitting sources and detectors can be replaced by those shown.
[0098] The pairs of light emitting and photodetectors of each column can be calibrated using the normalizing plate. After calibration, the detector head can be moved to a position such that a first column of pairs of light emitters and photodetectors is located on a first group of bands such that each pair of light emitters and photodetectors has access to a camera of the bands' reaction. The detection of the reaction chambers in the first group of bands will then be carried out using the first column of emitters / detectors. Then, the detector head can be moved to a second position such that the first column is over a second group of strips and the second column is over the first group of strips. The detection of the reaction chambers in the second group of bands will then be carried out using the first column of emitters / detectors and the detection of the reaction chambers in the first group of bands will then be carried out using the second column of emitters / detectors. The process can continue until each column has passed over each track. Thus, for detector N columns and camera M columns, the detector will detect at least M + N - 1 positions. For example, in the modalities of Figure 11 there are 6 columns. For a cartridge comprising 12 ranges, the detector would need to move between at least 17 positions (18 if the calibration position is considered).
[0099] Figure 7 describes the final results after the operation of certain modalities. Plots are the fluorescent levels detected for each pair of light emitter-photodetectors 801-805 over time for a single reaction chamber (or reactor) associated with a single band. After a sufficient number of iterations (about 30, in this example) of the annealing and denaturation protocol, the detectors identify the increasing levels of fluorescence in the reactor. Camera Plate
[00100] Certain of the present modalities refer to the surrounding coating and including the chamber layer. In particular, certain embodiments contemplate the manufacture of an opening layer comprising features that advantageously facilitate consistent results through experiments of the heating / detection module, as described in further details below.
[00101] Figure 8 illustrates the arrangement of the coating found in certain modalities of scanning the optical module of the thermal cycler and the associated receiving rail and cartridge. When the cartridge is carried close to the opening layer 540 of the optical module 500a, the thermal layer 600, chamber layer 200 (which may comprise a chamber substrate), and opening layer 540 can be located as described in the embodiment of the Figure 8. As described above, the chamber layer 200 may comprise a plurality of reaction chambers 1703a-d, which may be located to be thermally controlled separately from one another or in groups. The thermal layer 600 can comprise a plurality of thermal units 1605a, 1605b, 1605c. Figure 8 is a simplified diagram, abstract from the description above, and certain aspects of the microfluidic reaction series are not shown. In certain embodiments, the thermal units can be both mechanically and thermally disconnected from each other (as illustrated by their physical separation in Figure 4). However, in other modalities, the thermal units can each be placed with the same substrate material, however, spaced such that they remain thermally disconnected, as described above. In this way, it is possible for the thermal units to be thermally separated, but not mechanically separated.
[00102] In this way, each thermal unit can be associated with one or more reaction chambers 1703a-d, separately from the rest of the reaction chambers. According to the protocol specified for each reaction chamber, the thermal units can successively cool and / or heat their corresponding camera appropriately. For example, thermal unit 1605c can cool and / or heat chamber 1703a such that the temperature of chamber 1703a is substantially independent of the cooling and thermal state of chamber 1703a. While heating can be carried out by running the current through an electronic or microfluidic circuit, cooling can be “passive” in that only the convection between the microfluidic chamber is used to reduce the temperature of the chamber . Thermal units 1605a, 1605b, 1605c can be controlled using a closed loop control system.
[00103] In some embodiments, the perforated plate 540 can be located on the layer of the chamber 200 and can provide pressure to the layer of the chamber 200 to facilitate the heating and cooling of the microfluidic cartridge, for example, the layer of the chamber, by thermal layer 600. The perforated plate may include a plurality of openings 557a-d to facilitate each observation of the photodetectors 726b from an individual reaction chamber 1703a-d. In the absence of perforated plate 540, and depending on the configuration of the thermal layer 600 and the chamber layer 200, the chamber layer 200 may "deform" and / or be flexible enough that the thermal communication between the chambers and the respective thermal units is inconsistent . Inconsistent heating and cooling can lead to less precise execution of protocols and less precise and accurate results. As described above, significant deformation can restrict the optical head from lateral movement. Thus, the thickness of the perforated plate must be appropriately selected to facilitate an appropriate light path between each reaction chamber and the light sources and photodetectors while still ensuring proper heating and cooling of the chamber layer. If the opening layer is too thick, the distance from the photodetectors 726b to the chamber may be very large, undesirably attenuating the fluorescence reading from the reaction chamber. In addition to increasing the distance to the reaction chamber, an opening layer 540 that is too thick or too heavy will put a lot more pressure on the reaction chamber, making the convection very large. Conversely, if the opening layer 540 is too thin it cannot prevent the chamber layer 200 from bending and deforming, and the opening layer 540 may bend and deform. Deformation of openings 557a-d or chambers 1703a-d can deflect light from light source 726a and prevent accurate readings by photodetectors 726b.
[00104] Consequently, the modalities described here provide opening layers that advantageously avoid the drawbacks described above. In certain embodiments, the opening layer 540 is made, at least in part, of steel. In these modalities, steel provides the appropriate strength, density and strength for the desired deflection for operation. In addition, steel can provide low auto-fluorescence and is therefore less likely to adversely affect the reading of the 726b photodetectors. Steel can also be treated electrochemically to decrease its auto-fluorescence and thus be less likely to adversely affect the reading of the photodetectors. In certain embodiments, the opening layer may instead comprise black nickel (Ni), that is, Ni with a dye added to it to reduce auto-fluorescence. Certain modalities include combinations of these electrochemical treatments and different materials. In certain embodiments, the opening layer 540 is made of aluminum and when attached by the adjacent support panels 500, 506, and 546, provides the appropriate strength. Aluminum can be electrochemically coated with an anodic oxide finish, for example, with a black dye added to reduce auto-fluorescence.
[00105] The lighting optics can be designed so that the excitation light that falls on the reaction chamber or reactor, is incident over an area that is similar to the shape of the reactor. When the reactor can be long and narrow, the aluminum spot can also be long and narrow, that is, prolonged, too. In this way, the shape of the openings 557a-d can be designated taking into account both the dimensions of the reaction chamber below, as well as the relative positions of the corresponding light emitter and photodetectors. The stitch length can be adjusted by changing several factors, including: the diameter of the hole where the 726b photodetectors are placed (the tube that holds the filter and the lenses can have an opening effect); the distance of the photodetectors 726b from the PCR reactor; and the use of appropriate lenses in 726b photodetectors. Force Member
[00106] In certain embodiments, the receiving rail 520 places the layer of the chamber 200 in proximity to the thermal layer 600 or opening layer 540, however, it does not mechanically couple and / or thus puts the layers in contact with one another . In this way, the layer of the chamber 200 can be thermally, however, not mechanically, coupled to the thermal layer 600. In other embodiments, the receiving rail places the thermal layer 600 in both mechanical and thermal contact with the layer of the chamber 200 and the chamber layer in mechanical contact with opening layer 540. In various embodiments, the mechanism may include one or more force members (not shown) that are configured to apply pressure to the receiving rail 520 to thermally couple the heat sources to the microfluidic cartridge 200 positioned on the receiving rail 520. The application of pressure can be important to ensure consistent thermal contact between the heating substrate and the reaction chambers, inlets, and valves, etc., on the microfluidic cartridge 200. When the receiving rail 520 is in a closed position, thus being positioned under the perforated plate 540 of the optical module 502, the member of the force, such as a motor mount, below the t receiving rail 520 can begin to travel upward towards optical module 502, thereby bringing receiving rail 520 closer to optical module 502. When receiving rail 520 travels upward towards optical module 502, cartridge 200 can begin to come in contact with a base surface of the perforated plate 540. Cartridge 200 can continue to travel upward until sufficient pressure is received in cartridge 200. As described above, perforated plate 540 can apply equal pressure across all the upper part of the cartridge 200 and thereby press the cartridge 200 against the heating substrate 600 with uniform pressure. As described, the opening layer can be selected because it has properties that facilitate this operation. For example, the material selection of the perforated plate 540 can provide very little deflection of the cartridge 200 when pressed against it.
[00107] The application of uniform pressure of the cartridge 200 against the heating substrate 600 can allow uniform heating for each of the components of the cartridge when desirable. Although uniform pressure and contact can be obtained between the heaters on the heater substrate 600 and the components (valves, inlets, chambers, etc.) of the microfluidic networks in the cartridge 200, the heaters are not necessarily activated simultaneously, as described above. In certain embodiments, the application of uniform pressure does not necessarily result in equal heating of different components of the cartridge 200. In some embodiments, both the activation of a specific heater on the heating substrate 600 together with the pressure applied by the perforated plate 540 to the cartridge 200 activate a particular cartridge component 200.
[00108] Figures 9A-H are diagrams of the dimensions of a possible modality of the perforated plate. In this embodiment, a chemical conversion coating can be applied to adjust the reflective properties of the opening layer. Some 9002 parts can be selected to not receive the chemical conversion coating. The coating can be applied to the surface of the 540 plate or deposited in all its material. In some embodiments, the material of plate 540 may comprise steel. In other embodiments, plate 540 may comprise aluminum. In still other embodiments, the material of the plate 540 may comprise nickel. In some embodiments, the material of the plate may be a combination of two or more materials, including, for example, aluminum, nickel or steel.
[00109] In the modality shown in Figures 9A-H the dimensions of the plate were selected to meet the restrictions related to the pressure of the chamber and the optical path for the pairs of detectors described above. The material thickness of the 540 plate starts at 0.79 centimeter (0.3125 inch) and is machined to the desired thickness. As indicated, most of the plate is approximately 0.64 cm (0.25 inch) thick. However this thickness can vary, for example, the thickness over the openings of the opening 557 can be 0.48 cm (0.19 inch). As described above, the thickness of the aperture openings facilitates a free optical path between the photodetectors and the light source for the contents of the reaction chamber.
[00110] In general the dimensions of the perforated plate 540 are selected such that in combination with the properties of the materials constituting the perforated plate 540, the plate 540 provides sufficient pressure to the underlying chamber plate to facilitate proper heating and cooling as well as rigidity enough to prevent twisting or deformation of the chamber plate. Such deformation can result in obstructions to the optical path of the light source and photodetectors to the reaction chamber. At the same time, the dimensions of the plate must not impose an unfavorable distance from the reaction chamber of the chamber layer to the pair of light source and photodetectors through the openings 557. Nor should the dimensions 540 of the perforated plate obstruct the optical path of the source pair. of light and photodetectors for the contents of the chamber reactor.
[00111] In some embodiments, the normalizing plate 546 can be attached to the perforated plate by inserting screws in positions 9001 or other means of fixation through an opening. In other embodiments, these positions can facilitate wider calibration techniques through the openings on the standard plates than with respect to the rest of the openings.
[00112] Figure 10 illustrates various dimensions of the perspectives of the perforated plate of Figures 9A-H. As described above, in this embodiment, a chemical conversion coating can first be applied to prevent base materials, for example, aluminum, nickel or steel, from oxidation while also providing improved electrical grounding for proper electronics operation. Only the surfaces that can be exposed to optical operation are then selectively coated with black anodizing. Consistency of Diagnostic Analysis
[00113] Certain of the present modalities contemplate the methods to guarantee consistent diagnostic analyzes through experiments in the same heater / detector and through different heaters / detectors. In particular, the modalities of a system and process for determining the duration and tradeoffs for a plurality of PCR protocols for synchronizing detection between them are described. In addition, methods for adjusting the reactor's cooling time to ensure more consistent results are described.
[00114] Figure 11 is a temperature profile for a reaction chamber undergoing a particular protocol 2000. As illustrated above, the system in operation can comprise very different protocols of many different durations operating simultaneously in different reaction chambers. The 2000 protocol involves a plurality of identical heating / cooling cycles, where each cycle comprises 2000B denaturation stage and 2000D annealing stage where the temperature is kept constant over a period of time. These cycles can be preceded by a non-periodic cycle of the protocol, such as an incubation period. In certain embodiments, the protocol can be specified as a collection of temperatures and time periods. That is, the protocol can initially specify only that the chamber must be maintained at 95 ° C for a duration B and then maintained at 61 ° C for duration D. Certain modalities contemplate the grouping of these segments in “stages” and “sub- steps ”to facilitate automatic and user control. For example, the 2000B and D heating and cooling cycle can be referred to as a "stage" with duration B at 95 ° C and duration D at 61 ° C referred to as "sub-steps". In certain modalities, a user can specify the durations of the sub-steps. In other modalities, these durations can be retrieved from a database. Typically, these times are established either by a standard protocol or by user input, sometimes using an established “recipe” of temperature and time thresholds. In addition to these sub-steps, the temperature profile of the protocol will also comprise transitions, such as transition 2000A from 61 ° C to 95 ° C and transition 2000C from 95 ° C to 61 ° C. The duration of these transitions can be a consequence of the materials and environment on the reaction chamber and the nature of the heating elements employed.
[00115] In certain modalities the thermal trajectory for both heating and cooling can be determined for the entire reaction before the start of the run. In some systems, the temperature versus time contour is monitored and adjusted throughout the reaction to minimize transition temperatures, and to account for variations in efficiencies of different heating elements. In other words, some systems use return control loops to drive to a target temperature, the current contour of the temperature / time ratio varying from cycle to cycle. Such adjustments can result in different total reaction times, and, most importantly, different total reaction efficiencies. Consequently, in some embodiments, the systems and methods described here advantageously provide systems where the contour of the temperature versus complete reaction time for each independent reaction chamber (or group of chambers) is predetermined before the start of the run. This not only advantageously allows the synchronization of multiple detection steps through a plurality of different reactors, but it also allows for more rigorous control over parameters that minimize differences in reaction efficiencies that may arise as a result of different temperature contours / time. In some embodiments, the systems and methods provided here provide error reporting at the end of a reaction if the temperature measured differs from the expected value when a run is completed.
[00116] At several points in the temperature profile of the 2000 protocol, the user or container can specify that a detection occurs. For example, for some protocols a detection can be requested at the end of the 2000D segment. Where detections were arbitrarily specified in each protocol, the detector head would need to travel between positions inefficiently and might even find it impossible to perform the detections at the required times. That is, each of a plurality of protocols to be started simultaneously and executed in parallel simultaneously through each of the reaction chambers in the cartridge, it would be very inefficient for the detector to meet each of the protocol's detection requests. Particularly, once the calibration has been completed, the detector would first need to travel to suitable positions to perform detections for each pair of light sources - detectors in their first disposition for the first profile. By the time the detector is finished, however, each of the remaining protocols would be entering a period when detection should not be performed. Therefore, there is a “dead time” period when the detector cannot perform any detection and should instead simply remain idle waiting for the opportunity to perform the next detection. This “dead time” is inefficient and unnecessarily prolongs the diagnostic process. In addition, where successive detections must be made, “dead time” can generate irregular and aperiodic detections from the same chamber, possibly introducing inconsistent readings.
[00117] Certain of the present modalities include automatic adjustments for parts of the 2000 profile to facilitate efficient detection through multiple protocols. This can be accomplished by allowing the user to edit or the system can automatically edit the segment length 2000B or 2000D.
[00118] It should be understood as long as at least a minimum threshold time occurs, some minor extension of threshold times can be accommodated in most amplification protocols. This flexibility is used for all efficient accommodation of different tests being carried out simultaneously, while performing real-time monitoring of amplification by reading the various tests using a scan of the detector head.
[00119] If the detection should be carried out during the 2000B segment, for example, the system or the user can extend the duration of the 2000B segment when necessary to accommodate the movement of the detector head and coordinate the reading of a plurality of tests being performed simultaneously. The duration of the 2000A and 2000C segments can be calculated using a predetermined standard cooling rate from the preceding temperatures and incorporated into the analysis. Some modalities do not allow the user to edit these segments and they are instead held responsible for the system internally.
[00120] In certain modalities, the protocol adjustments determined by the system can comprise at least three separate forms. The first adjustment can comprise an “intra-cycle adjustment”, where the level such as 2000B and 2000D of the protocol is extended such that the cycle of the total step 2000A-D reaches a desired duration, in some cases a multiple of an integer of one detection cycle time. This adjustment is described with respect to Figure 13. Once the inter-cycle adjustment is complete, the system can then perform an “inter-cycle adjustment”. An inter-cycle adjustment can ensure that the detection events in each cycle occur in integer multiples of a desired duration apart from each other (such as an integer multiple of the detection cycle time) between cycles. These adjustments are described with respect to Figure 14. The third adjustment can comprise an “initial compensation adjustment” that can depend only on the range used for the execution of the protocol. These adjustments are described with respect to Figures 15A-C. Protocol Tuning Overview
[00121] Figure 12 describes a flow chart of a 4000 process used in certain of the described modalities to determine an appropriate solution during the detection times of the detector and protocol profiles. The 4000 process can be run on software, hardware or a combination of the two firmware. For example, the process can be performed on any of an FPGA, a microcontroller or software running on a computer processor. The parts of the process can be performed by a general purpose processor, such as a microcontroller, while other parts can be performed by dedicated hardware, software or firmware systems. The process begins 4001 by determining a detection cycle time (or using a predetermined detection cycle time, for example, already in memory) for the 4002 system. The detection cycle time can comprise the time that is required for the detector moves to each of the detection positions (detection with each of the pairs of emitters / detectors in a detection head in each of the six columns in Figure 6), make all necessary detections, and return to a starting position. Optionally, the user or system may be allowed to make adjustments to the detection procedure to modify the detection cycle time. For example, the user may wish to only perform the detection using a subset of the detectors. In some embodiments the detection cycle time is approximately 10 seconds, when the modality comprises six columns of pairs of detectors and all six columns are used.
[00122] In some embodiments, the process may first determine a plurality of “intra-cycle adjustments” for one or more of the 4003 protocols. As described below with respect to Figure 13, the durations for a step or sub-step may comprise the time to perform a particular sub-step or step in the protocol. Cycle times can be determined by a combination of user specifications and restrictions identified in the system. In certain embodiments, the system will require the plurality of cycle times to be integer multiples of the detection cycle time. “Intra-cycle adjustments” can be introduced to satisfy this restriction. For example, if the detection cycle times were 12.2 seconds, the cycle times for a protocol step can be 22.4, 33.6, 44.8 or any other duration N * 12.2, where N it is an integer greater than 0. In some modalities, it is only necessary to impose this restriction when a detection must be carried out in the cycle.
[00123] In this way, the intra-cycle adjustments ensure that the protocol cycle is an integer multiple of the detection cycle time. However, a detection can be requested at any point in a cycle. If the detection cycle time is 10 seconds, then the fastest detection can be performed is 10 seconds after the protocol starts. Detections can then be carried out in multiples of an integer after such time (20, 30, 40 seconds etc.).
[00124] In this way, another setting, an “inter-cycle” setting 4004, can then be determined to ensure that the requested detection occurs at the appropriate time. These “inter-cycle adjustments” can be incorporated into the protocol as additional delays between the protocol steps and sub-steps. Put differently, a PCR protocol once subjected to “intra-cycle” adjustments can comprise “valid” cycle steps. The PCR protocol can then be generated by chaining each step together and adding transitions from step to step. The “inter-cycle adjustment” 4004 ensures that the detection times occur at the desired integer multiples of the detection cycle time after the cycles have been chained together.
[00125] For example, for a system having a detection cycle time of 10 seconds a protocol can comprise a step having its first detection in 18 seconds in a cycle. The duration of the cycle (the duration of the total step) can last 30 seconds (perhaps after an “intra-cycle” adjustment). Thus, while the cycle time as a whole is properly aligned with the detection cycle time of 10 seconds (3 x 10 = 30 seconds) the first detection is alone not properly aligned with the detection (18 seconds is not a multiple of 10 seconds). The system will add 2 seconds of the “inter-cycle” setting to the first detection run so that the first detection occurs 20 seconds after the start of the protocol. This can be done by extending the final storage temperature of the previous stage for an additional 2 seconds through an “absorption adjustment”. If there is no previous step, the system would introduce a 2-second storage at room temperature at the beginning of the first run of the cycle. Thus, if the system starts operating at T0, the first detection will occur at T0 + 20 seconds, the second detection at T0 + 50 seconds, and so on.
[00126] Because of the inter and intra-cycle adjustments, the protocol is now in such a way that detections are only requested at times convenient for the detector head to move into the reaction chamber performing the protocol. All protocols were performed in reaction chambers located in the first column of the cartridge (and a sufficient number of detectors present in the detector head) intra and inter-cycle adjustments alone would be sufficient to appropriately modify the protocol for efficient detection (a first column here referring to a column of bands such as bands 1706a and 1706b with associated chambers 1703a and 1703b in Figure 3A). However, because the protocols operate on different columns of the cartridge, it is also necessary to compensate that the beginning of the protocol compensates for the delay of the detector head in reaching the chamber location.
[00127] In this way, the "initial adjustment compensations" are added to the protocol based on the location of the chamber in which the protocol is performed. These "initial adjustment offsets" 4005 are described in greater detail with respect to Figures 15A-C. In some embodiments, these adjustments are made at run time and depend solely on the location of the run range. For example, no adjustment may be necessary for the execution of a protocol in the bands located in a first column of the chamber, so that an execution of the protocol in these cameras of the band will have a delayed initial time of +0 seconds. Each subsequent column of tracks gains a delay of 400 milliseconds for its distance from the first column, due to the time required for detections (two detections in 100 milliseconds each, performed asynchronously in this mode) and the movement of the detector motor (200 milliseconds ). In this example, with a detection cycle time of 10 seconds, the first possible detection for each column of tracks is as follows: column 1 has its first detection in 10 seconds, column 2 has its first detection in 10.4 seconds, column 3 has its first detection in 10.8 seconds, etc. By delaying the start of a protocol properly aligned with the time required for a particular range, the expected alignment can be maintained. At the same time that this particular example assumes that the protocol is already aligned (of adjustments 4003 and 4004), the skilled technician will easily appreciate that other modalities can determine the compensations anticipating future adjustments.
[00128] Although described in the order of steps 4003, 4005, and 4004, someone will easily recognize that these steps can be arranged in any other appropriate order and neither the need for the system to perform each step successively. In some modalities, however, such as those described above, it may be necessary to perform the inter-cycle adjustment after making the intra-cycle adjustments, since the inter-cycle adjustment depends on the change of the intra-cycle. In contrast, the initial compensation adjustment 4005 may not depend on any prior determination. That is, in some modalities the initial compensation 4005 needs to be determined only once at the time of execution, whereas intra-cycle adjustments 4003 and inter-cycle adjustments 4004 can be performed for each cycle step in the protocols.
[00129] In some modalities, once the protocol times have been properly adjusted, the process can then start protocols 4006. In some modalities a processor can simply place the compensations in a memory location for retrieval by a separate dedicated component of the system that alone initiates each protocol. Intra-Cycle Adjustment
[00130] The "intra-cycle adjustments" comprise adjustments for the step or sub-step intervals, as may have been specified by a user or received from a database, so that the step as a whole is a multiple of integer of a predetermined duration. With reference to Figure 13 in certain modalities the user can specify certain aspects of the protocol profile, such as the desired times for a protocol sub-step, using a user interface or graphical user interface (GUI). In some modalities, the system can then validate the user's selection. After calculating the segment lengths for each of the sub-steps, the system software will validate the cycle time of the step and indicate whether any adjustments are necessary. In some embodiments, a “valid” step cycle time is a step cycle time that is an integer multiple of the detection cycle time. If a cycle time of the step is not valid, the user may be prone to make the adjustments for that step 5003b. If no adjustment is necessary, the user can be notified that the step is properly aligned 5003a.
[00131] In the example of Figure 13, the user requested an incubation step 5001 comprising a single sub-step of 900 seconds. The user has requested that step 5001 occur only once 5010 and therefore understand a single step cycle. In this example, the detection cycle comprises 10 seconds. The user did not specify that any detection should be performed and therefore the step is valid, since the step will not require the position of the detector head to be adjusted. When no detection is requested, the system records the requested time intervals for future compensation considerations, however it cannot impose any restrictions that the time interval is a multiple of the detection time (although the duration can be considered in determining an adjustment. subsequent inter-cycle). If, however, in this example the user requested detection during this step, the step would still be valid if no further delays were incurred, since 900 seconds is a multiple of the 10 seconds of the detection cycle. In any event, in the illustrated mode, the system determined that this step entry is valid.
[00132] In the example illustrated in Figure 13, the PCR 5002 step comprises two sub-steps, a first sub-step where the chamber must be kept at 95 ° C and the other sub-step where the chamber must be kept at 61 ° Ç. The user requested that 45 cycles of this step be performed 5011. The user requested that the first sub-step last 2 seconds and that the second sub-step last 10.2 seconds for a total of 12.2 seconds. As described above with respect to Figure 7, the system also calculated the transition time from 95 ° C to 61 ° C and added this duration to the user's requests. In this example, heating from 61 ° C to 95 ° C requires 4.25 seconds and cooling from 95 ° C to 61 ° C in 7.05 seconds. These values can be stored internally in the system's memory or determined dynamically based on user input. Finally, in some modalities, when a detection is requested for a sub-step 5004, as the user requested here, the system adds an additional delay to the retention time for this sub-step. In this example, this delay is 2.2 seconds, which represents the minimum time required to allow the detector to move and detect with each of the six columns of light emitting pairs - photodetectors on the detector head. That is, in this example, each color detection requires 200 milliseconds of exposure time and 200 milliseconds to move the motor between the columns (5 transitions * 200ms + 6 detections * 200ms = 2.2 seconds).
[00133] Thus, the total duration for the stage as a whole is: 4.25 (heat) + 2.0 (denatured) + 7.05 (cooling) + 10.2 (annealing) + 2.2 (detection ) = 25.7 seconds.
[00134] As 25.7 seconds is not a multiple of the 10 seconds of the detection time, adjustment will be necessary. As indicated 5003b, the system informs the user that he can either remove 5.7 seconds from the step duration or add an additional 4.3 seconds to obtain a multiple of the detection cycle time (that is, a multiple of 10 seconds ). These “intra-cycle step adjustments” will be incorporated into the protocol after user selection.
[00135] Someone will recognize that the system can consider a plurality of other factors not indicated in this example when providing the user with an adjustment range. For example, additional delays for engine movement or incubation preparation can be taken into account when analyzing the system. Intercycle Adjustment
[00136] As mentioned above, "inter-cycle adjustments" comprise the adjustments for the first cycle of a sub-step to create a delay between the steps of the cycle. The “inter-cycle adjustments” may depend on the time of the previous steps and the final temperature of the immediately preceding step (if any exists). With reference to Figure 14 the “inter-cycle adjustment” 6005 determined to obtain an appropriate detection time occurrence, will be described.
[00137] In some modalities the 6005 setting is determined first by determining the time required to heat or cool the temperature from the end of the previous step to the first temperature of the sub-step of the next step. If any additional time is required for alignment, the temperature at the end of the previous step can be maintained during this time. An example of alignment between the final temperature of a conservation step at 75 ° C to the first temperature of the 95 ° C sub-step is shown in Figure 14. The temperature is raised to 8 ° C / s from 75 ° C to 95 ° C from points 6001b to 6001c, with the remaining time required with the remaining time required for the spent alignment maintained at 75 ° C after the end of the previous step, from points 6001a to 6001b. This period can be referred to as an “inter-cycle adjustment”. To obtain continuation of the detection alignment between the stages, it may be necessary to change (or delay) the beginning of a stage cycle after the end of the previous stage by this “inter-cycle adjustment”. The time required to heat or cool the temperature from the end of the previous step to the first temperature of the sub-step of the next step can then be calculated. If any additional time is required for alignment, the temperature at the end of the previous step is maintained for the duration of the “inter-cycle adjustment”. In some modalities, the system can take these considerations into account when receiving user input through GUI 5000 and incorporate them in the proposed variation 5003b. Initial compensation adjustments
[00138] Figure 15A illustrates the beginning of the cycles of two separate protocol profiles 3001 and 3005. In each of these protocols the inter and intra-cycle adjustments may have been made, however, the initial compensation has already been applied. In this example, profile 3001 includes a step with a cycle time of 30 seconds (time interval 0 to time 30). A detection time of 3020a or a detection request occurs in 30 seconds. Note that in terms of the inter-cycle adjustments described above, a small delay may have been included in protocol 3001 just before the first heat ramp for the alignment of the first detection 3020a. As described above, inter-cycle and intra-cycle adjustments facilitate detection requests by being made in integer multiples of the detection cycle time. Here, for a detection cycle time of 10 seconds, requests 3020a and 3020b occur in integer multiples 30 and 60 seconds.
[00139] The second protocol 3005 includes a profile other than 3001. Profile 3005 comprises an initialization step lasting from 0 to 30 seconds. Profile 3005 is then followed by a plurality of 50-second cycles, with the first detection in 40 seconds. These cycles represent a 3 Temperature PCR, which includes a denatured at a high temperature, annealing and detection at a low temperature, and then an extension at a medium temperature. As before, the first initialization cycle can include a small inter-cycle delay at the beginning of the alignment. Someone will recognize that their inter-cycle delay can be inserted in a variety of positions over the initialization step to ensure detection alignment.
[00140] Figure 15B illustrates multiple cases of the two protocols in Figure 15A. The detections were possible to carry out through all the bands in all the columns of chamber simultaneously, the profiles illustrated in Figure 15B would be adequate. However, due to the delay in the time required for the detector head to scan through a column of the chamber with each of its columns of detector pairs, it is necessary to compensate each of the protocols 3001-3007 based on the location of the chamber in which they are executed. For simplicity, each of the protocols 3001 -3007 is assumed to run on a neighboring column. If protocol 3001 is executed in the first column of the chamber, protocol 3002 is executed in the second, 3003 in the third, 3004 in the fourth etc.
[00141] Figure 15C illustrates the execution of protocols 3001 -3007 with the “initial compensation adjustments” 3010-3015 introduced to guarantee the alignment of the detection. The initial compensations demonstrate the movement of the detector through the bands of the cartridge and the synchronization of such movement with the detections required by each of the execution protocols. In this way, protocol 3001 will request detection, using the first column of the detector head in request 3020a. When the detector head moves to align the second column of the detector head with the protocol chamber 3001, the first column of the detector head will be arranged over the chamber 3002 which, advantageously, is now also requesting a 3021a detection. Subsequently, the process continues with the first column of the detector head now reading protocol 3003 in request 3022a, the second reading of column 3002, and the third reading 3001. Someone will recognize that the distortion illustrated in Figure 15C is not for scale (in some modes the distortion can be in the order of -400 milliseconds), and has been illustrated as shown for explanation purposes only.
[00142] Thus, with the “initial settings” properly selected, the system can guarantee consistent detection times across each of the reactors. As illustrated in Figure 15C, orderly and efficient detections are made along lines 3007a-d when the determined solution is performed by the detector system. In this way, detection for a particular reactor will occur at the same time from cycle to cycle. The details for a modality to determine these solutions will be described in greater detail with respect to Figure 16. Active Cooling
[00143] In certain modalities at the same time that the heating of the reactor chamber is active, that is, heaters are actively applied to the chamber, the cooling of the reactor chamber can be passive, where the convection alone is used to cool the contents of the reactor. To also provide consistent diagnostic performance, certain modalities include active participation in the reactor's cooling process to ensure consistent behavior. Figure 16 illustrates a thermal profile 7001 comprising a cooling component. Profile 7001 comprises an elevation time 7006, a threshold 7005, and a cooling period 7002/7003.
[00144] The ambient temperature in the location where the heating / detection unit is located may not be the same. That is, an operating system in southern Arizona cannot be subjected to the same ambient temperature as an operating system in northern Alaska. Thus, at the warmer ambient temperature at which the system is expected to be operated, profile 7001 may have a cooling curve 7003. In a colder environment, cooling profile 7002 may result instead. To compensate for the difference, certain modalities include monitoring the reactor's cooling profile through temperature sensors, possibly those described with respect to Figure 3b. When deviations from the maximum profile 7003 are detected, sufficient heating can be applied so that profile 7002 instead follows profile 7003. In some embodiments the heat can be applied periodically at times 7004a-c, whereas heat can be applied continuously in other modalities. In this way, consistent profiles can be obtained regardless of the geographic location of the thermal cycler or the operating ambient temperature.
[00145] Certain of these modalities apply Newton's law of cooling to determine when to apply heaters: T (t) = Ta + (T (0) - Ta) e-rt
[00146] Where: T (t) is the temperature at time t, T (0) is the initial temperature, Ta is the room temperature parameter, r is the constant decay parameter, and t is the time. In some embodiments, 50.2 degrees Celsius and 0.098 can be used as the room temperature parameter and constant decay parameter, respectively. In this mode, the room temperature parameter is selected to be higher than any expected room operating temperature, thereby allowing full control over the cooling cycle by applying at least a small amount of heat during each cooling cycle, regardless of ambient temperature, to combine the current cooling with the cooling curve of the maximum profile 7003 in each case.
[00147] As used here, an "entry" can be, for example, data received from a keyboard, scroll wheel, mouse, voice recognition system or other device capable of transmitting information from a user to a computer. The input device can also be a touch screen associated with the monitor, in which case the user responds to requests on the display by touching the screen. The user can enter text information through the input device such as the keyboard or the touch screen.
[00148] The invention is operational with numerous other configurations or general-purpose or special-purpose computing system environments. Examples of well-known computing systems, environments, and / or configurations that may be suitable for use with the invention include, but are not limited to, microcontrollers, personal computers, server computers, portable or laptop devices, multiprocessor systems, systems with microprocessor based, programmable consumer electronics, network PCs, minicomputers, large computers, distributed computing environments that include any of the above devices or systems.
[00149] As used here, "instructions" refers to the steps taken by the computer to process information in the system. The instructions can be executed in software, firmware or hardware and include any type of program step accepted by the system components.
[00150] A "microprocessor" or "processor" can be any conventional general purpose single or multiple core microprocessor such as a Pentium®, Intel® Core ™ processor, an 8051 processor, a MIPS® processor or an ALPHA® processor. In addition, the microprocessor can be any conventional special purpose microprocessor such as a digital signal processor or graphics processor. A “processor” can also refer, however, without limitation, microcontrollers, sets of programmable field inputs (FPGAs), application-specific integrated circuits (ASICs), complex programmable logic devices (CPLDs), programmable logic sets (PLAs) , microprocessors or other similar processing devices.
[00151] The system is comprised of several modules as described in detail below. As can be appreciated by someone with ordinary experience in the technique, each of the modules comprises several subroutines, procedures, definitions declarations and macros. Each of the modules is typical and separately compiled and linked in a single executable program. Therefore, the following description of each of the modules is used for convenience to describe the functionality of the preferred system. In this way, the processes that are going through each of the modules can be arbitrarily redistributed to one of the other modules, combined together in a single module or made available in, for example, a shareable dynamic link library.
[00152] Certain system modalities can be used in conjunction with various operating systems such as SNOW LEOPARD®, iOS®, LINUX, UNIX or MICROSOFT WINDOWS® or any other suitable operating system.
[00153] Certain modalities of the system can be written in any conventional programming language, such as assembly, C, C ++, BASIC, Pascal or Java, and executed under a conventional or similar operating system or any other suitable programming language.
[00154] In addition, modules or instructions can be stored on one or more programmable storage devices, such as FLASH drives, CD-ROMs, hard drives, and DVDs. One mode includes a programmable storage device having instructions stored on it.
[00155] While the above processes and methods are described above as including certain steps and are described in a particular order, it must be recognized that these processes and methods may include additional steps or may omit some of these steps described. In addition, each of the process steps does not necessarily need to be carried out in the order that is described.
[00156] While the above description showed, described and pointed out new aspects of the invention as applied to various modalities, it will be understood that various omissions, substitutions, and changes in the shape and details of the illustrated system or process can be made by those versed in the technique without departing from the spirit of the invention. As will be recognized, the present invention can be incorporated in a way that does not provide all the aspects and benefits presented here, since some aspects can be used or practiced separately from others.
[00157] The steps of a method or algorithm described together with the modalities described here can be incorporated directly in hardware, in a software module executed by a processor or in a combination of the two. A software module can reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, removable disk, CD-ROM or any other form of storage medium known in the art. An exemplary storage medium can be coupled to the processor such that the processor can read information from, and write information to, the storage medium. Alternatively, the storage medium can be integral to the processor. The processor and storage medium can reside in an ASIC. The ASIC can reside on a user terminal. Alternatively, the processor and the storage medium can reside as discrete components in a user terminal.

权利要求:
Claims (15)
[0001]
1. System for Conducting Molecular Diagnostic Tests on Multiple Samples in Parallel, characterized by the fact that the system comprises: a plurality of reaction chambers (1703); a detector head (700) comprising a plurality of light detector (726b, 727b) and light source pairs (726a, 727a) for performing detections in said plurality of reaction chambers; a processor configured to perform the following: determining or providing or accessing a detection cycle time, the detection cycle time being the amount of time required to perform a predetermined plurality of detections by said detector head in said plurality of detection chambers reaction; receiving or accessing a protocol step (2000B, 2000D) of a protocol (2000), the step having a step duration associated with it, the step comprising a time during which the detection must occur during the step; and determining a first adjustment for the step such that the step duration is an integer multiple of the detection cycle time.
[0002]
2. System for Conducting Molecular Diagnostic Tests on Multiple Samples in Parallel, according to Claim 1, characterized in that the protocol step is associated with a protocol from a plurality of protocols, each of which is associated with a plurality of protocols at least one of a plurality of thermal cycling reactions, where each thermal cycling reaction comprises one or more detection steps and in which the determination of a first adjustment is based, at least in part, on a measurement of time one or more detection steps associated with thermal cycling reactions of at least two or more of the plurality of protocols, when two or more of the plurality of protocols are executed simultaneously.
[0003]
3. System for Conducting Molecular Diagnostic Tests on Several Samples in Parallel, according to Claim 1, characterized in that the processor is further configured to determine a second step adjustment, in which the detection time is a multiple of the time of the detection cycle, when the step is adjusted by the first adjustment and the second adjustment.
[0004]
4. System for Conducting Molecular Diagnostic Tests on Multiple Samples in Parallel, according to Claim 1, characterized in that the processor is further configured to determine an initial compensation adjustment (3010-3015) based on a position of a reaction (1703) associated with the protocol (3001-3007).
[0005]
5. System for Conducting Molecular Diagnostic Tests on Several Samples in Parallel, according to Claim 1, characterized in that the detection cycle time also comprises a time necessary for the movement of the detector head (700) for each of a plurality of detection positions of the reaction chamber and the movement of the detector head to the starting position.
[0006]
6. System for Conducting Molecular Diagnostic Tests on Multiple Samples in Parallel, according to Claim 1, characterized in that the protocol comprises a polymerase chain reaction (PCR) protocol.
[0007]
7. System for Conducting Molecular Diagnostic Tests on Multiple Samples in Parallel, according to Claim 1, characterized in that the processor is still configured to start the protocol.
[0008]
8. System for Conducting Molecular Diagnostic Tests on Multiple Samples in Parallel, according to Claim 1, characterized in that the protocol has cycles and in which the first adjustment is an intra-cycle adjustment to increase or decrease the duration of a sub -stage of the protocol step (5002).
[0009]
9. System for Conducting Molecular Diagnostic Tests on Multiple Samples in Parallel, according to Claim 1, characterized in that the protocol has cycles and in which the processor is further configured to determine an inter-cycle adjustment (6005) to increase or decrease the time between protocol steps of the protocol.
[0010]
10. Method for Simultaneously Performing Real-Time Amplification in Plurality of Reaction Chambers, (1703), of Amplification, comprising: (a) providing sufficient scanning time for a detector assembly (700) to perform a scanning cycle, during which it can scan each of the plurality of amplification reaction chambers for at least one detectable signal and become ready to repeat the scan; (b) provide a reaction protocol (2000) for each of the amplification reaction chambers, which includes multiple cycles, each cycle comprising a cycle time that includes at least one heating step (2000A), at least, a cooling step (2000B) and at least one temperature threshold (2000B, 2000D) that includes a reading cycle period during which the detector assembly must scan the reaction chamber for at least one detectable signal; (c) determine, using a processor, whether the cycle time for that reaction chamber is the same or an integer multiple of the scan time and, otherwise, adjust the cycle time so that the cycle time is the same or an integer multiple of the scan time; (d) perform at least steps (b) and (c) for the reaction protocol for each of the plurality of amplification reaction chambers, so that the cycle time for each reaction protocol is the same or a multiple scan time integer; and (e) under the direction of a processor, perform real-time amplification in each of the reaction chambers, using the reaction protocol for each of the reaction chambers, including performing multiple scanning cycles with the detector assembly, characterized by that each amplification reaction chamber is scanned by the detector assembly during each reading cycle period for that reaction chamber.
[0011]
11. Method for Simultaneously Performing Real-Time Amplification in Plurality of Reaction Chambers, (1703), of Amplification, according to Claim 10, characterized in that it further comprises adjusting the cycle time phase of the reaction protocol to at least one of the reaction chambers (1703).
[0012]
12. Method for Simultaneously Performing Real-Time Amplification in Plurality of Reaction Chambers, (1703), of Amplification, according to Claim 10, characterized in that at least one said reaction protocol is different from another said reaction protocol.
[0013]
13. Method for Simultaneously Performing Real-Time Amplification in Plurality of Reaction Chambers, (1703), of Amplification, according to Claim 12, characterized in that at least one cycle time in a reaction protocol is different from the time cycle in another reaction protocol.
[0014]
14. Method for Simultaneously Performing Real-Time Amplification in Plurality of Reaction Chambers, (1703), of Amplification, according to Claim 10, characterized in that adjusting the cycle time of a reaction chamber (1703) comprises increasing or decrease the duration of at least one heating step (7006), at least one cooling step (7002, 7003) or at least one temperature threshold (7005) in the cycle.
[0015]
15. Method for Simultaneously Performing Real-Time Amplification in Plurality of Reaction Chambers, (1703), of Amplification, according to Claim 10, characterized in that it further comprises determining, using the processor, whether the cycle time for that chamber reaction time (1703) is the same or an integer multiple of the scan time and, otherwise, adjust the time between successive cycles, so that the cycle time is the same or an integer multiple of the scan time.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US1434314A|1921-08-04|1922-10-31|Raich Anthony|Lunch pail|

---

US1616419A|1925-04-03|1927-02-01|Everlasting Valve Co|Automatic shut-off device for gas in case of fire|

---

US1733401A|1928-03-29|1929-10-29|Christman Matthias|Journal box|

---

NL109202C|1959-11-20|

---

GB1095429A|1965-05-17|

---

US3528449A|1968-02-27|1970-09-15|Trw Inc|Fluid flow control apparatus|

---

US3813316A|1972-06-07|1974-05-28|Gen Electric|Microorganisms having multiple compatible degradative energy-generating plasmids and preparation thereof|

---

US4038192A|1973-12-03|1977-07-26|International Biomedical Laboratories, Inc.|Device for exchange between fluids suitable for treatment of blood|

---

US3985649A|1974-11-25|1976-10-12|Eddelman Roy T|Ferromagnetic separation process and material|

---

JPS5255578A|1975-10-31|1977-05-07|Hitachi Ltd|Analyzing apparatus|

---

US4018652A|1976-01-09|1977-04-19|Mcdonnell Douglas Corporation|Process and apparatus for ascertaining the concentration of microorganism in a water specimen|

---

US4018089A|1976-05-05|1977-04-19|Beckman Instruments, Inc.|Fluid sampling apparatus|

---

USD249706S|1976-12-17|1978-09-26|Eastman Kodak Company|Sample cup tray for chemical analysis of biological fluids|

---

USD252157S|1977-04-14|1979-06-19|Warner-Lambert Company|Diagnostic device for measuring biochemical characteristics of microorganisms and the like|

---

USD252341S|1977-05-12|1979-07-10|Ryder International Corporation|Testing tray|

---

JPS5616667B2|1977-06-21|1981-04-17|

---

US4139005A|1977-09-01|1979-02-13|Dickey Gilbert C|Safety release pipe cap|

---

USD254687S|1979-01-25|1980-04-08|Mcdonnell Douglas Corporation|Biochemical card for use with an automated microbial identification machine|

---

USD261033S|1979-02-05|1981-09-29|American Optical Corporation|Bilirubin concentration analyzer|

---

USD261173S|1979-02-05|1981-10-06|American Optical Corporation|Bilirubinometer|

---

US4301412A|1979-10-29|1981-11-17|United States Surgical Corporation|Liquid conductivity measuring system and sample cards therefor|

---

JPS6360854B2|1980-10-09|1988-11-25|

---

US4472357A|1981-11-18|1984-09-18|Medical Laboratory Automation, Inc.|Blood bank cuvette cassette and label therefor|

---

US4457329A|1981-12-04|1984-07-03|Air Products And Chemicals, Inc.|Safety pressure regulator|

---

JPH0155082B2|1982-06-04|1989-11-22|Aron Kasei Kk|

---

USD279817S|1982-07-19|1985-07-23|Daryl Laboratories, Inc.|Immunoassay test slide|

---

US4504582A|1982-07-20|1985-03-12|Genex Corporation|Vermiculite as a carrier support for immobilized biological materials|

---

US4439526A|1982-07-26|1984-03-27|Eastman Kodak Company|Clustered ingress apertures for capillary transport devices and method of use|

---

DE3376763D1|1982-09-02|1988-06-30|Hettich Andreas Fa|Centrifugation chambers for the cytodiagnostic preparation of epithelial cells and their application|

---

US4647432A|1982-11-30|1987-03-03|Japan Tectron Instruments Corporation Tokuyama Soda Kabushiki Kaisha|Automatic analysis apparatus|

---

USD282208S|1983-02-07|1986-01-14|Data Packaging Corporation|Pipetter tip cartridge|

---

US4724207A|1984-02-02|1988-02-09|Cuno Incorporated|Modified siliceous chromatographic supports|

---

US4698302A|1983-05-12|1987-10-06|Advanced Magnetics, Inc.|Enzymatic reactions using magnetic particles|

---

US4522786A|1983-08-10|1985-06-11|E. I. Du Pont De Nemours And Company|Multilayered test device for detecting analytes in liquid test samples|

---

US4673657A|1983-08-26|1987-06-16|The Regents Of The University Of California|Multiple assay card and system|

---

US4599315A|1983-09-13|1986-07-08|University Of California Regents|Microdroplet test apparatus|

---

USD292735S|1983-11-02|1987-11-10|A/S Nunc|Tube for the immunological adsorption analysis|

---

US4654127A|1984-04-11|1987-03-31|Sentech Medical Corporation|Self-calibrating single-use sensing device for clinical chemistry and method of use|

---

JP2502961B2|1984-04-26|1996-05-29|日本碍子株式会社|Method for manufacturing electrochemical device|

---

USD288478S|1984-06-21|1987-02-24|Sentech Medical Corporation|Clinical chemistry analyzer|

---

EP0215849B1|1985-03-13|1993-03-17|BAXTER INTERNATIONAL INC. |Platelet collection system|

---

US4683202B1|1985-03-28|1990-11-27|Cetus Corp|

---

US4612959A|1985-05-07|1986-09-23|Mobil Oil Corporation|Valveless shut-off and transfer device|

---

US4720374A|1985-07-22|1988-01-19|E. I. Du Pont De Nemours And Company|Container having a sonication compartment|

---

US4963498A|1985-08-05|1990-10-16|Biotrack|Capillary flow device|

---

US4678752A|1985-11-18|1987-07-07|Becton, Dickinson And Company|Automatic random access analyzer|

---

US4871779A|1985-12-23|1989-10-03|The Dow Chemical Company|Ion exchange/chelation resins containing dense star polymers having ion exchange or chelate capabilities|

---

US4683195B1|1986-01-30|1990-11-27|Cetus Corp|

---

DE3614955C1|1986-05-02|1987-08-06|Schulz Peter|Sample distribution system|

---

US4978622A|1986-06-23|1990-12-18|Regents Of The University Of California|Cytophaga-derived immunopotentiator|

---

US5849478A|1986-08-14|1998-12-15|Cashman; Daniel P.|Blocked-polymerase polynucleotide immunoassay method and kit|

---

US5763262A|1986-09-18|1998-06-09|Quidel Corporation|Immunodiagnostic device|

---

USD302294S|1986-10-03|1989-07-18|Biotrack, Inc.|Reagent cartridge for blood analysis|

---

US4935342A|1986-12-01|1990-06-19|Syngene, Inc.|Method of isolating and purifying nucleic acids from biological samples|

---

US4978502A|1987-01-05|1990-12-18|Dole Associates, Inc.|Immunoassay or diagnostic device and method of manufacture|

---

US5004583A|1987-01-29|1991-04-02|Medtest Systems, Inc.|Universal sensor cartridge for use with a universal analyzer for sensing components in a multicomponent fluid|

---

US4946562A|1987-01-29|1990-08-07|Medtest Systems, Inc.|Apparatus and methods for sensing fluid components|

---

US5599667A|1987-03-02|1997-02-04|Gen-Probe Incorporated|Polycationic supports and nucleic acid purification separation and hybridization|

---

KR960000479B1|1987-03-02|1996-01-08|젠-프로우브 인코오퍼레이티드|Polycationic supports for nucleic acid purification separation and hybridization|

---

US4855110A|1987-05-06|1989-08-08|Abbott Laboratories|Sample ring for clinical analyzer network|

---

US5001417A|1987-06-01|1991-03-19|Abbott Laboratories|Apparatus for measuring electrolytes utilizing optical signals related to the concentration of the electrolytes|

---

US5192507A|1987-06-05|1993-03-09|Arthur D. Little, Inc.|Receptor-based biosensors|

---

US5416000A|1989-03-16|1995-05-16|Chemtrak, Inc.|Analyte immunoassay in self-contained apparatus|

---

WO1989000446A1|1987-07-16|1989-01-26|E.I. Du Pont De Nemours And Company|Affinity separating using immobilized flocculating reagents|

---

US4827944A|1987-07-22|1989-05-09|Becton, Dickinson And Company|Body fluid sample collection tube composite|

---

GB8720470D0|1987-08-29|1987-10-07|Emi Plc Thorn|Sensor arrangements|

---

US4921809A|1987-09-29|1990-05-01|Findley Adhesives, Inc.|Polymer coated solid matrices and use in immunoassays|

---

USD312692S|1987-10-09|1990-12-04|Bradley Marshall C|Pipette holder|

---

USD310413S|1987-12-17|1990-09-04|Miles Inc.|Sample processor|

---

US5130238A|1988-06-24|1992-07-14|Cangene Corporation|Enhanced nucleic acid amplification process|

---

US4895650A|1988-02-25|1990-01-23|Gen-Probe Incorporated|Magnetic separation rack for diagnostic assays|

---

JPH01219669A|1988-02-29|1989-09-01|Shimadzu Corp|Detecting method of liquid sample vessel according to assortment|

---

US4988617A|1988-03-25|1991-01-29|California Institute Of Technology|Method of detecting a nucleotide change in nucleic acids|

---

US5503803A|1988-03-28|1996-04-02|Conception Technologies, Inc.|Miniaturized biological assembly|

---

DE3811713C2|1988-04-08|1990-02-08|Robert Bosch Gmbh, 7000 Stuttgart, De|

---

US5700637A|1988-05-03|1997-12-23|Isis Innovation Limited|Apparatus and method for analyzing polynucleotide sequences and method of generating oligonucleotide arrays|

---

US5096669A|1988-09-15|1992-03-17|I-Stat Corporation|Disposable sensing device for real time fluid analysis|

---

US5060823A|1988-09-15|1991-10-29|Brandeis University|Sterile transfer system|

---

DE8813340U1|1988-10-24|1988-12-08|Laboratorium Prof. Dr. Rudolf Berthold, 7547 Wildbad, De|

---

JPH0814337B2|1988-11-11|1996-02-14|株式会社日立製作所|Opening / closing control valve and opening / closing control method for flow path using phase change of fluid itself|

---

US5530101A|1988-12-28|1996-06-25|Protein Design Labs, Inc.|Humanized immunoglobulins|

---

US4919829A|1988-12-30|1990-04-24|The United States Of America As Represented By The Secretary Of Commerce|Aluminum hydroxides as solid lubricants|

---

US5229297A|1989-02-03|1993-07-20|Eastman Kodak Company|Containment cuvette for PCR and method of use|

---

US5053199A|1989-02-21|1991-10-01|Boehringer Mannheim Corporation|Electronically readable information carrier|

---

FI86229C|1989-04-10|1992-07-27|Niilo Kaartinen|FOERFARANDE FOER FORMNING AV ETT UPPVAERMBART OCH NEDKYLBART ELEMENT VID ETT SYSTEM BEHANDLANDE SMAO VAETSKEMAENGDER SAMT ETT MEDELST FOERFARANDET FRAMSTAELLT ELEMENT.|

---

US4949742A|1989-04-26|1990-08-21|Spectra-Physics, Inc.|Temperature operated gas valve|

---

US5135872A|1989-04-28|1992-08-04|Sangstat Medical Corporation|Matrix controlled method of delayed fluid delivery for assays|

---

US5061336A|1989-05-01|1991-10-29|Soane Technologies, Inc.|Gel casting method and apparatus|

---

US5071531A|1989-05-01|1991-12-10|Soane Technologies, Inc.|Casting of gradient gels|

---

AU109440S|1989-05-03|1990-10-31|Bayer Diagnostic G M B H|Diagnostic working station evaluation device|

---

USD325638S|1989-07-10|1992-04-21|Hach Company|Microtester or the like|

---

CA2020958C|1989-07-11|2005-01-11|Daniel L. Kacian|Nucleic acid sequence amplification methods|

---

USD328794S|1989-07-19|1992-08-18|Pb Diagnostic Systems, Inc.|Diagnostic instrument or similar article|

---

JP2881826B2|1989-07-24|1999-04-12|東ソー株式会社|Automatic analyzer|

---

AU635314B2|1989-09-08|1993-03-18|Terumo Kabushiki Kaisha|Measuring apparatus|

---

US5126002A|1989-09-29|1992-06-30|Glory Kogyo Kabushiki Kaisha|Leaf paper bundling apparatus|

---

US5275787A|1989-10-04|1994-01-04|Canon Kabushiki Kaisha|Apparatus for separating or measuring particles to be examined in a sample fluid|

---

LU87601A1|1989-10-05|1990-02-07|Ceodeux Sa|TAP FOR GAS BOTTLE|

---

USD324426S|1989-10-20|1992-03-03|Pacific Biotech, Inc.|Reaction unit for use in analyzing biological fluids|

---

US4967950A|1989-10-31|1990-11-06|International Business Machines Corporation|Soldering method|

---

US6967088B1|1995-03-16|2005-11-22|Allergan, Inc.|Soluble recombinant botulinum toxin proteins|

---

US5252743A|1989-11-13|1993-10-12|Affymax Technologies N.V.|Spatially-addressable immobilization of anti-ligands on surfaces|

---

US5091328A|1989-11-21|1992-02-25|National Semiconductor Corporation|Method of late programming MOS devices|

---

JP2731613B2|1989-12-12|1998-03-25|株式会社クラレ|Cartridge for enzyme immunoassay, measuring method and measuring apparatus using the same|

---

US5279936A|1989-12-22|1994-01-18|Syntex Inc.|Method of separation employing magnetic particles and second medium|

---

USD328135S|1990-01-12|1992-07-21|Pacific Biotech, Inc.|Reaction unit for use in analyzing biological fluids|

---

US5427930A|1990-01-26|1995-06-27|Abbott Laboratories|Amplification of target nucleic acids using gap filling ligase chain reaction|

---

US5750015A|1990-02-28|1998-05-12|Soane Biosciences|Method and device for moving molecules by the application of a plurality of electrical fields|

---

US6054034A|1990-02-28|2000-04-25|Aclara Biosciences, Inc.|Acrylic microchannels and their use in electrophoretic applications|

---

US5126022A|1990-02-28|1992-06-30|Soane Tecnologies, Inc.|Method and device for moving molecules by the application of a plurality of electrical fields|

---

US5858188A|1990-02-28|1999-01-12|Aclara Biosciences, Inc.|Acrylic microchannels and their use in electrophoretic applications|

---

US20020053399A1|1996-07-30|2002-05-09|Aclara Biosciences, Inc|Methods for fabricating enclosed microchannel structures|

---

DE69126690T2|1990-04-06|1998-01-02|Perkin Elmer Corp|AUTOMATED LABORATORY FOR MOLECULAR BIOLOGY|

---

GB9007791D0|1990-04-06|1990-06-06|Foss Richard C|High voltage boosted wordline supply charge pump and regulator for dram|

---

WO1991017446A1|1990-05-01|1991-11-14|Autogen Instruments, Inc.|Integral biomolecule preparation device|

---

US5667976A|1990-05-11|1997-09-16|Becton Dickinson And Company|Solid supports for nucleic acid hybridization assays|

---

US5935522A|1990-06-04|1999-08-10|University Of Utah Research Foundation|On-line DNA analysis system with rapid thermal cycling|

---

DE4023194A1|1990-07-20|1992-01-23|Kodak Ag|DEVICE WITH SEVERAL RECEIVER ARRANGEMENTS FOR LIQUID-FILLED CONTAINERS|

---

US5147606A|1990-08-06|1992-09-15|Miles Inc.|Self-metering fluid analysis device|

---

US5208163A|1990-08-06|1993-05-04|Miles Inc.|Self-metering fluid analysis device|

---

JPH0734375Y2|1990-09-11|1995-08-02|株式会社シノテスト|Instrument for measuring and measuring reaction of analyte|

---

WO1992005443A1|1990-09-15|1992-04-02|Medical Research Council|Reagent separation|

---

US5135627A|1990-10-15|1992-08-04|Soane Technologies, Inc.|Mosaic microcolumns, slabs, and separation media for electrophoresis and chromatography|

---

US5652141A|1990-10-26|1997-07-29|Oiagen Gmbh|Device and process for isolating nucleic acids from cell suspension|

---

US5141718A|1990-10-30|1992-08-25|Millipore Corporation|Test plate apparatus|

---

DE59105165D1|1990-11-01|1995-05-18|Ciba Geigy Ag|Device for the preparation or preparation of liquid samples for chemical analysis.|

---

EP0488947B1|1990-11-26|1995-02-15|Ciba-Geigy Ag|Detector cell|

---

KR100236506B1|1990-11-29|2000-01-15|퍼킨-엘머시터스인스트루먼츠|Apparatus for polymerase chain reaction|

---

US6703236B2|1990-11-29|2004-03-09|Applera Corporation|Thermal cycler for automatic performance of the polymerase chain reaction with close temperature control|

---

US5273716A|1991-01-14|1993-12-28|Electric Power Research Institute, Inc.|pH optrode|

---

US5455166A|1991-01-31|1995-10-03|Becton, Dickinson And Company|Strand displacement amplification|

---

FR2672301A1|1991-02-01|1992-08-07|Larzul Daniel|Process and device for amplifying the number of a defined sequence of nucleic acid in a biological sample|

---

US5327038A|1991-05-09|1994-07-05|Rockwell International Corporation|Walking expansion actuator|

---

JPH05345900A|1991-07-08|1993-12-27|Fuji Oil Co Ltd|Production of hard fat and oil|

---

DE4123348A1|1991-07-15|1993-01-21|Boehringer Mannheim Gmbh|ELECTROCHEMICAL ANALYSIS SYSTEM|

---

USD333522S|1991-07-23|1993-02-23|P B Diagnostic Systems, Inc.|Sample tube holder|

---

IT1249433B|1991-08-06|1995-02-23|Pompeo Moscetta|PROCEDURE FOR DOSING ANALYTES IN LIQUID SAMPLES AND RELATED EQUIPMENT.|

---

US7297313B1|1991-08-31|2007-11-20|The Regents Of The University Of California|Microfabricated reactor, process for manufacturing the reactor, and method of amplification|

---

US5474796A|1991-09-04|1995-12-12|Protogene Laboratories, Inc.|Method and apparatus for conducting an array of chemical reactions on a support surface|

---

US5256376A|1991-09-12|1993-10-26|Medical Laboratory Automation, Inc.|Agglutination detection apparatus|

---

EP0606309B1|1991-10-04|1995-08-30|Alcan International Limited|Peelable laminated structures and process for production thereof|

---

CA2074671A1|1991-11-04|1993-05-05|Thomas Bormann|Device and method for separating plasma from a biological fluid|

---

USD347478S|1991-11-05|1994-05-31|Hybaid Ltd.|Laboratory instrument for handling bimolecular samples|

---

WO1993009128A1|1991-11-07|1993-05-13|Nanotronics, Inc.|Hybridization of polynucleotides conjugated with chromophores and fluorophores to generate donor-to-donor energy transfer system|

---

US5787032A|1991-11-07|1998-07-28|Nanogen|Deoxyribonucleic acid optical storage using non-radiative energy transfer between a donor group, an acceptor group and a quencher group|

---

USD340289S|1992-01-30|1993-10-12|Jan Gerber|Diagnostic testing material|

---

US5559432A|1992-02-27|1996-09-24|Logue; Delmar L.|Joystick generating a polar coordinates signal utilizing a rotating magnetic field within a hollow toroid core|

---

US5217694A|1992-03-25|1993-06-08|Gibler W Brian|Holder for evacuated test tubes|

---

US5646049A|1992-03-27|1997-07-08|Abbott Laboratories|Scheduling operation of an automated analytical system|

---

WO1993020240A1|1992-04-06|1993-10-14|Abbott Laboratories|Method and device for detection of nucleic acid or analyte using total internal reflectance|

---

US5223226A|1992-04-14|1993-06-29|Millipore Corporation|Insulated needle for forming an electrospray|

---

US6235313B1|1992-04-24|2001-05-22|Brown University Research Foundation|Bioadhesive microspheres and their use as drug delivery and imaging systems|

---

US5498392A|1992-05-01|1996-03-12|Trustees Of The University Of Pennsylvania|Mesoscale polynucleotide amplification device and method|

---

US5304487A|1992-05-01|1994-04-19|Trustees Of The University Of Pennsylvania|Fluid handling in mesoscale analytical devices|

---

US5744366A|1992-05-01|1998-04-28|Trustees Of The University Of Pennsylvania|Mesoscale devices and methods for analysis of motile cells|

---

US6953676B1|1992-05-01|2005-10-11|Trustees Of The University Of Pennsylvania|Mesoscale polynucleotide amplification device and method|

---

US5486335A|1992-05-01|1996-01-23|Trustees Of The University Of Pennsylvania|Analysis based on flow restriction|

---

US5637469A|1992-05-01|1997-06-10|Trustees Of The University Of Pennsylvania|Methods and apparatus for the detection of an analyte utilizing mesoscale flow systems|

---

US5587128A|1992-05-01|1996-12-24|The Trustees Of The University Of Pennsylvania|Mesoscale polynucleotide amplification devices|

---

US5726026A|1992-05-01|1998-03-10|Trustees Of The University Of Pennsylvania|Mesoscale sample preparation device and systems for determination and processing of analytes|

---

US5296375A|1992-05-01|1994-03-22|Trustees Of The University Of Pennsylvania|Mesoscale sperm handling devices|

---

US5401465A|1992-05-05|1995-03-28|Chiron Corporation|Luminometer with reduced sample crosstalk|

---

US5364591A|1992-06-01|1994-11-15|Eastman Kodak Company|Device for moving a target-bearing solid through a liquid for detection while being contained|

---

US5414245A|1992-08-03|1995-05-09|Hewlett-Packard Corporation|Thermal-ink heater array using rectifying material|

---

US5639423A|1992-08-31|1997-06-17|The Regents Of The University Of Calfornia|Microfabricated reactor|

---

DE4231966A1|1992-09-24|1994-03-31|Bosch Gmbh Robert|Planar polarographic probe for determining the lambda value of gas mixtures|

---

US5569364A|1992-11-05|1996-10-29|Soane Biosciences, Inc.|Separation media for electrophoresis|

---

US5885432A|1992-11-05|1999-03-23|Soane Biosciences|Un-crosslinked polymeric media for electrophoresis|

---

GB9223334D0|1992-11-06|1992-12-23|Hybaid Ltd|Magnetic solid phase supports|

---

US5422271A|1992-11-20|1995-06-06|Eastman Kodak Company|Nucleic acid material amplification and detection without washing|

---

US5500187A|1992-12-08|1996-03-19|Westinghouse Electric Corporation|Disposable optical agglutination assay device and method for use|

---

US5302348A|1992-12-10|1994-04-12|Itc Corporation|Blood coagulation time test apparatus and method|

---

US5311996A|1993-01-05|1994-05-17|Duffy Thomas J|Edge protector|

---

JPH0664156U|1993-02-16|1994-09-09|株式会社ニッテク|Blood container holding structure|

---

USD351913S|1993-02-25|1994-10-25|Diametrics Medical, Inc.|Disposable electrochemical measurement cartridge for a portable medical analyzer|

---

US5339486A|1993-03-10|1994-08-23|Persic Jr William V|Golf ball cleaner|

---

US5565171A|1993-05-28|1996-10-15|Governors Of The University Of Alberta|Continuous biochemical reactor for analysis of sub-picomole quantities of complex organic molecules|

---

FI932866A0|1993-06-21|1993-06-21|Labsystems Oy|Separeringsfoerfarande|

---

JP3339650B2|1993-07-02|2002-10-28|和光純薬工業株式会社|Liquid dispensing device|

---

EP0636413B1|1993-07-28|2001-11-14|PE Corporation |Nucleic acid amplification reaction apparatus and method|

---

USD356232S|1993-08-20|1995-03-14|Flair Communications Agency, Inc.|Dual vesselled beverage container|

---

US5397709A|1993-08-27|1995-03-14|Becton Dickinson And Company|System for detecting bacterial growth in a plurality of culture vials|

---

JP2948069B2|1993-09-20|1999-09-13|株式会社日立製作所|Chemical analyzer|

---

DE4334834A1|1993-10-13|1995-04-20|Andrzej Dr Ing Grzegorzewski|Biosensor for measuring changes in viscosity and / or density|

---

US5374395A|1993-10-14|1994-12-20|Amoco Corporation|Diagnostics instrument|

---

US5415839A|1993-10-21|1995-05-16|Abbott Laboratories|Apparatus and method for amplifying and detecting target nucleic acids|

---

US5645801A|1993-10-21|1997-07-08|Abbott Laboratories|Device and method for amplifying and detecting target nucleic acids|

---

US5605662A|1993-11-01|1997-02-25|Nanogen, Inc.|Active programmable electronic devices for molecular biological analysis and diagnostics|

---

US5849486A|1993-11-01|1998-12-15|Nanogen, Inc.|Methods for hybridization analysis utilizing electrically controlled hybridization|

---

US5632957A|1993-11-01|1997-05-27|Nanogen|Molecular biological diagnostic systems including electrodes|

---

EP0653631B1|1993-11-11|2003-05-14|Aclara BioSciences, Inc.|Apparatus and method for the electrophoretical separation of mixtures of fluid substances|

---

DE4343089A1|1993-12-17|1995-06-29|Bosch Gmbh Robert|Planar sensor element based on solid electrolyte|

---

US5725831A|1994-03-14|1998-03-10|Becton Dickinson And Company|Nucleic acid amplification apparatus|

---

CA2143365A1|1994-03-14|1995-09-15|Hugh V. Cottingham|Nucleic acid amplification method and apparatus|

---

DE4408361C2|1994-03-14|1996-02-01|Bosch Gmbh Robert|Electrochemical sensor for determining the oxygen concentration in gas mixtures|

---

JPH09510614A|1994-03-24|1997-10-28|ガメラ・バイオサイエンス・コーポレイション|DNA melt meter and method of using the same|

---

US5580523A|1994-04-01|1996-12-03|Bard; Allen J.|Integrated chemical synthesizers|

---

US5475487A|1994-04-20|1995-12-12|The Regents Of The University Of California|Aqueous carrier waveguide in a flow cytometer|

---

USD366116S|1994-05-03|1996-01-09|Thomas Biskupski|Electrical box for storing dental wax|

---

DE4420732A1|1994-06-15|1995-12-21|Boehringer Mannheim Gmbh|Device for the treatment of nucleic acids from a sample|

---

US5514343A|1994-06-22|1996-05-07|Nunc, As|Microtitration system|

---

FR2722294B1|1994-07-07|1996-10-04|Lyon Ecole Centrale|PROCESS FOR THE QUALITATIVE AND / OR QUANTITATIVE ANALYSIS OF BIOLOGICAL SUBSTANCES PRESENT IN A CONDUCTIVE LIQUID MEDIUM AND BIOCHEMICAL AFFINITY SENSORS USED FOR THE IMPLEMENTATION OF THIS PROCESS|

---

CN1069909C|1994-07-14|2001-08-22|特恩杰特有限公司|Solid ink jet ink|

---

US5639428A|1994-07-19|1997-06-17|Becton Dickinson And Company|Method and apparatus for fully automated nucleic acid amplification, nucleic acid assay and immunoassay|

---

US6001229A|1994-08-01|1999-12-14|Lockheed Martin Energy Systems, Inc.|Apparatus and method for performing microfluidic manipulations for chemical analysis|

---

CA2156226C|1994-08-25|1999-02-23|Takayuki Taguchi|Biological fluid analyzing device and method|

---

US5627041A|1994-09-02|1997-05-06|Biometric Imaging, Inc.|Disposable cartridge for an assay of a biological sample|

---

US5582988A|1994-09-15|1996-12-10|Johnson & Johnson Clinical Diagnostics, Inc.|Methods for capture and selective release of nucleic acids using weakly basic polymer and amplification of same|

---

JP3652424B2|1994-10-27|2005-05-25|日本政策投資銀行|Automatic analyzer and method|

---

JP3403839B2|1994-10-27|2003-05-06|プレシジョン・システム・サイエンス株式会社|Cartridge container|

---

US5721136A|1994-11-09|1998-02-24|Mj Research, Inc.|Sealing device for thermal cycling vessels|

---

AT277450T|1994-11-10|2004-10-15|Orchid Biosciences Inc|LIQUID DISTRIBUTION SYSTEM|

---

US5585069A|1994-11-10|1996-12-17|David Sarnoff Research Center, Inc.|Partitioned microelectronic and fluidic device array for clinical diagnostics and chemical synthesis|

---

US5538848A|1994-11-16|1996-07-23|Applied Biosystems Division, Perkin-Elmer Corp.|Method for detecting nucleic acid amplification using self-quenching fluorescence probe|

---

US5654141A|1994-11-18|1997-08-05|Thomas Jefferson University|Amplification based detection of bacterial infection|

---

GB9425138D0|1994-12-12|1995-02-08|Dynal As|Isolation of nucleic acid|

---

US5731212A|1994-12-20|1998-03-24|International Technidyne Corporation|Test apparatus and method for testing cuvette accommodated samples|

---

US5846493A|1995-02-14|1998-12-08|Promega Corporation|System for analyzing a substance from a solution following filtering of the substance from the solution|

---

US6884357B2|1995-02-21|2005-04-26|Iqbal Waheed Siddiqi|Apparatus and method for processing magnetic particles|

---

US5683659A|1995-02-22|1997-11-04|Hovatter; Kenneth R.|Integral assembly of microcentrifuge strip tubes and strip caps|

---

US5579928A|1995-03-06|1996-12-03|Anukwuem; Chidi I.|Test tube holder with lock down clamp|

---

US5578270A|1995-03-24|1996-11-26|Becton Dickinson And Company|System for nucleic acid based diagnostic assay|

---

US5674394A|1995-03-24|1997-10-07|Johnson & Johnson Medical, Inc.|Single use system for preparation of autologous plasma|

---

DE19512368A1|1995-04-01|1996-10-02|Boehringer Mannheim Gmbh|Nucleic acid release and isolation system|

---

USD382346S|1995-04-19|1997-08-12|Roche Diagnostic Systems, Inc.|Vessel holder|

---

US5700429A|1995-04-19|1997-12-23|Roche Diagnostic Systems, Inc.|Vessel holder for automated analyzer|

---

US5578818A|1995-05-10|1996-11-26|Molecular Dynamics|LED point scanning system|

---

DE19519015C1|1995-05-24|1996-09-05|Inst Physikalische Hochtech Ev|Miniaturised multi-chamber thermo-cycler for polymerase chain reaction|

---

WO1996039547A2|1995-06-01|1996-12-12|The Regents Of The University Of California|Multiple source deposition of shape-memory alloy thin films|

---

AU712934B2|1995-06-06|1999-11-18|Interpore International Inc.|Device and method for concentrating plasma|

---

US5632876A|1995-06-06|1997-05-27|David Sarnoff Research Center, Inc.|Apparatus and methods for controlling fluid flow in microchannels|

---

US5842106A|1995-06-06|1998-11-24|Sarnoff Corporation|Method of producing micro-electrical conduits|

---

US5603351A|1995-06-07|1997-02-18|David Sarnoff Research Center, Inc.|Method and system for inhibiting cross-contamination in fluids of combinatorial chemistry device|

---

US6228635B1|1995-06-07|2001-05-08|Aastrom Bioscience, Inc.|Portable cell growth cassette for use in maintaining and growing biological cells|

---

JP3554612B2|1995-06-12|2004-08-18|マツダ株式会社|Roll curtain for vehicles|

---

US6521181B1|1995-06-20|2003-02-18|The Regents Of The University Of Calfornia|Microfabricated electrochemiluminescence cell for chemical reaction detection|

---

US6524532B1|1995-06-20|2003-02-25|The Regents Of The University Of California|Microfabricated sleeve devices for chemical reactions|

---

US5589136A|1995-06-20|1996-12-31|Regents Of The University Of California|Silicon-based sleeve devices for chemical reactions|

---

US5968745A|1995-06-27|1999-10-19|The University Of North Carolina At Chapel Hill|Polymer-electrodes for detecting nucleic acid hybridization and method of use thereof|

---

US20020022261A1|1995-06-29|2002-02-21|Anderson Rolfe C.|Miniaturized genetic analysis systems and methods|

---

US6168948B1|1995-06-29|2001-01-02|Affymetrix, Inc.|Miniaturized genetic analysis systems and methods|

---

US5856174A|1995-06-29|1999-01-05|Affymetrix, Inc.|Integrated nucleic acid diagnostic device|

---

US6158269A|1995-07-13|2000-12-12|Bayer Corporation|Method and apparatus for aspirating and dispensing sample fluids|

---

US5872010A|1995-07-21|1999-02-16|Northeastern University|Microscale fluid handling system|

---

WO1997005492A1|1995-07-31|1997-02-13|Precision System Science Co., Ltd|Vessel|

---

JP3923968B2|1995-07-31|2007-06-06|プレシジョン・システム・サイエンス株式会社|Container usage|

---

JP3927570B2|1995-07-31|2007-06-13|プレシジョン・システム・サイエンス株式会社|container|

---

US5849208A|1995-09-07|1998-12-15|Microfab Technoologies, Inc.|Making apparatus for conducting biochemical analyses|

---

KR970706902A|1995-09-12|1997-12-01|로드릭 리차드 제이|DEVICE AND METHOD FOR DNA AMPLIFICATION AND ASSAY|

---

US6911183B1|1995-09-15|2005-06-28|The Regents Of The University Of Michigan|Moving microdroplets|

---

US6057149A|1995-09-15|2000-05-02|The University Of Michigan|Microscale devices and reactions in microscale devices|

---

US6048734A|1995-09-15|2000-04-11|The Regents Of The University Of Michigan|Thermal microvalves in a fluid flow method|

---

US6130098A|1995-09-15|2000-10-10|The Regents Of The University Of Michigan|Moving microdroplets|

---

GB9519346D0|1995-09-22|1995-11-22|English Glass Company The Limi|Dispensing systems|

---

US5658515A|1995-09-25|1997-08-19|Lee; Abraham P.|Polymer micromold and fabrication process|

---

US5771902A|1995-09-25|1998-06-30|Regents Of The University Of California|Micromachined actuators/sensors for intratubular positioning/steering|

---

US5628890A|1995-09-27|1997-05-13|Medisense, Inc.|Electrochemical sensor|

---

US6132580A|1995-09-28|2000-10-17|The Regents Of The University Of California|Miniature reaction chamber and devices incorporating same|

---

US20020068357A1|1995-09-28|2002-06-06|Mathies Richard A.|Miniaturized integrated nucleic acid processing and analysis device and method|

---

DE69513658T2|1995-09-29|2000-05-31|St Microelectronics Srl|Voltage regulator for non-volatile, electrically programmable semiconductor memory devices|

---

US5651839A|1995-10-26|1997-07-29|Queen's University At Kingston|Process for engineering coherent twin and coincident site lattice grain boundaries in polycrystalline materials|

---

US5705813A|1995-11-01|1998-01-06|Hewlett-Packard Company|Integrated planar liquid handling system for maldi-TOF MS|

---

DE19540877C2|1995-11-02|1998-02-26|Byk Sangtec Diagnostica|Modular reagent cartridge|

---

US5854033A|1995-11-21|1998-12-29|Yale University|Rolling circle replication reporter systems|

---

AT291225T|1995-12-05|2005-04-15|Gamera Bioscience Corp|APPARATUS AND METHOD FOR MOVING FLUIDS BY CENTRIFUGAL ACCELERATION IN AUTOMATIC LABORATORY TREATMENT|

---

US20010055812A1|1995-12-05|2001-12-27|Alec Mian|Devices and method for using centripetal acceleration to drive fluid movement in a microfluidics system with on-board informatics|

---

US6068751A|1995-12-18|2000-05-30|Neukermans; Armand P.|Microfluidic valve and integrated microfluidic system|

---

USD382647S|1996-01-17|1997-08-19|Biomerieux Vitek, Inc.|Biochemical test card|

---

US5631337A|1996-01-19|1997-05-20|Soane Bioscience|Thermoreversible hydrogels comprising linear copolymers and their use in electrophoresis|

---

US5883211A|1996-01-19|1999-03-16|Aclara Biosciences, Inc.|Thermoreversible hydrogels comprising linear copolymers and their use in electrophoresis|

---

US5863502A|1996-01-24|1999-01-26|Sarnoff Corporation|Parallel reaction cassette and associated devices|

---

US5726944A|1996-02-05|1998-03-10|Motorola, Inc.|Voltage regulator for regulating an output voltage from a charge pump and method therefor|

---

US5981735A|1996-02-12|1999-11-09|Cobra Therapeutics Limited|Method of plasmid DNA production and purification|

---

AU715627B2|1996-02-21|2000-02-03|Biomerieux Vitek, Inc.|Automatic sample testing machine|

---

US5736102A|1996-02-21|1998-04-07|Biomerieux Vitek, Inc.|Test sample positioning system|

---

USD378782S|1996-03-01|1997-04-08|Johnson & Johnson Clinical Diagnostics, Inc.|Processor for nucleic acid detection|

---

US5849598A|1996-03-15|1998-12-15|Washington University|Method for transferring micro quantities of liquid samples to discrete locations|

---

EP0890106A4|1996-03-25|2002-08-28|Diasys Corp|Apparatus and method for handling fluid samples of body materials|

---

US6114122A|1996-03-26|2000-09-05|Affymetrix, Inc.|Fluidics station with a mounting system and method of using|

---

US5844238A|1996-03-27|1998-12-01|David Sarnoff Research Center, Inc.|Infrared imager using room temperature capacitance sensor|

---

US7244622B2|1996-04-03|2007-07-17|Applera Corporation|Device and method for multiple analyte detection|

---

US7235406B1|1996-04-03|2007-06-26|Applera Corporation|Nucleic acid analysis device|

---

US5788814A|1996-04-09|1998-08-04|David Sarnoff Research Center|Chucks and methods for positioning multiple objects on a substrate|

---

JP3898228B2|1996-04-12|2007-03-28|ザパブリックヘルスリサーチインスティチュートオブザシティーオブニューヨークインク|Detection probes, kits and assays|

---

US6399023B1|1996-04-16|2002-06-04|Caliper Technologies Corp.|Analytical system and method|

---

US5671303A|1996-04-17|1997-09-23|Motorola, Inc.|Molecular detection apparatus and method using optical waveguide detection|

---

US5948363A|1996-04-22|1999-09-07|Gaillard; Patrick|Micro-well strip with print tabs|

---

US6001307A|1996-04-26|1999-12-14|Kyoto Daiichi Kagaku Co., Ltd.|Device for analyzing a sample|

---

US6221672B1|1996-04-30|2001-04-24|Medtronic, Inc.|Method for determining platelet inhibitor response|

---

US6054277A|1996-05-08|2000-04-25|Regents Of The University Of Minnesota|Integrated microchip genetic testing system|

---

US6180950B1|1996-05-14|2001-01-30|Don Olsen|Micro heating apparatus for synthetic fibers|

---

JP3682302B2|1996-05-20|2005-08-10|プレシジョン・システム・サイエンス株式会社|Method and apparatus for controlling magnetic particles by dispenser|

---

US6083762A|1996-05-31|2000-07-04|Packard Instruments Company|Microvolume liquid handling system|

---

US5726404A|1996-05-31|1998-03-10|University Of Washington|Valveless liquid microswitch|

---

DE69735313T2|1996-06-04|2006-11-02|University Of Utah Research Foundation, Salt Lake City|Fluorescence donor-acceptor pair|

---

US5912124A|1996-06-14|1999-06-15|Sarnoff Corporation|Padlock probe detection|

---

US5863801A|1996-06-14|1999-01-26|Sarnoff Corporation|Automated nucleic acid isolation|

---

US5939291A|1996-06-14|1999-08-17|Sarnoff Corporation|Microfluidic method for nucleic acid amplification|

---

US5914229A|1996-06-14|1999-06-22|Sarnoff Corporation|Method for amplifying a polynucleotide|

---

WO1997048818A1|1996-06-17|1997-12-24|The Board Of Trustees Of The Leland Stanford Junior University|Thermocycling apparatus and method|

---

US5942443A|1996-06-28|1999-08-24|Caliper Technologies Corporation|High throughput screening assay systems in microscale fluidic devices|

---

US5779868A|1996-06-28|1998-07-14|Caliper Technologies Corporation|Electropipettor and compensation means for electrophoretic bias|

---

NZ333345A|1996-06-28|2000-09-29|Caliper Techn Corp|Electropipettor and compensation for electrophoretic bias during electroosmotic microfluid transport|

---

JP3788519B2|1996-06-28|2006-06-21|カリパー・ライフ・サイエンシズ・インコーポレーテッド|High-throughput screening assay system for microscale fluid devices|

---

US5800690A|1996-07-03|1998-09-01|Caliper Technologies Corporation|Variable control of electroosmotic and/or electrophoretic forces within a fluid-containing structure via electrical forces|

---

US5699157A|1996-07-16|1997-12-16|Caliper Technologies Corp.|Fourier detection of species migrating in a microchannel|

---

US5866336A|1996-07-16|1999-02-02|Oncor, Inc.|Nucleic acid amplification oligonucleotides with molecular energy transfer labels and methods based thereon|

---

US6074827A|1996-07-30|2000-06-13|Aclara Biosciences, Inc.|Microfluidic method for nucleic acid purification and processing|

---

US5770029A|1996-07-30|1998-06-23|Soane Biosciences|Integrated electrophoretic microdevices|

---

US5804436A|1996-08-02|1998-09-08|Axiom Biotechnologies, Inc.|Apparatus and method for real-time measurement of cellular response|

---

US6280967B1|1996-08-02|2001-08-28|Axiom Biotechnologies, Inc.|Cell flow apparatus and method for real-time of cellular responses|

---

US6558916B2|1996-08-02|2003-05-06|Axiom Biotechnologies, Inc.|Cell flow apparatus and method for real-time measurements of patient cellular responses|

---

US5935401A|1996-09-18|1999-08-10|Aclara Biosciences|Surface modified electrophoretic chambers|

---

US5872623A|1996-09-26|1999-02-16|Sarnoff Corporation|Massively parallel detection|

---

US5858187A|1996-09-26|1999-01-12|Lockheed Martin Energy Systems, Inc.|Apparatus and method for performing electrodynamic focusing on a microchip|

---

US6110343A|1996-10-04|2000-08-29|Lockheed Martin Energy Research Corporation|Material transport method and apparatus|

---

WO1998016527A1|1996-10-15|1998-04-23|Fujisawa Pharmaceutical Co., Ltd.|Benzoxepine derivatives which promote release of growth hormone|

---

US6500390B1|1996-10-17|2002-12-31|David A. Boulton|Method for sealing and venting a microplate assembly|

---

US5874046A|1996-10-30|1999-02-23|Raytheon Company|Biological warfare agent sensor system employing ruthenium-terminated oligonucleotides complementary to target live agent DNA sequences|

---

US6133436A|1996-11-06|2000-10-17|Sequenom, Inc.|Beads bound to a solid support and to nucleic acids|

---

USD421653S|1996-11-18|2000-03-14|Tekmar Company|Housing for a laboratory instrument|

---

DE19749011A1|1996-11-19|1998-05-20|Lang Volker|Micro=valve for one time use has opening closed by plug mounted on resistance plate|

---

US6447727B1|1996-11-19|2002-09-10|Caliper Technologies Corp.|Microfluidic systems|

---

US6465257B1|1996-11-19|2002-10-15|Caliper Technologies Corp.|Microfluidic systems|

---

CA2276251A1|1996-11-20|1998-05-28|The Regents Of The University Of Michigan|Microfabricated isothermal nucleic acid amplification devices and methods|

---

US5772966A|1997-01-24|1998-06-30|Maracas; George N.|Assay dispensing apparatus|

---

USD399959S|1997-01-24|1998-10-20|Abbott Laboratories|Housing for a device for measuring the concentration of an analyte in a sample of blood|

---

USD414271S|1997-02-03|1999-09-21|Eli Lilly And Company|Reaction vessel for combining chemicals|

---

US5972694A|1997-02-11|1999-10-26|Mathus; Gregory|Multi-well plate|

---

DE19707226A1|1997-02-24|1998-08-27|Bodenseewerk Perkin Elmer Co|Light scanner|

---

US5882496A|1997-02-27|1999-03-16|The Regents Of The University Of California|Porous silicon structures with high surface area/specific pore size|

---

US5958349A|1997-02-28|1999-09-28|Cepheid|Reaction vessel for heat-exchanging chemical processes|

---

DK2333520T3|1997-02-28|2014-09-29|Cepheid|Heat-exchanging, requested chemical reaction device|

---

US7255833B2|2000-07-25|2007-08-14|Cepheid|Apparatus and reaction vessel for controlling the temperature of a sample|

---

CA2574107C|1997-02-28|2011-08-16|Cepheid|Heat exchanging, optically interrogated chemical reaction assembly|

---

US6369893B1|1998-05-19|2002-04-09|Cepheid|Multi-channel optical detection system|

---

US5911737A|1997-02-28|1999-06-15|The Regents Of The University Of California|Microfabricated therapeutic actuators|

---

US5861563A|1997-03-20|1999-01-19|Bayer Corporation|Automatic closed tube sampler|

---

US5964997A|1997-03-21|1999-10-12|Sarnoff Corporation|Balanced asymmetric electronic pulse patterns for operating electrode-based pumps|

---

US5747666A|1997-03-26|1998-05-05|Willis; John P.|Point-of-care analyzer module|

---

US6235471B1|1997-04-04|2001-05-22|Caliper Technologies Corp.|Closed-loop biochemical analyzers|

---

US5964995A|1997-04-04|1999-10-12|Caliper Technologies Corp.|Methods and systems for enhanced fluid transport|

---

US6391622B1|1997-04-04|2002-05-21|Caliper Technologies Corp.|Closed-loop biochemical analyzers|

---

US5993750A|1997-04-11|1999-11-30|Eastman Kodak Company|Integrated ceramic micro-chemical plant|

---

US5885470A|1997-04-14|1999-03-23|Caliper Technologies Corporation|Controlled fluid transport in microfabricated polymeric substrates|

---

DE19717085C2|1997-04-23|1999-06-17|Bruker Daltonik Gmbh|Processes and devices for extremely fast DNA multiplication using polymerase chain reactions |

---

CN1105914C|1997-04-25|2003-04-16|卡钳技术有限公司|Microfluidic devices incorporating improved channel geometries|

---

US5976336A|1997-04-25|1999-11-02|Caliper Technologies Corp.|Microfluidic devices incorporating improved channel geometries|

---

US5997708A|1997-04-30|1999-12-07|Hewlett-Packard Company|Multilayer integrated assembly having specialized intermediary substrate|

---

DK1216754T3|1997-05-02|2005-03-14|Gen Probe Inc|Reactor Unit|

---

AU7477398A|1997-05-09|1998-11-27|Regents Of The University Of California, The|Peltier-assisted microfabricated reaction chambers for thermal cycling|

---

US5944717A|1997-05-12|1999-08-31|The Regents Of The University Of California|Micromachined electrical cauterizer|

---

US6106685A|1997-05-13|2000-08-22|Sarnoff Corporation|Electrode combinations for pumping fluids|

---

US5980719A|1997-05-13|1999-11-09|Sarnoff Corporation|Electrohydrodynamic receptor|

---

US6861035B2|1998-02-24|2005-03-01|Aurora Discovery, Inc.|Multi-well platforms, caddies, lids and combinations thereof|

---

JP3937107B2|1997-05-23|2007-06-27|東拓工業株式会社|Bell mouth for annular corrugated tube|

---

WO1998053311A2|1997-05-23|1998-11-26|Gamera Bioscience Corporation|Devices and methods for using centripetal acceleration to drive fluid movement in a microfluidics system|

---

CA2291854A1|1997-06-09|1998-12-17|Steven A. Sundberg|Apparatus and methods for correcting for variable velocity in microfluidic systems|

---

EP0884104B1|1997-06-09|2005-10-12|F. Hoffmann-La Roche Ag|Disposable process device|

---

US5869004A|1997-06-09|1999-02-09|Caliper Technologies Corp.|Methods and apparatus for in situ concentration and/or dilution of materials in microfluidic systems|

---

US6190619B1|1997-06-11|2001-02-20|Argonaut Technologies, Inc.|Systems and methods for parallel synthesis of compounds|

---

US5882465A|1997-06-18|1999-03-16|Caliper Technologies Corp.|Method of manufacturing microfluidic devices|

---

US5900130A|1997-06-18|1999-05-04|Alcara Biosciences, Inc.|Method for sample injection in microchannel device|

---

US6425972B1|1997-06-18|2002-07-30|Calipher Technologies Corp.|Methods of manufacturing microfabricated substrates|

---

US5959291A|1997-06-27|1999-09-28|Caliper Technologies Corporation|Method and apparatus for measuring low power signals|

---

JP3191150B2|1997-06-30|2001-07-23|株式会社アステックコーポレーション|Blood collection tube rack|

---

US5928161A|1997-07-03|1999-07-27|The Regents Of The University Of California|Microbiopsy/precision cutting devices|

---

US6001231A|1997-07-15|1999-12-14|Caliper Technologies Corp.|Methods and systems for monitoring and controlling fluid flow rates in microfluidic systems|

---

US5985217A|1997-07-17|1999-11-16|The Regents Of The University Of California|Microfabricated instrument for tissue biopsy and analysis|

---

US5932799A|1997-07-21|1999-08-03|Ysi Incorporated|Microfluidic analyzer module|

---

US5827481A|1997-07-31|1998-10-27|Hewlett-Packard Company|Cartridge system for effecting sample acquisition and introduction|

---

US5876675A|1997-08-05|1999-03-02|Caliper Technologies Corp.|Microfluidic devices and systems|

---

US5919711A|1997-08-07|1999-07-06|Careside, Inc.|Analytical cartridge|

---

US5916522A|1997-08-07|1999-06-29|Careside, Inc.|Electrochemical analytical cartridge|

---

US6156199A|1997-08-11|2000-12-05|Zuk, Jr.; Peter|Centrifugal filtration apparatus|

---

EP1003759A2|1997-08-13|2000-05-31|Cepheid|Microstructures for the manipulation of fluid samples|

---

AU4437702A|1997-08-13|2002-07-11|Cepheid|Microstructures for the manipulation of fluid samples|

---

US7914994B2|1998-12-24|2011-03-29|Cepheid|Method for separating an analyte from a sample|

---

AU4437602A|1997-08-13|2002-07-11|Cepheid|Microstructures for the manipulation of fluid samples|

---

US6368871B1|1997-08-13|2002-04-09|Cepheid|Non-planar microstructures for manipulation of fluid samples|

---

US5916776A|1997-08-27|1999-06-29|Sarnoff Corporation|Amplification method for a polynucleotide|

---

US5989402A|1997-08-29|1999-11-23|Caliper Technologies Corp.|Controller/detector interfaces for microfluidic systems|

---

AU746098B2|1997-09-02|2002-04-18|Caliper Life Sciences, Inc.|Microfluidic system with electrofluidic and electrothermal controls|

---

US5965410A|1997-09-02|1999-10-12|Caliper Technologies Corp.|Electrical current for controlling fluid parameters in microchannels|

---

US6174675B1|1997-11-25|2001-01-16|Caliper Technologies Corp.|Electrical current for controlling fluid parameters in microchannels|

---

US6597450B1|1997-09-15|2003-07-22|Becton, Dickinson And Company|Automated Optical Reader for Nucleic Acid Assays|

---

EP1019696A4|1997-09-19|2003-07-23|Aclara Biosciences Inc|Apparatus and method for transferring liquids|

---

US20020092767A1|1997-09-19|2002-07-18|Aclara Biosciences, Inc.|Multiple array microfluidic device units|

---

US5961925A|1997-09-22|1999-10-05|Bristol-Myers Squibb Company|Apparatus for synthesis of multiple organic compounds with pinch valve block|

---

US5993611A|1997-09-24|1999-11-30|Sarnoff Corporation|Capacitive denaturation of nucleic acid|

---

US6012902A|1997-09-25|2000-01-11|Caliper Technologies Corp.|Micropump|

---

DE69839294T2|1997-09-29|2009-04-09|F. Hoffmann-La Roche Ag|Apparatus for depositing magnetic particles|

---

WO1999018438A1|1997-10-02|1999-04-15|Aclara Biosciences, Inc.|Capillary assays involving separation of free and bound species|

---

US5842787A|1997-10-09|1998-12-01|Caliper Technologies Corporation|Microfluidic systems incorporating varied channel dimensions|

---

WO1999019717A1|1997-10-15|1999-04-22|Aclara Biosciences, Inc.|Laminate microstructure device and method for making same|

---

US5958694A|1997-10-16|1999-09-28|Caliper Technologies Corp.|Apparatus and methods for sequencing nucleic acids in microfluidic systems|

---

US6132684A|1997-10-31|2000-10-17|Becton Dickinson And Company|Sample tube holder|

---

US6287831B1|1997-11-14|2001-09-11|California Institute Of Technology|Cell lysis device|

---

JP4163382B2|1997-11-14|2008-10-08|ジェン−プローブ・インコーポレイテッド|Assay workstation|

---

DE59810859D1|1997-11-19|2004-04-01|Inoex Gmbh|DEVICE FOR ERROR DETECTION AND / OR WALL THICKNESS MEASUREMENT IN CONTINUOUS TAPES OR TUBES MADE OF PLASTIC WITH ULTRASONIC SIGNALS|

---

US5992820A|1997-11-19|1999-11-30|Sarnoff Corporation|Flow control in microfluidics devices by controlled bubble formation|

---

US6123205A|1997-11-26|2000-09-26|Bayer Corporation|Sample tube rack|

---

USD413677S|1997-11-26|1999-09-07|Bayer Corporation|Sample tube rack|

---

US6197503B1|1997-11-26|2001-03-06|Ut-Battelle, Llc|Integrated circuit biochip microsystem containing lens|

---

US6258264B1|1998-04-10|2001-07-10|Transgenomic, Inc.|Non-polar media for polynucleotide separations|

---

US6914137B2|1997-12-06|2005-07-05|Dna Research Innovations Limited|Isolation of nucleic acids|

---

ES2301581T3|1997-12-06|2008-07-01|Invitrogen Corporation|ISOLATION OF NUCLEIC ACIDS.|

---

US6074725A|1997-12-10|2000-06-13|Caliper Technologies Corp.|Fabrication of microfluidic circuits by printing techniques|

---

US5948227A|1997-12-17|1999-09-07|Caliper Technologies Corp.|Methods and systems for performing electrophoretic molecular separations|

---

WO1999033559A1|1997-12-24|1999-07-08|Cepheid|Integrated fluid manipulation cartridge|

---

US6887693B2|1998-12-24|2005-05-03|Cepheid|Device and method for lysing cells, spores, or microorganisms|

---

WO1999034205A1|1997-12-30|1999-07-08|Caliper Technologies Corp.|Software for the display of chromatographic separation data|

---

US6167910B1|1998-01-20|2001-01-02|Caliper Technologies Corp.|Multi-layer microfluidic devices|

---

JP3551293B2|1998-02-02|2004-08-04|東洋紡績株式会社|Nucleic acid extraction device|

---

USD413391S|1998-02-05|1999-08-31|Bayer Corporation|Test tube sample rack|

---

US6420143B1|1998-02-13|2002-07-16|Caliper Technologies Corp.|Methods and systems for performing superheated reactions in microscale fluidic systems|

---

US6756019B1|1998-02-24|2004-06-29|Caliper Technologies Corp.|Microfluidic devices and systems incorporating cover layers|

---

US6537432B1|1998-02-24|2003-03-25|Target Discovery, Inc.|Protein separation via multidimensional electrophoresis|

---

US6251343B1|1998-02-24|2001-06-26|Caliper Technologies Corp.|Microfluidic devices and systems incorporating cover layers|

---

US6100541A|1998-02-24|2000-08-08|Caliper Technologies Corporation|Microfluidic devices and systems incorporating integrated optical elements|

---

USD417009S|1998-03-02|1999-11-23|Bayer Corporation|Sample tube rack|

---

WO1999045146A1|1998-03-05|1999-09-10|Johnson & Johnson Research Pty. Ltd.|Zymogenic nucleic acid detection methods, and related molecules and kits|

---

USD428497S|1998-03-06|2000-07-18|Bayer Corporation|Test tube sample rack|

---

AU764319B2|1998-03-17|2003-08-14|Cepheid|Chemical processing device|

---

WO1999047255A1|1998-03-17|1999-09-23|Cepheid|Unitary chemical processing device|

---

US6979424B2|1998-03-17|2005-12-27|Cepheid|Integrated sample analysis device|

---

US7188001B2|1998-03-23|2007-03-06|Cepheid|System and method for temperature control|

---

AU1357102A|1998-03-23|2002-03-14|Cepheid|Multi-site reactor system with dynamic independent control of indvidual reaction sites|

---

JPH11295323A|1998-04-13|1999-10-29|Matsushita Electric Ind Co Ltd|Automatic dispenser and its method|

---

US6024920A|1998-04-21|2000-02-15|Bio-Rad Laboratories, Inc.|Microplate scanning read head|

---

EP2316570A3|1998-05-01|2011-07-27|Gen-Probe Incorporated|Automated diagnostic analyzer and method|

---

US6123798A|1998-05-06|2000-09-26|Caliper Technologies Corp.|Methods of fabricating polymeric structures incorporating microscale fluidic elements|

---

JPH11316226A|1998-05-06|1999-11-16|Olympus Optical Co Ltd|Cartridge for automatic measurement and automatic measuring method|

---

EP2315002A3|1998-05-16|2012-12-05|Life Technologies Corporation|Filter module for an optical instrument used in particular for monitoring DNA polymerase chain reactions|

---

US7635588B2|2001-11-29|2009-12-22|Applied Biosystems, Llc|Apparatus and method for differentiating multiple fluorescence signals by excitation wavelength|

---

US6818437B1|1998-05-16|2004-11-16|Applera Corporation|Instrument for monitoring polymerase chain reaction of DNA|

---

EP0964555A1|1998-06-04|1999-12-15|Siemens Aktiengesellschaft|Threshold control and adaptive filtering in CAP receivers|

---

US6274089B1|1998-06-08|2001-08-14|Caliper Technologies Corp.|Microfluidic devices, systems and methods for performing integrated reactions and separations|

---

US6306590B1|1998-06-08|2001-10-23|Caliper Technologies Corp.|Microfluidic matrix localization apparatus and methods|

---

US6149882A|1998-06-09|2000-11-21|Symyx Technologies, Inc.|Parallel fixed bed reactor and fluid contacting apparatus|

---

USD421130S|1998-06-15|2000-02-22|Bayer Corporation|Sample tube rack|

---

US7799521B2|1998-06-24|2010-09-21|Chen & Chen, Llc|Thermal cycling|

---

US6375901B1|1998-06-29|2002-04-23|Agilent Technologies, Inc.|Chemico-mechanical microvalve and devices comprising the same|

---

US6787111B2|1998-07-02|2004-09-07|Amersham Biosciences Corp.|Apparatus and method for filling and cleaning channels and inlet ports in microchips used for biological analysis|

---

USD420747S|1998-07-10|2000-02-15|Bayer Corporation|Sample tube rack|

---

DE19833087A1|1998-07-23|2000-01-27|Bosch Gmbh Robert|Gas sensor for vehicle engine; has measuring electrode comprising platinum base with sintered porous layer and noble metal covering layer, applied in galvanic bath|

---

DE19833293C1|1998-07-24|2000-01-20|Gunther Botsch|Continuous separation apparatus for solids and gases from liquids, e.g. removal of magnetizable particles and air from water or fuel systems|

---

US6366924B1|1998-07-27|2002-04-02|Caliper Technologies Corp.|Distributed database for analytical instruments|

---

US6037130A|1998-07-28|2000-03-14|The Public Health Institute Of The City Of New York, Inc.|Wavelength-shifting probes and primers and their use in assays and kits|

---

AT303598T|1998-07-31|2005-09-15|Tecan Trading Ag|magnetic separator|

---

US6540896B1|1998-08-05|2003-04-01|Caliper Technologies Corp.|Open-Field serial to parallel converter|

---

US6316774B1|1998-08-18|2001-11-13|Molecular Devices Corporation|Optical system for a scanning fluorometer|

---

US6236456B1|1998-08-18|2001-05-22|Molecular Devices Corporation|Optical system for a scanning fluorometer|

---

US6740518B1|1998-09-17|2004-05-25|Clinical Micro Sensors, Inc.|Signal detection techniques for the detection of analytes|

---

USD439673S1|1998-10-06|2001-03-27|Sorenson Bioscience|Multi-well microcentrifuge tube|

---

JP2003517591A|1999-12-09|2003-05-27|モトローラ・インコーポレイテッド|Multilayer microfluidic device for reaction of analytical samples|

---

US6958392B2|1998-10-09|2005-10-25|Whatman, Inc.|Methods for the isolation of nucleic acids and for quantitative DNA extraction and detection for leukocyte evaluation in blood products|

---

US6572830B1|1998-10-09|2003-06-03|Motorola, Inc.|Integrated multilayered microfludic devices and methods for making the same|

---

US6875619B2|1999-11-12|2005-04-05|Motorola, Inc.|Microfluidic devices comprising biochannels|

---

US6296020B1|1998-10-13|2001-10-02|Biomicro Systems, Inc.|Fluid circuit components based upon passive fluid dynamics|

---

US6149787A|1998-10-14|2000-11-21|Caliper Technologies Corp.|External material accession systems and methods|

---

US6498497B1|1998-10-14|2002-12-24|Caliper Technologies Corp.|Microfluidic controller and detector system with self-calibration|

---

US6948843B2|1998-10-28|2005-09-27|Covaris, Inc.|Method and apparatus for acoustically controlling liquid solutions in microfluidic devices|

---

US6086740A|1998-10-29|2000-07-11|Caliper Technologies Corp.|Multiplexed microfluidic devices and systems|

---

US5973138A|1998-10-30|1999-10-26|Becton Dickinson And Company|Method for purification and manipulation of nucleic acids using paramagnetic particles|

---

EP2045337B1|1998-11-09|2011-08-24|Eiken Kagaku Kabushiki Kaisha|Process for synthesizing nucleic acid|

---

WO2000034521A1|1998-12-08|2000-06-15|Boston Probes, Inc.|Methods, kits and compositions for the identification of nucleic acids electrostatically bound to matrices|

---

JP2000180455A|1998-12-15|2000-06-30|Sanuki Kogyo Kk|Flow injection automatic analyzer|

---

US6062261A|1998-12-16|2000-05-16|Lockheed Martin Energy Research Corporation|MicrofluIdic circuit designs for performing electrokinetic manipulations that reduce the number of voltage sources and fluid reservoirs|

---

US6261431B1|1998-12-28|2001-07-17|Affymetrix, Inc.|Process for microfabrication of an integrated PCR-CE device and products produced by the same|

---

AT343425T|1999-01-08|2006-11-15|Applera Corp|FASERMATRIX FOR MEASURING CHEMICALS, AND METHOD FOR THE PRODUCTION AND USE THEREOF|

---

US6150119A|1999-01-19|2000-11-21|Caliper Technologies Corp.|Optimized high-throughput analytical system|

---

IT1306964B1|1999-01-19|2001-10-11|St Microelectronics Srl|CAPACITIVE BOOSTING CIRCUIT FOR REGULATION OF LINE VOLTAGE READING IN NON-VOLATILE MEMORIES|

---

US6416642B1|1999-01-21|2002-07-09|Caliper Technologies Corp.|Method and apparatus for continuous liquid flow in microscale channels using pressure injection, wicking, and electrokinetic injection|

---

US20020019059A1|1999-01-28|2002-02-14|Calvin Y.H. Chow|Devices, systems and methods for time domain multiplexing of reagents|

---

AU758309B2|1999-02-02|2003-03-20|Caliper Life Sciences, Inc.|Methods, devices and systems for characterizing proteins|

---

US6294063B1|1999-02-12|2001-09-25|Board Of Regents, The University Of Texas System|Method and apparatus for programmable fluidic processing|

---

DE60044490D1|1999-02-23|2010-07-15|Caliper Life Sciences Inc|MANIPULATION OF MICROTEILS IN MICROFLUID SYSTEMS|

---

US6143547A|1999-03-02|2000-11-07|Academia Sinica|Cell line derived from Penaeus monodon and a method of growing virus using the same|

---

US6749814B1|1999-03-03|2004-06-15|Symyx Technologies, Inc.|Chemical processing microsystems comprising parallel flow microreactors and methods for using same|

---

US6326083B1|1999-03-08|2001-12-04|Calipher Technologies Corp.|Surface coating for microfluidic devices that incorporate a biopolymer resistant moiety|

---

US6558945B1|1999-03-08|2003-05-06|Aclara Biosciences, Inc.|Method and device for rapid color detection|

---

US6171850B1|1999-03-08|2001-01-09|Caliper Technologies Corp.|Integrated devices and systems for performing temperature controlled reactions and analyses|

---

US6148508A|1999-03-12|2000-11-21|Caliper Technologies Corp.|Method of making a capillary for electrokinetic transport of materials|

---

JP2000266760A|1999-03-17|2000-09-29|Hitachi Ltd|Dispenser|

---

EP1041386B1|1999-03-25|2007-10-17|Tosoh Corporation|Analyzer|

---

JP3988306B2|1999-03-25|2007-10-10|東ソー株式会社|Automatic measuring device|

---

US6500323B1|1999-03-26|2002-12-31|Caliper Technologies Corp.|Methods and software for designing microfluidic devices|

---

US6194563B1|1999-03-26|2001-02-27|Vysis, Inc.|Solid phase nucleic acid labeling by transamination|

---

US6783962B1|1999-03-26|2004-08-31|Upfront Chromatography|Particulate material for purification of bio-macromolecules|

---

US6303343B1|1999-04-06|2001-10-16|Caliper Technologies Corp.|Inefficient fast PCR|

---

US6306273B1|1999-04-13|2001-10-23|Aclara Biosciences, Inc.|Methods and compositions for conducting processes in microfluidic devices|

---

US6322683B1|1999-04-14|2001-11-27|Caliper Technologies Corp.|Alignment of multicomponent microfabricated structures|

---

US6942771B1|1999-04-21|2005-09-13|Clinical Micro Sensors, Inc.|Microfluidic systems in the electrochemical detection of target analytes|

---

CA2270106C|1999-04-23|2006-03-14|Yousef Haj-Ahmad|Nucleic acid purification and process|

---

US6773676B2|1999-04-27|2004-08-10|Agilent Technologies, Inc.|Devices for performing array hybridization assays and methods of using the same|

---

WO2000065352A1|1999-04-28|2000-11-02|Eidgenossisch Technische Hochschule Zurich|Polyionic coatings in analytic and sensor devices|

---

US6902703B2|1999-05-03|2005-06-07|Ljl Biosystems, Inc.|Integrated sample-processing system|

---

US6458259B1|1999-05-11|2002-10-01|Caliper Technologies Corp.|Prevention of surface adsorption in microchannels by application of electric current during pressure-induced flow|

---

US6555389B1|1999-05-11|2003-04-29|Aclara Biosciences, Inc.|Sample evaporative control|

---

US6838680B2|1999-05-12|2005-01-04|Aclara Biosciences, Inc.|Multiplexed fluorescent detection in microfluidic devices|

---

US6399952B1|1999-05-12|2002-06-04|Aclara Biosciences, Inc.|Multiplexed fluorescent detection in microfluidic devices|

---

US6326147B1|1999-05-13|2001-12-04|The Perkin-Elmer Corporation|Methods, apparatus, articles of manufacture, and user interfaces for performing automated biological assay preparation and macromolecule purification|

---

US6310199B1|1999-05-14|2001-10-30|Promega Corporation|pH dependent ion exchange matrix and method of use in the isolation of nucleic acids|

---

US7078224B1|1999-05-14|2006-07-18|Promega Corporation|Cell concentration and lysate clearance using paramagnetic particles|

---

CA2373347A1|1999-05-17|2000-11-23|Caliper Technologies Corporation|Focusing of microparticles in microfluidic systems|

---

US6592821B1|1999-05-17|2003-07-15|Caliper Technologies Corp.|Focusing of microparticles in microfluidic systems|

---

US6287774B1|1999-05-21|2001-09-11|Caliper Technologies Corp.|Assay methods and system|

---

US6472141B2|1999-05-21|2002-10-29|Caliper Technologies Corp.|Kinase assays using polycations|

---

US6277607B1|1999-05-24|2001-08-21|Sanjay Tyagi|High specificity primers, amplification methods and kits|

---

US20040200909A1|1999-05-28|2004-10-14|Cepheid|Apparatus and method for cell disruption|

---

ES2272289T5|1999-05-28|2011-10-21|Cepheid|CARTRIDGE TO PERFORM A CHEMICAL REACTION.|

---

DE60014676T2|1999-05-28|2005-11-17|Cepheid, Sunnyvale|DEVICE AND METHOD FOR THE ANALYSIS OF LIQUID SAMPLES|

---

WO2001012325A1|1999-05-28|2001-02-22|Bio/Data Corporation|Method and apparatus for directly sampling a fluid for microfiltration|

---

DE29909529U1|1999-06-01|1999-08-12|Festo Ag & Co|Fluid control unit|

---

AU5291600A|1999-06-01|2000-12-18|Caliper Technologies Corporation|Microscale assays and microfluidic devices for transporter, gradient induced, and binding activities|

---

FR2795426A1|1999-06-22|2000-12-29|Commissariat Energie Atomique|Support for genetic analysis comprising reservoir for a medium to be analyzed connected by passage having temperature control device to a test strip with analysis sites having biological probes|

---

US6811668B1|1999-06-22|2004-11-02|Caliper Life Sciences, Inc.|Apparatus for the operation of a microfluidic device|

---

US6706519B1|1999-06-22|2004-03-16|Tecan Trading Ag|Devices and methods for the performance of miniaturized in vitro amplification assays|

---

CN100402850C|1999-06-28|2008-07-16|加利福尼亚技术学院|Microfabricated elastomeric valve and pump systems|

---

US7306672B2|2001-04-06|2007-12-11|California Institute Of Technology|Microfluidic free interface diffusion techniques|

---

AU6068300A|1999-07-06|2001-01-22|Caliper Technologies Corporation|Microfluidic systems and methods for determining modulator kinetics|

---

US6353475B1|1999-07-12|2002-03-05|Caliper Technologies Corp.|Light source power modulation for use with chemical and biochemical analysis|

---

AU777180B2|1999-07-19|2004-10-07|Organon Teknika B.V.|Device and method for mixing magnetic particles with a fluid|

---

US20040053290A1|2000-01-11|2004-03-18|Terbrueggen Robert Henry|Devices and methods for biochip multiplexing|

---

USD438311S1|1999-07-28|2001-02-27|Matsushita Electric Industrial Co.,Ltd.|Strip for blood test|

---

US6337435B1|1999-07-30|2002-01-08|Bio-Rad Laboratories, Inc.|Temperature control for multi-vessel reaction apparatus|

---

US6818060B2|1999-08-02|2004-11-16|Emerald Biostructures, Inc.|Robot for mixing crystallization trial matrices|

---

US6524456B1|1999-08-12|2003-02-25|Ut-Battelle, Llc|Microfluidic devices for the controlled manipulation of small volumes|

---

EP1077086B1|1999-08-18|2004-10-27|Becton Dickinson and Company|Stopper-shield assembly|

---

US6495104B1|1999-08-19|2002-12-17|Caliper Technologies Corp.|Indicator components for microfluidic systems|

---

WO2001014931A1|1999-08-23|2001-03-01|Mitsubishi Chemical Corporation|Photopolymerizable composition and photopolymerizable lithographic plate|

---

US6858185B1|1999-08-25|2005-02-22|Caliper Life Sciences, Inc.|Dilutions in high throughput systems with a single vacuum source|

---

US6613581B1|1999-08-26|2003-09-02|Caliper Technologies Corp.|Microfluidic analytic detection assays, devices, and integrated systems|

---

US6824663B1|1999-08-27|2004-11-30|Aclara Biosciences, Inc.|Efficient compound distribution in microfluidic devices|

---

US6613211B1|1999-08-27|2003-09-02|Aclara Biosciences, Inc.|Capillary electrokinesis based cellular assays|

---

US6633785B1|1999-08-31|2003-10-14|Kabushiki Kaisha Toshiba|Thermal cycler and DNA amplifier method|

---

WO2001017797A1|1999-09-10|2001-03-15|Caliper Technologies Corp.|Microfabrication methods and devices|

---

US6906797B1|1999-09-13|2005-06-14|Aclara Biosciences, Inc.|Side light activated microfluid channels|

---

USD466219S1|1999-09-13|2002-11-26|Micronic B.V.|Carrier for test-tubes|

---

DE19945604A1|1999-09-23|2003-08-07|Aclara Biosciences Inc|Method of joining workpieces made of plastic and its use in microstructure and nanostructure technology|

---

WO2001027253A1|1999-10-08|2001-04-19|Caliper Technologies Corp.|Use of nernstein voltage sensitive dyes in measuring transmembrane voltage|

---

US6221600B1|1999-10-08|2001-04-24|Board Of Regents, The University Of Texas System|Combinatorial oligonucleotide PCR: a method for rapid, global expression analysis|

---

DE19948473A1|1999-10-08|2001-04-12|Nmi Univ Tuebingen|Method and device for measuring cells in a liquid environment|

---

US6272939B1|1999-10-15|2001-08-14|Applera Corporation|System and method for filling a substrate with a liquid sample|

---

US6232072B1|1999-10-15|2001-05-15|Agilent Technologies, Inc.|Biopolymer array inspection|

---

US6908594B1|1999-10-22|2005-06-21|Aclara Biosciences, Inc.|Efficient microfluidic sealing|

---

USD461906S1|1999-10-25|2002-08-20|Tuan Hung Pham|Diagnostic test card|

---

GB2355717A|1999-10-28|2001-05-02|Amersham Pharm Biotech Uk Ltd|DNA isolation method|

---

US6300124B1|1999-11-02|2001-10-09|Regents Of The University Of Minnesota|Device and method to directly control the temperature of microscope slides|

---

US6287254B1|1999-11-02|2001-09-11|W. Jean Dodds|Animal health diagnosis|

---

US20040043479A1|2000-12-11|2004-03-04|Briscoe Cynthia G.|Multilayerd microfluidic devices for analyte reactions|

---

USD438632S1|1999-12-21|2001-03-06|Compucyte Corporation|Multi-well reagent cartridge for treating a sample|

---

USD438633S1|1999-12-21|2001-03-06|Compucyte Corporation|Reagent cartridge for treating a sample|

---

DE60042370D1|1999-12-21|2009-07-23|Ortho Clinical Diagnostics Inc|DETECTION OF NUCLEIC ACIDS|

---

US6936414B2|1999-12-22|2005-08-30|Abbott Laboratories|Nucleic acid isolation method and kit|

---

US6699713B2|2000-01-04|2004-03-02|The Regents Of The University Of California|Polymerase chain reaction system|

---

US6620625B2|2000-01-06|2003-09-16|Caliper Technologies Corp.|Ultra high throughput sampling and analysis systems and methods|

---

EP1244810B1|2000-01-06|2008-02-20|Caliper Life Sciences, Inc.|Methods and systems for monitoring intracellular binding reactions|

---

US6468761B2|2000-01-07|2002-10-22|Caliper Technologies, Corp.|Microfluidic in-line labeling method for continuous-flow protease inhibition analysis|

---

WO2001054813A2|2000-01-11|2001-08-02|Clinical Micro Sensors, Inc.|Devices and methods for biochip multiplexing|

---

US6790328B2|2000-01-12|2004-09-14|Ut-Battelle, Llc|Microfluidic device and method for focusing, segmenting, and dispensing of a fluid stream|

---

US7037416B2|2000-01-14|2006-05-02|Caliper Life Sciences, Inc.|Method for monitoring flow rate using fluorescent markers|

---

JP3397737B2|2000-01-24|2003-04-21|倉敷紡績株式会社|Nucleic acid extraction method|

---

US6556923B2|2000-01-26|2003-04-29|Caliper Technologies Corp.|Software for high throughput microfluidic systems|

---

JP2004508919A|2000-05-24|2004-03-25|セルラー　プロセス　ケミストリー　インコーポレイテッド|Modular chemical production system incorporating microreactor|

---

US6589729B2|2000-02-04|2003-07-08|Caliper Technologies Corp.|Methods, devices, and systems for monitoring time dependent reactions|

---

US6685813B2|2000-02-11|2004-02-03|Aclara Biosciences, Inc.|Tandem isotachophoresis/zone electrophoresis method and system|

---

AT445155T|2000-02-11|2009-10-15|Aclara Biosciences Inc|MICROFLUIDIC DEVICE WITH A LIQUID SAMPLE INJECTION DEVICE AND USE METHOD|

---

US7332271B2|2000-02-18|2008-02-19|Board Of Trustees Of The Leland Stanford Junior University|Apparatus and methods for parallel processing of micro-volume liquid reactions|

---

JP3750460B2|2000-02-18|2006-03-01|日立工機株式会社|Dispensing device and dispensing method|

---

WO2001063270A1|2000-02-23|2001-08-30|Caliper Technologies, Inc.|Multi-reservoir pressure control system|

---

US7040144B2|2000-02-23|2006-05-09|Caliper Life Sciences, Inc.|Microfluidic viscometer|

---

US6681616B2|2000-02-23|2004-01-27|Caliper Technologies Corp.|Microfluidic viscometer|

---

AU4925301A|2000-03-17|2001-10-03|Aclara Biosciences Inc|Microfluidic device and system with improved sample handling|

---

US20020012971A1|2000-03-20|2002-01-31|Mehta Tammy Burd|PCR compatible nucleic acid sieving medium|

---

US6358387B1|2000-03-27|2002-03-19|Caliper Technologies Corporation|Ultra high throughput microfluidic analytical systems and methods|

---

US6927851B2|2000-03-31|2005-08-09|Neogen Corporation|Methods and apparatus to improve the sensitivity and reproducibility of bioluminescent analytical methods|

---

US6401552B1|2000-04-17|2002-06-11|Carlos D. Elkins|Centrifuge tube and method for collecting and dispensing mixed concentrated fluid samples|

---

US6733645B1|2000-04-18|2004-05-11|Caliper Technologies Corp.|Total analyte quantitation|

---

USD446306S1|2000-04-26|2001-08-07|Matsushita Electric Industrial Co., Ltd.|Medical information communication apparatus|

---

US6787016B2|2000-05-01|2004-09-07|Aclara Biosciences, Inc.|Dynamic coating with linear polymer mixture for electrophoresis|

---

DE60144278D1|2000-05-03|2011-05-05|Caliper Life Sciences Inc|MANUFACTURING PROCESSES FOR SUBSTRATES WITH MULTIPLE DEPTHS|

---

US7578976B1|2000-05-10|2009-08-25|Lawrence Livermore National Security, Llc|Sleeve reaction chamber system|

---

AU2001261541B2|2000-05-11|2004-10-14|Caliper Life Sciences, Inc.|Microfluidic devices and methods to regulate hydrodynamic and electrical resistance utilizing bulk viscosity enhancers|

---

AU6152301A|2000-05-12|2001-11-26|Caliper Techn Corp|Detection of nucleic acid hybridization by fluorescence polarization|

---

US6672458B2|2000-05-19|2004-01-06|Becton, Dickinson And Company|System and method for manipulating magnetically responsive particles fluid samples to collect DNA or RNA from a sample|

---

US6515753B2|2000-05-19|2003-02-04|Aclara Biosciences, Inc.|Optical alignment in capillary detection using capillary wall scatter|

---

ES2319101T3|2000-05-19|2009-05-04|Becton Dickinson And Company|SYSTEM AND PROCEDURE FOR MAGNETICALLY SENSITIVE PARTICLE HANDLING IN FLUID SAMPLES TO EXTRACT DNA OR RNA FROM A SAMPLE.|

---

US8323564B2|2004-05-14|2012-12-04|Honeywell International Inc.|Portable sample analyzer system|

---

US6520197B2|2000-06-02|2003-02-18|The Regents Of The University Of California|Continuous laminar fluid mixing in micro-electromechanical systems|

---

US7351376B1|2000-06-05|2008-04-01|California Institute Of Technology|Integrated active flux microfluidic devices and methods|

---

US6790330B2|2000-06-14|2004-09-14|Board Of Regents, The University Of Texas System|Systems and methods for cell subpopulation analysis|

---

WO2001097974A1|2000-06-19|2001-12-27|Caliper Technologies Corp.|Methods and devices for enhancing bonded substrate yields and regulating temperature|

---

US20030211517A1|2001-06-22|2003-11-13|Carulli John P.|Gp354 nucleic acids and polypeptides|

---

US6720187B2|2000-06-28|2004-04-13|3M Innovative Properties Company|Multi-format sample processing devices|

---

US7169618B2|2000-06-28|2007-01-30|Skold Technology|Magnetic particles and methods of producing coated magnetic particles|

---

US6734401B2|2000-06-28|2004-05-11|3M Innovative Properties Company|Enhanced sample processing devices, systems and methods|

---

AU8292001A|2000-07-19|2002-01-30|Genisphere Inc|Methods for detecting and assaying nucleic acid sequences|

---

JP4896349B2|2000-07-21|2012-03-14|アクララバイオサイエンシーズ，インコーポレイテッド|Methods and devices for capillary electrophoresis using a norbornene-based surface coating.|

---

FR2812088B1|2000-07-21|2003-01-24|Abx Sa|DEVICE FOR PROCESSING SAMPLES OF BLOOD PRODUCTS|

---

US7004184B2|2000-07-24|2006-02-28|The Reagents Of The University Of Michigan|Compositions and methods for liquid metering in microchannels|

---

US7169277B2|2000-08-02|2007-01-30|Caliper Life Sciences, Inc.|High throughput separations based analysis systems|

---

US20020142618A1|2000-08-04|2002-10-03|Caliper Technologies Corp.|Control of operation conditions within fluidic systems|

---

FR2813207B1|2000-08-28|2002-10-11|Bio Merieux|REACTIONAL CARD AND USE OF SUCH A CARD|

---

JP3993372B2|2000-09-13|2007-10-17|独立行政法人理化学研究所|Reactor manufacturing method|

---

AT448875T|2000-09-14|2009-12-15|Caliper Life Sciences Inc|MICROFLUIDIC DEVICES AND METHODS FOR CARRYING OUT TEMPERATURE-MEDIATED REACTIONS|

---

WO2002023163A1|2000-09-15|2002-03-21|California Institute Of Technology|Microfabricated crossflow devices and methods|

---

US6939451B2|2000-09-19|2005-09-06|Aclara Biosciences, Inc.|Microfluidic chip having integrated electrodes|

---

WO2002028532A2|2000-10-06|2002-04-11|Protasis Corporation|Microfluidic substrate assembly and method for making same|

---

US6623860B2|2000-10-10|2003-09-23|Aclara Biosciences, Inc.|Multilevel flow structures|

---

USD463031S1|2000-10-11|2002-09-17|Aclara Biosciences, Inc.|Microvolume sample plate|

---

GB2384309B8|2000-10-13|2016-03-02|Irm Llc|High throughput processing system and method of using|

---

US6375185B1|2000-10-20|2002-04-23|Gamemax Corporation|Paper currency receiving control assembly for currency-coin exchange machine|

---

DE60138824D1|2000-10-31|2009-07-09|Caliper Life Sciences Inc|MICROFLUIDIC PROCESS FOR IN-SITU MATERIAL CONCENTRATION|

---

US7514046B2|2000-10-31|2009-04-07|Caliper Life Sciences, Inc.|Methods and systems for processing microscale devices for reuse|

---

US7105304B1|2000-11-07|2006-09-12|Caliper Life Sciences, Inc.|Pressure-based mobility shift assays|

---

US8900811B2|2000-11-16|2014-12-02|Caliper Life Sciences, Inc.|Method and apparatus for generating thermal melting curves in a microfluidic device|

---

EP1345698A4|2000-11-16|2006-05-17|Fluidigm Corp|Microfluidic devices for introducing and dispensing fluids from microfluidic systems|

---

US20050202470A1|2000-11-16|2005-09-15|Caliper Life Sciences, Inc.|Binding assays using molecular melt curves|

---

CH695544A5|2000-11-17|2006-06-30|Tecan Trading Ag|Apparatus for dispensing or aspirating / dispensing liquid samples.|

---

USD468437S1|2000-11-21|2003-01-07|Acon Laboratories, Inc.|Test platform|

---

US6521188B1|2000-11-22|2003-02-18|Industrial Technology Research Institute|Microfluidic actuator|

---

SE0004296D0|2000-11-23|2000-11-23|Gyros Ab|Device and method for the controlled heating in micro channel systems|

---

US7024281B1|2000-12-11|2006-04-04|Callper Life Sciences, Inc.|Software for the controlled sampling of arrayed materials|

---

US6382254B1|2000-12-12|2002-05-07|Eastman Kodak Company|Microfluidic valve and method for controlling the flow of a liquid|

---

US6453928B1|2001-01-08|2002-09-24|Nanolab Ltd.|Apparatus, and method for propelling fluids|

---

JP4505776B2|2001-01-19|2010-07-21|凸版印刷株式会社|Gene detection system, gene detection apparatus equipped with the same, detection method, and gene detection chip|

---

JP3548858B2|2001-01-22|2004-07-28|独立行政法人産業技術総合研究所|Flow control method and microvalve used therefor|

---

US6878755B2|2001-01-22|2005-04-12|Microgen Systems, Inc.|Automated microfabrication-based biodetector|

---

EP1355823A4|2001-01-29|2005-04-20|Caliper Life Sciences Inc|Non-mechanical valves for fluidic systems|

---

US6692700B2|2001-02-14|2004-02-17|Handylab, Inc.|Heat-reduction methods and systems related to microfluidic devices|

---

US7670559B2|2001-02-15|2010-03-02|Caliper Life Sciences, Inc.|Microfluidic systems with enhanced detection systems|

---

US6509186B1|2001-02-16|2003-01-21|Institute Of Microelectronics|Miniaturized thermal cycler|

---

US6432695B1|2001-02-16|2002-08-13|Institute Of Microelectronics|Miniaturized thermal cycler|

---

US6720148B1|2001-02-22|2004-04-13|Caliper Life Sciences, Inc.|Methods and systems for identifying nucleotides by primer extension|

---

US7867776B2|2001-03-02|2011-01-11|Caliper Life Sciences, Inc.|Priming module for microfluidic chips|

---

US7150999B1|2001-03-09|2006-12-19|Califer Life Sciences, Inc.|Process for filling microfluidic channels|

---

CA2450676C|2001-03-09|2010-03-30|Biomicro Systems, Inc.|Method and system for microfluidic interfacing to arrays|

---

US6576459B2|2001-03-23|2003-06-10|The Regents Of The University Of California|Sample preparation and detection device for infectious agents|

---

US8895311B1|2001-03-28|2014-11-25|Handylab, Inc.|Methods and systems for control of general purpose microfluidic devices|

---

US7270786B2|2001-03-28|2007-09-18|Handylab, Inc.|Methods and systems for processing microfluidic samples of particle containing fluids|

---

US7192557B2|2001-03-28|2007-03-20|Handylab, Inc.|Methods and systems for releasing intracellular material from cells within microfluidic samples of fluids|

---

US7323140B2|2001-03-28|2008-01-29|Handylab, Inc.|Moving microdroplets in a microfluidic device|

---

US7829025B2|2001-03-28|2010-11-09|Venture Lending & Leasing Iv, Inc.|Systems and methods for thermal actuation of microfluidic devices|

---

US20140227710A1|2001-03-28|2014-08-14|Handylab, Inc.|Moving microdroplets in a microfluidic device|

---

US7010391B2|2001-03-28|2006-03-07|Handylab, Inc.|Methods and systems for control of microfluidic devices|

---

EP3427834A1|2001-07-26|2019-01-16|Handylab, Inc.|Methods and systems for microfluidic processing|

---

JP2002355038A|2001-03-29|2002-12-10|Japan Science & Technology Corp|Gene analysis method and analyzer therefor|

---

US20020143297A1|2001-03-30|2002-10-03|Becton, Dickinson And Company|Adaptor for use with point-of-care testing cartridge|

---

WO2002081729A2|2001-04-06|2002-10-17|California Institute Of Technology|Nucleic acid amplification utilizing microfluidic devices|

---

USD500142S1|2001-04-10|2004-12-21|Andrea Crisanti|Assay device|

---

USD470595S1|2001-04-10|2003-02-18|Andrea Crisanti|Assay device|

---

US7440684B2|2001-04-12|2008-10-21|Spaid Michael A|Method and apparatus for improved temperature control in microfluidic devices|

---

US20020155010A1|2001-04-24|2002-10-24|Karp Christoph D.|Microfluidic valve with partially restrained element|

---

US6588625B2|2001-04-24|2003-07-08|Abbott Laboratories|Sample handling system|

---

USD495805S1|2001-05-25|2004-09-07|Umedik, Inc.|Assay device|

---

US7723123B1|2001-06-05|2010-05-25|Caliper Life Sciences, Inc.|Western blot by incorporating an affinity purification zone|

---

US20020187557A1|2001-06-07|2002-12-12|Hobbs Steven E.|Systems and methods for introducing samples into microfluidic devices|

---

US7041068B2|2001-06-12|2006-05-09|Pelikan Technologies, Inc.|Sampling module device and method|

---

US6977163B1|2001-06-13|2005-12-20|Caliper Life Sciences, Inc.|Methods and systems for performing multiple reactions by interfacial mixing|

---

US6859698B2|2001-06-21|2005-02-22|Snap-On Incorporated|Detachable cartridge unit and auxiliary unit for function expansion of a data processing system|

---

US6709857B2|2001-06-26|2004-03-23|Becton, Dickinson And Company|System and method for optically monitoring the concentration of a gas in a sample vial using photothermal spectroscopy to detect sample growth|

---

US6514750B2|2001-07-03|2003-02-04|Pe Corporation |PCR sample handling device|

---

US6762049B2|2001-07-05|2004-07-13|Institute Of Microelectronics|Miniaturized multi-chamber thermal cycler for independent thermal multiplexing|

---

AU2002316302A1|2001-07-12|2003-01-29|Aclara Biosciences, Inc.|Submersible light-directing member for material excitation in microfluidic devices|

---

EP1952886B1|2001-07-16|2021-06-23|BioFire Defense, LLC|Thermal cycling system and method of use|

---

US7023007B2|2001-07-17|2006-04-04|Caliper Life Sciences, Inc.|Methods and systems for alignment of detection optics|

---

US6766817B2|2001-07-25|2004-07-27|Tubarc Technologies, Llc|Fluid conduction utilizing a reversible unsaturated siphon with tubarc porosity action|

---

US7270959B2|2001-07-25|2007-09-18|Oakville Hong Kong Company Limited|Specimen collection container|

---

US20030064507A1|2001-07-26|2003-04-03|Sean Gallagher|System and methods for mixing within a microfluidic device|

---

US6575188B2|2001-07-26|2003-06-10|Handylab, Inc.|Methods and systems for fluid control in microfluidic devices|

---

US20060062696A1|2001-07-27|2006-03-23|Caliper Life Sciences, Inc.|Optimized high throughput analytical systems|

---

US7060171B1|2001-07-31|2006-06-13|Caliper Life Sciences, Inc.|Methods and systems for reducing background signal in assays|

---

JP2003047839A|2001-08-06|2003-02-18|Yamatake Corp|Micro reactor|

---

JP2003047840A|2001-08-06|2003-02-18|Yamatake Corp|Micro reactor|

---

US6640981B2|2001-08-14|2003-11-04|3088081 Canada Inc.|Modular test tube rack|

---

USD482796S1|2001-09-11|2003-11-25|Sysmex Corporation|Sample analyzer|

---

US6852287B2|2001-09-12|2005-02-08|Handylab, Inc.|Microfluidic devices having a reduced number of input and output connections|

---

USD512155S1|2001-09-12|2005-11-29|Techno Medica Co., Ltd.|Automatic blood sampling tube preparation apparatus|

---

JP3996416B2|2001-09-21|2007-10-24|Ｊｕｋｉ株式会社|B / F separation method in nucleic acid hybridization|

---

US20030059823A1|2001-09-21|2003-03-27|Juki Corporation|Hybridization apparatus and method for detecting nucleic acid in sample using the same|

---

USD467349S1|2001-09-28|2002-12-17|Orasure Technologies, Inc.|Analyzer|

---

US6977148B2|2001-10-15|2005-12-20|Qiagen Gmbh|Multiple displacement amplification|

---

USD467348S1|2001-10-15|2002-12-17|Kimberly-Clark Worldwide, Inc.|Diagnostic test carrier|

---

WO2003047712A2|2001-10-18|2003-06-12|The Board Of Trustees Of The University Of Illinois|Hybrid microfluidic and nanofluidic system|

---

US20030156991A1|2001-10-23|2003-08-21|William Marsh Rice University|Optomechanically-responsive materials for use as light-activated actuators and valves|

---

US7338760B2|2001-10-26|2008-03-04|Ntu Ventures Private Limited|Sample preparation integrated chip|

---

US7247274B1|2001-11-13|2007-07-24|Caliper Technologies Corp.|Prevention of precipitate blockage in microfluidic channels|

---

US6750661B2|2001-11-13|2004-06-15|Caliper Life Sciences, Inc.|Method and apparatus for controllably effecting samples using two signals|

---

US7069952B1|2001-11-14|2006-07-04|Caliper Life Sciences, Inc.|Microfluidic devices and methods of their manufacture|

---

DE10156790A1|2001-11-19|2003-06-18|Chemagen Biopolymer Technologi|Device and method for treating magnetic particles|

---

US20030099954A1|2001-11-26|2003-05-29|Stefan Miltenyi|Apparatus and method for modification of magnetically immobilized biomolecules|

---

AU2002351187A1|2001-11-30|2003-06-17|Fluidigm Corporation|Microfluidic device and methods of using same|

---

US6960235B2|2001-12-05|2005-11-01|The Regents Of The University Of California|Chemical microreactor and method thereof|

---

JP2003185584A|2001-12-18|2003-07-03|Fuji Photo Film Co Ltd|Scanner|

---

DE10163476A1|2001-12-21|2003-10-30|Siemens Ag|Arrangement for separating a component from a fluid|

---

US20060113190A1|2002-12-27|2006-06-01|Kurnik Ronald T|Microfluidic device and method for improved sample handling|

---

US20030127327A1|2002-01-04|2003-07-10|Kurnik Ronald T.|Microfluidic device and method for improved sample handling|

---

US7410615B2|2002-01-24|2008-08-12|Perkinelmer Las, Inc.|Precision liquid dispensing system|

---

US7205154B2|2002-01-31|2007-04-17|Agilent Technologies, Inc.|Calibrating array scanners|

---

US7288228B2|2002-02-12|2007-10-30|Gilson, Inc.|Sample injection system|

---

US6819027B2|2002-03-04|2004-11-16|Cepheid|Method and apparatus for controlling ultrasonic transducer|

---

US7101467B2|2002-03-05|2006-09-05|Caliper Life Sciences, Inc.|Mixed mode microfluidic systems|

---

EP2497564B1|2002-03-05|2014-05-14|Caliper Life Sciences, Inc.|Electrophoretic separation in a microfluidic channel network|

---

US7303727B1|2002-03-06|2007-12-04|Caliper Life Sciences, Inc|Microfluidic sample delivery devices, systems, and methods|

---

US7195986B1|2002-03-08|2007-03-27|Caliper Life Sciences, Inc.|Microfluidic device with controlled substrate conductivity|

---

KR100450818B1|2002-03-09|2004-10-01|삼성전자주식회사|Multi chamber PCR chip|

---

US7252928B1|2002-03-12|2007-08-07|Caliper Life Sciences, Inc.|Methods for prevention of surface adsorption of biological materials to capillary walls in microchannels|

---

US7223371B2|2002-03-14|2007-05-29|Micronics, Inc.|Microfluidic channel network device|

---

US7689022B2|2002-03-15|2010-03-30|Affymetrix, Inc.|System, method, and product for scanning of biological materials|

---

DE10212761B4|2002-03-22|2009-12-31|Eppendorf Ag|microtiter plate|

---

US7312085B2|2002-04-01|2007-12-25|Fluidigm Corporation|Microfluidic particle-analysis systems|

---

EP2442102B1|2002-04-02|2019-06-26|Caliper Life Sciences Inc.|Methods, systems and apparatus for separation and isolation of one or more sample components of a sample biological material|

---

USD472324S1|2002-04-05|2003-03-25|Charles River Laboratories, Inc.|Cuvette|

---

JP2003299485A|2002-04-10|2003-10-21|Sekisui Chem Co Ltd|Temperature control-type microreactor and microreactor system|

---

AU2003228514A1|2002-04-11|2003-10-27|Sequenom, Inc.|Methods and devices for performing chemical reactions on a solid support|

---

US8241883B2|2002-04-24|2012-08-14|Caliper Life Sciences, Inc.|High throughput mobility shift|

---

JP3972189B2|2002-05-10|2007-09-05|日本パルスモーター株式会社|Dispensing device with detachable cartridge rack structure|

---

JP3839349B2|2002-05-15|2006-11-01|株式会社堀場製作所|Chemiluminescent enzyme immunoassay device|

---

USD474279S1|2002-05-15|2003-05-06|Monogen, Inc.|Specimen processing instrument|

---

AT375823T|2002-05-17|2007-11-15|Gen Probe Inc|SAMPLE CARRIER WITH DETACHABLE LOCKING DEVICE|

---

JP4235171B2|2002-05-17|2009-03-11|ジェン−プロウブインコーポレイテッド|Sample carrier with sample tube blocking means and drip shield for use therewith|

---

JP4532264B2|2002-05-17|2010-08-25|ベクトン・ディキンソン・アンド・カンパニー|Automatic system, automatic processing method, and automatic nucleic acid extraction method|

---

WO2003099442A1|2002-05-24|2003-12-04|Epr Labautomation Ag|Method and device for dosing small volumes of liquid|

---

US7161356B1|2002-06-05|2007-01-09|Caliper Life Sciences, Inc.|Voltage/current testing equipment for microfluidic devices|

---

USD480814S1|2002-06-11|2003-10-14|Diversa Corporation|Gigamatrix holding tray|

---

US7208125B1|2002-06-28|2007-04-24|Caliper Life Sciences, Inc|Methods and apparatus for minimizing evaporation of sample materials from multiwell plates|

---

US7482169B2|2002-07-15|2009-01-27|Phynexus, Inc.|Low dead volume extraction column device|

---

EP1539352B1|2002-07-23|2009-12-23|Protedyne Corporation|Liquid handling tool having hollow plunger|

---

US7041258B2|2002-07-26|2006-05-09|Applera Corporation|Micro-channel design features that facilitate centripetal fluid transfer|

---

US7214348B2|2002-07-26|2007-05-08|Applera Corporation|Microfluidic size-exclusion devices, systems, and methods|

---

WO2004010760A2|2002-07-26|2004-02-05|Applera Corporation|Microfluidic size-exclusion devices, systems, and methods|

---

DE10236029A1|2002-08-02|2004-02-19|Cybio Systems Gmbh|Device for dispensing and monitoring the luminescence of individual samples in multi-sample arrangements|

---

US20040053315A1|2002-08-12|2004-03-18|Caliper Technologies Corp.|Methods and systems for monitoring molecular interactions|

---

GB0219457D0|2002-08-21|2002-09-25|Amersham Biosciences Uk Ltd|Fluorescence reference plate|

---

US7001853B1|2002-08-30|2006-02-21|Caliper Life Sciences, Inc.|Flow control of photo-polymerizable resin|

---

USD516221S1|2002-09-09|2006-02-28|Meso Scale Technologies, Llc.|Diagnostic instrument|

---

JP3756477B2|2002-09-17|2006-03-15|横河電機株式会社|Method for extracting nucleic acid or protein with dendrimer and dendrimer composition|

---

ITTO20020808A1|2002-09-17|2004-03-18|St Microelectronics Srl|INTEGRATED DNA ANALYSIS DEVICE.|

---

USD484989S1|2002-09-20|2004-01-06|Dade Behring Inc.|Multi-well liquid container|

---

TW590982B|2002-09-27|2004-06-11|Agnitio Science & Technology I|Micro-fluid driving device|

---

US6730883B2|2002-10-02|2004-05-04|Stratagene|Flexible heating cover assembly for thermal cycling of samples of biological material|

---

US7351303B2|2002-10-09|2008-04-01|The Board Of Trustees Of The University Of Illinois|Microfluidic systems and components|

---

US7932098B2|2002-10-31|2011-04-26|Hewlett-Packard Development Company, L.P.|Microfluidic system utilizing thin-film layers to route fluid|

---

US7122384B2|2002-11-06|2006-10-17|E. I. Du Pont De Nemours And Company|Resonant light scattering microparticle methods|

---

EP1567638A1|2002-11-08|2005-08-31|Irm, Llc|Apparatus and methods to process substrate surface features|

---

JP2004170159A|2002-11-18|2004-06-17|Hitachi Koki Co Ltd|Automatic dispenser|

---

AU2003298724B2|2002-11-26|2009-12-24|University Of Massachusetts|Delivery of siRNAs|

---

USD491276S1|2002-12-09|2004-06-08|Babette Langille|Plastic diagnostic card|

---

USD491272S1|2002-12-13|2004-06-08|Immunivest Corporation|Autoprep instrument|

---

WO2004055492A2|2002-12-13|2004-07-01|Aclara Biosciences, Inc.|Closed-loop control of electrokinetic processes in microfludic devices based on optical readings|

---

AU2002350779A1|2002-12-13|2004-07-09|Innotrac Diagnostics Oy|Analyzer and analysing method and a fluid cartridge|

---

SE0203781D0|2002-12-19|2002-12-19|Alphahelix Ab|Holder and method for cooling or heating samples|

---

USD491273S1|2002-12-19|2004-06-08|3M Innovative Properties Company|Hybridization cartridge|

---

US20060094108A1|2002-12-20|2006-05-04|Karl Yoder|Thermal cycler for microfluidic array assays|

---

US7648678B2|2002-12-20|2010-01-19|Dako Denmark A/S|Method and system for pretreatment of tissue slides|

---

AU2003302770B2|2002-12-20|2007-07-12|Caliper Life Sciences, Inc.|Single molecule amplification and detection of DNA|

---

US20050042639A1|2002-12-20|2005-02-24|Caliper Life Sciences, Inc.|Single molecule amplification and detection of DNA length|

---

US7850912B2|2003-05-14|2010-12-14|Dako Denmark A/S|Method and apparatus for automated pre-treatment and processing of biological samples|

---

US8676383B2|2002-12-23|2014-03-18|Applied Biosystems, Llc|Device for carrying out chemical or biological reactions|

---

EP2711415B1|2002-12-26|2022-02-16|Meso Scale Technologies, LLC.|Assay cartridges and methods of using the same|

---

JP2006512092A|2002-12-30|2006-04-13|ザ・リージェンツ・オブ・ジ・ユニバーシティ・オブ・カリフォルニア|Method and apparatus for pathogen detection and analysis|

---

US20070269891A9|2003-01-13|2007-11-22|Yasunobu Tanaka|Solid surface with immobilized degradable cationic polymer for transfecting eukaryotic cells|

---

US7419638B2|2003-01-14|2008-09-02|Micronics, Inc.|Microfluidic devices for fluid manipulation and analysis|

---

US6964747B2|2003-01-21|2005-11-15|Bioarray Solutions, Ltd.|Production of dyed polymer microparticles|

---

US7049558B2|2003-01-27|2006-05-23|Arcturas Bioscience, Inc.|Apparatus and method for heating microfluidic volumes and moving fluids|

---

JP4021335B2|2003-01-31|2007-12-12|ユニバーサル・バイオ・リサーチ株式会社|Dispensing device with monitoring function and method for monitoring dispensing device|

---

US7338637B2|2003-01-31|2008-03-04|Hewlett-Packard Development Company, L.P.|Microfluidic device with thin-film electronic devices|

---

AU2004220626B2|2003-02-05|2010-07-29|Iquum Inc.|Sample processing tubule|

---

US20040157220A1|2003-02-10|2004-08-12|Purnima Kurnool|Methods and apparatus for sample tracking|

---

KR100959101B1|2003-02-20|2010-05-25|삼성전자주식회사|Polymerase chain reaction device and method for regulating opening or shutting of inlet and outlet of PCR device|

---

US20050129580A1|2003-02-26|2005-06-16|Swinehart Philip R.|Microfluidic chemical reactor for the manufacture of chemically-produced nanoparticles|

---

US6905612B2|2003-03-21|2005-06-14|Hanuman Llc|Plasma concentrate apparatus and method|

---

JP2004305009A|2003-04-02|2004-11-04|Hitachi Ltd|Apparatus for amplifying nucleic acid and method for amplifying nucleic acid|

---

EP1617951A4|2003-04-08|2006-08-02|Irm Llc|Material removal and dispensing devices, systems, and methods|

---

DE602004017443D1|2003-04-14|2008-12-11|Caliper Life Sciences Inc|REDUCTION OF MIGRATION SHIFT ASSAY INTERFERENCE|

---

WO2004094986A2|2003-04-16|2004-11-04|Handylab, Inc.|System and method for electrochemical detection of biological compounds|

---

GB2401237A|2003-04-28|2004-11-03|Hewlett Packard Development Co|Data transfer arrangement for disaster recovery|

---

US7148043B2|2003-05-08|2006-12-12|Bio-Rad Laboratories, Inc.|Systems and methods for fluorescence detection with a movable detection module|

---

AU2004238846B2|2003-05-09|2007-10-25|Caliper Life Sciences, Inc.|Automated sample analysis|

---

US7038472B1|2003-05-12|2006-05-02|Caliper Life Sciences, Inc.|Methods and systems for measuring internal dimensions of microscale structures|

---

US7374949B2|2003-05-29|2008-05-20|Bayer Healthcare Llc|Diagnostic test strip for collecting and detecting an analyte in a fluid sample|

---

US7055695B2|2003-06-02|2006-06-06|Caliper Life Sciencee, Inc.|Container providing a controlled hydrated environment|

---

JP2005009870A|2003-06-16|2005-01-13|Fuji Photo Film Co Ltd|Suction method of analyzer|

---

JP4531698B2|2003-07-17|2010-08-25|三菱化学メディエンス株式会社|Automatic measuring cartridge and measuring apparatus using the same|

---

US7381370B2|2003-07-18|2008-06-03|Dade Behring Inc.|Automated multi-detector analyzer|

---

US20060177376A1|2003-07-21|2006-08-10|Dendritic Nanotechnologies, Inc.|Stabilized and chemically functionalized nanoparticles|

---

USD508999S1|2003-07-24|2005-08-30|Biomerieux, Inc.|Sample testing machine|

---

USD500363S1|2003-07-24|2004-12-28|Biomerieux Inc.|Sample holder|

---

EP2402089A1|2003-07-31|2012-01-04|Handylab, Inc.|Processing particle-containing samples|

---

US7744817B2|2003-08-11|2010-06-29|Sakura Finetek U.S.A., Inc.|Manifold assembly|

---

US7413712B2|2003-08-11|2008-08-19|California Institute Of Technology|Microfluidic rotary flow reactor matrix|

---

US7347617B2|2003-08-19|2008-03-25|Siemens Healthcare Diagnostics Inc.|Mixing in microfluidic devices|

---

USD499813S1|2003-08-22|2004-12-14|As.Pire Bioresearch Inc.|Assay testing device|

---

JP2005065607A|2003-08-26|2005-03-17|Hitachi Ltd|Gene treating chip and gene treating apparatus|

---

USD515707S1|2003-09-01|2006-02-21|Matsushita Electric Industrial Co., Ltd.|Fluorescent reader|

---

AU2004271205B2|2003-09-05|2008-06-26|Caliper Life Sciences, Inc.|Analyte injection system|

---

US7501094B2|2003-09-15|2009-03-10|Syngenta Limited|Preparation and characterization of formulations in a high throughput mode|

---

AU2004273996A1|2003-09-19|2005-03-31|University Of Rochester|Biagnostic system for otolaryngologic pathogens and use thereof|

---

US20050220675A1|2003-09-19|2005-10-06|Reed Mark T|High density plate filler|

---

US20050069898A1|2003-09-25|2005-03-31|Cepheid|Lyophilized beads containing mannitol|

---

JP2007506439A|2003-09-26|2007-03-22|データスコープ・インベストメント・コーポレイション|Method for synthesizing a small amount of nucleic acid|

---

DE10344700A1|2003-09-26|2005-04-14|Hirschmann Laborgeräte GmbH & Co. KG|Multichannel pipetting|

---

WO2005031312A1|2003-09-29|2005-04-07|Vision Biosystems Limited|System and method for histological tissue specimen processing|

---

USD528215S1|2003-09-30|2006-09-12|Biacore Ab|Chip carrier for biosensor|

---

WO2005033672A1|2003-10-01|2005-04-14|Caliper Life Sciences, Inc.|Method for measuring diffusivities of compounds using microfluidic devices|

---

NL1024578C2|2003-10-21|2005-04-22|Univ Delft Tech|Device for carrying out a reaction.|

---

AU2004291066C1|2003-11-12|2011-08-04|Van Lue Veterinary Surgical, Llc|Trocars and trocar assemblies|

---

WO2005051295A2|2003-11-21|2005-06-09|Anp Technologies, Inc.|Asymmetrically branched polymer conjugates and microarray assays|

---

EP1541237A3|2003-12-10|2006-02-01|Samsung Electronics Co., Ltd.|Polymerase chain reaction module and multiple pcr system using the same|

---

JP4595446B2|2003-12-12|2010-12-08|Ｄｉｃ株式会社|Nucleic acid amplification method|

---

JP2005176613A|2003-12-16|2005-07-07|Yokogawa Electric Corp|Method for extracting dna and biochip utilizing dendrimer|

---

US7122799B2|2003-12-18|2006-10-17|Palo Alto Research Center Incorporated|LED or laser enabled real-time PCR system and spectrophotometer|

---

KR20070094669A|2003-12-23|2007-09-20|칼리퍼 라이프 사이언시즈, 인크.|Analyte injection system|

---

JP4750412B2|2003-12-25|2011-08-17|モレックスインコーポレイテド|Biologically derived molecules, dioxins and endocrine disrupting substance detection apparatus and detection method using the apparatus|

---

KR100750586B1|2003-12-26|2007-08-20|한국전자통신연구원|Micro-fluidic heating system|

---

JP4732683B2|2003-12-29|2011-07-27|ユニバーサル・バイオ・リサーチ株式会社|Target substance detection method|

---

US7099778B2|2003-12-30|2006-08-29|Caliper Life Sciences, Inc.|Method for determining diffusivity and molecular weight in a microfluidic device|

---

US7867763B2|2004-01-25|2011-01-11|Fluidigm Corporation|Integrated chip carriers with thermocycler interfaces and methods of using the same|

---

SG10202107927VA|2004-01-25|2021-08-30|Fluidigm Corp|Crystal forming devices and systems and methods for making and using the same|

---

US8765454B2|2004-02-18|2014-07-01|Xiaochuan Zhou|Fluidic devices and methods for multiplex chemical and biochemical reactions|

---

EP1733023B1|2004-02-24|2013-01-23|Thermal Gradient|Thermal cycling device|

---

US20050196321A1|2004-03-03|2005-09-08|Zhili Huang|Fluidic programmable array devices and methods|

---

USD517554S1|2004-03-05|2006-03-21|Seiko Epson Corporation|Film scanner|

---

KR100552706B1|2004-03-12|2006-02-20|삼성전자주식회사|Method and apparatus for nucleic acid amplification|

---

AU2005226651A1|2004-03-19|2005-10-06|Espir Kahatt|Device for aspirating, manipulating, mixing and dispensing nano-volumes of liquids|

---

WO2005094981A1|2004-03-29|2005-10-13|Agilent Technologies, Inc.|Cyclic pcr system|

---

JP2005291954A|2004-03-31|2005-10-20|Olympus Corp|Disposable reagent pack and analyzer using the reagent pack|

---

EP3167961A1|2004-04-08|2017-05-17|Biomatrica, Inc.|Integration of sample storage and sample management for life science|

---

ES2360801T3|2004-04-09|2011-06-09|Vivebio, Llc|DEVICES AND METHODS FOR COLLECTION, STORAGE AND TRANSPORTATION OF BIOLOGICAL SAMPLES.|

---

US20070259348A1|2005-05-03|2007-11-08|Handylab, Inc.|Lyophilized pellets|

---

WO2005108620A2|2004-05-03|2005-11-17|Handylab, Inc.|Processing polynucleotide-containing samples|

---

US20060183216A1|2005-01-21|2006-08-17|Kalyan Handique|Containers for liquid storage and delivery with application to microfluidic devices|

---

US8852862B2|2004-05-03|2014-10-07|Handylab, Inc.|Method for processing polynucleotide-containing samples|

---

JP4784508B2|2004-05-07|2011-10-05|コニカミノルタエムジー株式会社|Inspection microreactor, inspection apparatus, and inspection method|

---

GB2414059B|2004-05-10|2008-06-11|E2V Tech Uk Ltd|Microfluidic device|

---

JP3952036B2|2004-05-13|2007-08-01|コニカミノルタセンシング株式会社|Microfluidic device, test solution test method and test system|

---

CA2567537A1|2004-05-21|2005-12-01|Caliper Life Sciences, Inc.|Automated system for handling microfluidic devices|

---

US7553671B2|2004-05-25|2009-06-30|Vertex Pharmaceuticals, Inc.|Modular test tube rack|

---

WO2005116202A1|2004-05-27|2005-12-08|Universal Bio Research Co., Ltd.|Reaction vessel, reaction measuring device, and liquid rotating treatment device|

---

US7311794B2|2004-05-28|2007-12-25|Wafergen, Inc.|Methods of sealing micro wells|

---

US7799553B2|2004-06-01|2010-09-21|The Regents Of The University Of California|Microfabricated integrated DNA analysis system|

---

EP1771249A4|2004-06-07|2010-02-24|Irm Llc|Dispensing systems, software, and related methods|

---

WO2006004929A2|2004-06-28|2006-01-12|Boise State University|Electrochemical deposition method utilizing microdroplets of solution|

---

US7480042B1|2004-06-30|2009-01-20|Applied Biosystems Inc.|Luminescence reference standards|

---

US20060002817A1|2004-06-30|2006-01-05|Sebastian Bohm|Flow modulation devices|

---

US8965710B2|2004-07-02|2015-02-24|The United States Of America, As Represented By The Secretary Of The Navy|Automated sample-to-microarray apparatus and method|

---

JP4440020B2|2004-07-09|2010-03-24|株式会社神戸製鋼所|Microreactor and manufacturing method thereof|

---

USD523153S1|2004-07-23|2006-06-13|Hitachi High-Technologies Corporation|Main part for immunity analysis machine|

---

EP1621890A1|2004-07-26|2006-02-01|bioMerieux B.V.|Device and method for separating, mixing and concentrating magnetic particles with a fluid and use thereof in purification methods|

---

US8053214B2|2004-09-09|2011-11-08|Microfluidic Systems, Inc.|Apparatus and method of extracting and optically analyzing an analyte from a fluid-based sample|

---

EP1794581A2|2004-09-15|2007-06-13|Microchip Biotechnologies, Inc.|Microfluidic devices|

---

KR100668304B1|2004-09-16|2007-01-12|삼성전자주식회사|A device for the injection of PCR solution into a PCR channel and a PCR chip unit comprising the device|

---

CN101031801B|2004-09-30|2010-12-01|爱科来株式会社|Thin film heater and analytical instrument|

---

USD548841S1|2004-10-15|2007-08-14|Microsulis, Ltd|Electrical equipment for ablative treatment|

---

WO2006043642A1|2004-10-20|2006-04-27|Ebara Corporation|Fluid reactor|

---

US20060094004A1|2004-10-28|2006-05-04|Akihisa Nakajima|Micro-reactor, biological material inspection device, and microanalysis system|

---

JP2006145458A|2004-11-24|2006-06-08|Yaskawa Electric Corp|Dispensing device|

---

US7785868B2|2004-12-02|2010-08-31|Microfluidic Systems, Inc.|Apparatus to automatically lyse a sample|

---

US7727477B2|2004-12-10|2010-06-01|Bio-Rad Laboratories, Inc.|Apparatus for priming microfluidics devices with feedback control|

---

JP4573243B2|2004-12-15|2010-11-04|小林クリエイト株式会社|Test tube tray|

---

JP4739352B2|2004-12-17|2011-08-03|日東電工株式会社|Solid surface with immobilized degradable cationic polymer for transfecting eukaryotic cells|

---

US20060165558A1|2004-12-21|2006-07-27|Thomas Witty|Cartridge for diagnostic assays|

---

US7315376B2|2005-01-07|2008-01-01|Advanced Molecular Systems, Llc|Fluorescence detection system|

---

US7964380B2|2005-01-21|2011-06-21|Argylia Technologies|Nanoparticles for manipulation of biopolymers and methods of thereof|

---

DE102005004664B4|2005-02-02|2007-06-21|Chemagen Biopolymer-Technologie Aktiengesellschaft|Apparatus and method and use for separating magnetic or magnetizable particles from a liquid and their uses|

---

WO2006089252A2|2005-02-16|2006-08-24|Mcneely Michael R|Liquid valving using reactive or responsive materials|

---

WO2006089192A2|2005-02-18|2006-08-24|Canon U.S. Life Sciences, Inc.|Devices and methods for identifying genomic dna of organisms|

---

USD535403S1|2005-02-25|2007-01-16|Fuji Photo Film Co., Ltd.|Component extractor for biochemistry|

---

CA2600934A1|2005-03-07|2006-09-14|Novx Systems Inc.|Automated analyzer|

---

EP1868725B1|2005-03-08|2012-01-18|Authentix, Inc.|Use of microfluidic device for identification, quantification, and authentication of latent markers|

---

EP2348321A3|2005-03-10|2014-06-11|Gen-Probe Incorporated|System and methods to perform assays for detecting or quantifying analytes within samples|

---

US20060228734A1|2005-03-18|2006-10-12|Applera Corporation|Fluid processing device with captured reagent beads|

---

US7507575B2|2005-04-01|2009-03-24|3M Innovative Properties Company|Multiplex fluorescence detection device having removable optical modules|

---

US9097723B2|2005-04-01|2015-08-04|Caliper Life Sciences, Inc.|Method and apparatus for performing peptide digestion on a microfluidic device|

---

JP4525427B2|2005-04-01|2010-08-18|パナソニック株式会社|Analysis disk, and method for inspecting analysis disk and analyzer|

---

US20060246493A1|2005-04-04|2006-11-02|Caliper Life Sciences, Inc.|Method and apparatus for use in temperature controlled processing of microfluidic samples|

---

CA112854S|2005-04-10|2007-03-27|Akubio Ltd|Microbalance analyser cartridge|

---

EP2453223B1|2005-04-12|2019-07-03|Caliper Life Sciences Inc.|Optical detection system for a microfluidic device and method for aligning and focusing an optical detection system|

---

US20060234251A1|2005-04-19|2006-10-19|Lumigen, Inc.|Methods of enhancing isolation of RNA from biological samples|

---

US7300631B2|2005-05-02|2007-11-27|Bioscale, Inc.|Method and apparatus for detection of analyte using a flexural plate wave device and magnetic particles|

---

USD566291S1|2005-05-03|2008-04-08|Handylab, Inc.|Microfluidic cartridge|

---

USD534280S1|2005-05-04|2006-12-26|Abbott Laboratories|Reagent carrier for use in an automated analyzer|

---

JP4875066B2|2005-05-06|2012-02-15|カリパー・ライフ・サイエンシズ・インク．|Microtiter plate with perimeter removed|

---

WO2006122311A2|2005-05-11|2006-11-16|The Trustees Of The University Of Pennsylvania|Microfluidic chip|

---

WO2007005907A1|2005-07-01|2007-01-11|Honeywell International, Inc.|A molded cartridge with 3-d hydrodynamic focusing|

---

US7527763B2|2005-07-05|2009-05-05|3M Innovative Properties Company|Valve control system for a rotating multiplex fluorescence detection device|

---

US20080226502A1|2005-07-07|2008-09-18|Jacques Jonsmann|Microfluidic Methods and Support Instruments|

---

US20070020699A1|2005-07-19|2007-01-25|Idexx Laboratories, Inc.|Lateral flow assay and device using magnetic particles|

---

JP4581128B2|2005-07-20|2010-11-17|独立行政法人産業技術総合研究所|Enzyme immunoassay method and enzyme immunosensor therefor|

---

US20070020764A1|2005-07-20|2007-01-25|Miller Kerry L|Method for processing chemistry and coagulation test samples in a laboratory workcell|

---

EP2660482B1|2005-08-22|2019-08-07|Life Technologies Corporation|Vorrichtung, System und Verfahren unter Verwendung von nichtmischbaren Flüssigkeiten mit unterschiedlichen Volumen|

---

JP2007074960A|2005-09-13|2007-03-29|Shimadzu Corp|Method for amplifying gene|

---

USD549827S1|2005-09-16|2007-08-28|Horiba, Ltd.|Blood analyzer|

---

AU2006299414A1|2005-09-30|2007-04-12|Caliper Life Sciences, Inc.|Microfluidic device for purifying a biological component using magnetic beads|

---

JP4827483B2|2005-10-04|2011-11-30|キヤノン株式会社|Nucleic acid sample processing equipment|

---

JP4630786B2|2005-10-04|2011-02-09|キヤノン株式会社|Biochemical treatment apparatus, DNA amplification and purification apparatus, and DNA testing apparatus including the apparatus|

---

US20070199821A1|2005-10-05|2007-08-30|Chow Andrea W|Automated two-dimensional gel electrophoresis|

---

US7727371B2|2005-10-07|2010-06-01|Caliper Life Sciences, Inc.|Electrode apparatus for use with a microfluidic device|

---

WO2007044917A2|2005-10-11|2007-04-19|Handylab, Inc.|Polynucleotide sample preparation device|

---

DE102005049920A1|2005-10-17|2007-04-19|Manz Automation Ag|robotic assembly|

---

US20070092403A1|2005-10-21|2007-04-26|Alan Wirbisky|Compact apparatus, compositions and methods for purifying nucleic acids|

---

USD556914S1|2005-10-21|2007-12-04|Sanyo Electric Co., Ltd.|Gene amplification apparatus|

---

USD537951S1|2005-10-21|2007-03-06|Sanyo Electric Co., Ltd.|Gene amplification apparatus|

---

DE102005051850A1|2005-10-28|2007-05-03|Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.|Device for duplication and detection of nucleic acids|

---

US20070104617A1|2005-11-04|2007-05-10|Advanced Biotechnologies Limited|Capped tubes|

---

US20070116613A1|2005-11-23|2007-05-24|Donat Elsener|Sample tube and system for storing and providing nucleic acid samples|

---

EP2283923A2|2005-11-30|2011-02-16|F. Hoffmann-La Roche AG|Linear cuvette array without positioning means|

---

WO2007064117A1|2005-11-30|2007-06-07|Electronics And Telecommunications Research Institute|Affinity chromatography microdevice and method for manufacturing the same|

---

JP3899360B2|2005-12-19|2007-03-28|オリンパス株式会社|DNA amplification equipment|

---

JP2007178328A|2005-12-28|2007-07-12|Shimadzu Corp|Reaction container kit and reaction container treatment apparatus|

---

WO2007079257A2|2005-12-30|2007-07-12|Caliper Life Sciences, Inc.|Integrated dissolution processing and sample transfer system|

---

US20070154895A1|2005-12-30|2007-07-05|Caliper Life Sciences, Inc.|Multi-assay microfluidic chips|

---

SG134186A1|2006-01-12|2007-08-29|Nanyang Polytechnic|Smart nano-integrated system assembly|

---

JP5006215B2|2006-02-07|2012-08-22|古河電気工業株式会社|Photodetector and measuring object reader|

---

US8124033B2|2006-02-17|2012-02-28|Agency, Science, Technology and Research|Apparatus for regulating the temperature of a biological and/or chemical sample and method of using the same|

---

USD538436S1|2006-03-06|2007-03-13|Steris Inc.|Reprocessor for decontaminating medical, dental and veterinary instruments and articles|

---

EP2007905B1|2006-03-15|2012-08-22|Micronics, Inc.|Integrated nucleic acid assays|

---

US9186677B2|2007-07-13|2015-11-17|Handylab, Inc.|Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples|

---

US8133671B2|2007-07-13|2012-03-13|Handylab, Inc.|Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples|

---

US8088616B2|2006-03-24|2012-01-03|Handylab, Inc.|Heater unit for microfluidic diagnostic system|

---

US8883490B2|2006-03-24|2014-11-11|Handylab, Inc.|Fluorescence detector for microfluidic diagnostic system|

---

US8105783B2|2007-07-13|2012-01-31|Handylab, Inc.|Microfluidic cartridge|

---

WO2007112114A2|2006-03-24|2007-10-04|Handylab, Inc.|Integrated system for processing microfluidic samples, and method of using same|

---

US7998708B2|2006-03-24|2011-08-16|Handylab, Inc.|Microfluidic system for amplifying and detecting polynucleotides in parallel|

---

USD569526S1|2006-03-27|2008-05-20|Handylab, Inc.|Molecular diagnostic instrument|

---

USD559995S1|2006-03-27|2008-01-15|Handylab, Inc.|Controller cartridge for a diagnostic instrument|

---

EP1839756A1|2006-03-31|2007-10-03|F.Hoffmann-La Roche Ag|Apparatus for separating magnetic particles from liquids containing said particles, and an array of vessels suitable for use with such an apparatus|

---

US8021531B2|2006-04-14|2011-09-20|Caliper Life Sciences, Inc.|Method for modifying the concentration of reactants in a microfluidic device|

---

USD554070S1|2006-05-03|2007-10-30|Data I/O Corporation|Processing apparatus|

---

USD554069S1|2006-05-03|2007-10-30|Data I/O Corporation|Processing apparatus|

---

US8232091B2|2006-05-17|2012-07-31|California Institute Of Technology|Thermal cycling system|

---

CN101522909A|2006-05-17|2009-09-02|加利福尼亚技术学院|Thermal cycling system|

---

WO2008070198A2|2006-05-17|2008-06-12|California Institute Of Technology|Thermal cycling system|

---

EP2029772B1|2006-06-08|2020-03-18|Koninklijke Philips N.V.|Microelectronic sensor device for dna detection|

---

US7629124B2|2006-06-30|2009-12-08|Canon U.S. Life Sciences, Inc.|Real-time PCR in micro-channels|

---

US7858366B2|2006-08-24|2010-12-28|Microfluidic Systems, Inc|Integrated airborne substance collection and detection system|

---

US7633606B2|2006-08-24|2009-12-15|Microfluidic Systems, Inc.|Integrated airborne substance collection and detection system|

---

US7705739B2|2006-08-24|2010-04-27|Microfluidic Systems, Inc.|Integrated airborne substance collection and detection system|

---

US9278321B2|2006-09-06|2016-03-08|Canon U.S. Life Sciences, Inc.|Chip and cartridge design configuration for performing micro-fluidic assays|

---

US8246919B2|2006-09-21|2012-08-21|Abbott Laboratories|Specimen sample rack|

---

WO2008147382A1|2006-09-27|2008-12-04|Micronics, Inc.|Integrated microfluidic assay devices and methods|

---

US20080095673A1|2006-10-20|2008-04-24|Lin Xu|Microplate with fewer peripheral artifacts|

---

WO2008061165A2|2006-11-14|2008-05-22|Handylab, Inc.|Microfluidic cartridge and method of making same|

---

KR101422467B1|2007-02-08|2014-07-24|삼성전자주식회사|A system and a method for detecting fluorescence in microfluidic chip|

---

US7985375B2|2007-04-06|2011-07-26|Qiagen Gaithersburg, Inc.|Sample preparation system and method for processing clinical specimens|

---

JP2008267950A|2007-04-19|2008-11-06|Enplas Corp|Fluid handling device|

---

US20080257882A1|2007-04-20|2008-10-23|Bioinnovations Oy|Vessel for accurate analysis|

---

WO2008149282A2|2007-06-06|2008-12-11|Koninklijke Philips Electronics N. V.|Microfluidic device and method of operating a microfluidic device|

---

US8182763B2|2007-07-13|2012-05-22|Handylab, Inc.|Rack for sample tubes and reagent holders|

---

EP3741869A1|2007-07-13|2020-11-25|Handylab, Inc.|Polynucleotide capture materials and methods of using same|

---

USD787087S1|2008-07-14|2017-05-16|Handylab, Inc.|Housing|

---

US9618139B2|2007-07-13|2017-04-11|Handylab, Inc.|Integrated heater and magnetic separator|

---

US20090136385A1|2007-07-13|2009-05-28|Handylab, Inc.|Reagent Tube|

---

US8287820B2|2007-07-13|2012-10-16|Handylab, Inc.|Automated pipetting apparatus having a combined liquid pump and pipette head system|

---

GB0719193D0|2007-10-02|2007-11-07|Advanced Biotech Ltd|A Vessel|

---

WO2009049171A2|2007-10-10|2009-04-16|Pocared Diagnostics Ltd.|System for conducting the identification of bacteria in urine|

---

USD632799S1|2008-05-15|2011-02-15|The Automation Partnership|Cell dispenser|

---

CA2726636C|2008-06-09|2017-02-14|Qiagen Gaithersburg, Inc.|Magnetic microplate assembly|

---

USD596312S1|2008-06-13|2009-07-14|Csp Technologies, Inc.|Vial rack|

---

USD595423S1|2008-06-30|2009-06-30|Ge Healthcare Bio-Sciences Ab|Magnetic rack|

---

US20100009351A1|2008-07-11|2010-01-14|Handylab, Inc.|Polynucleotide Capture Materials, and Method of Using Same|

---

USD618820S1|2008-07-11|2010-06-29|Handylab, Inc.|Reagent holder|

---

USD621060S1|2008-07-14|2010-08-03|Handylab, Inc.|Microfluidic cartridge|

---

USD598566S1|2008-08-12|2009-08-18|Diagenode Societe Anonyme|Medical instrument for laboratory use|

---

EP2331954B1|2008-08-27|2020-03-25|Life Technologies Corporation|Apparatus for and method of processing biological samples|

---

WO2010118541A1|2009-04-15|2010-10-21|Biocartis Sa|OPTICAL DETECTION SYSTEM FOR MONITORING rtPCR REACTION|

---

USD599234S1|2009-04-28|2009-09-01|Shiseido Co., Ltd.|Auto-sampler for chromatograph|

---

USD638953S1|2009-05-12|2011-05-31|Invitrogen Dynal As|Laboratory apparatus|

---

US8329117B2|2009-05-14|2012-12-11|Canon U.S. Life Sciences, Inc.|Microfluidic chip features for optical and thermal isolation|

---

WO2010130310A1|2009-05-15|2010-11-18|Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.|Pipette head with filter and flushing means|

---

EP2263802A1|2009-05-25|2010-12-22|F. Hoffmann-La Roche AG|System and method for dispensing fluids|

---

TWI571241B|2009-06-04|2017-02-21|環球生物研究股份有限公司|Apparatus for inspecting samples and method for same|

---

USD628305S1|2009-07-14|2010-11-30|Medical Research Council|Sitting-drop microwell plate for crystalization|

---

EP2454381A1|2009-07-16|2012-05-23|Abbott Laboratories|A method for amplification of nucleic acids|

---

US8282895B2|2009-09-15|2012-10-09|Qiagen Gaithersburg, Inc.|Reagent cabinet system|

---

GB2473868A|2009-09-28|2011-03-30|Invitrogen Dynal As|Apparatus and method of automated processing of biological samples|

---

US20110097493A1|2009-10-27|2011-04-28|Kerr Roger S|Fluid distribution manifold including non-parallel non-perpendicular slots|

---

US20130029343A1|2010-02-22|2013-01-31|4Titude Ltd.|Multiwell strips|

---

ES2583643T3|2010-04-01|2016-09-21|F. Hoffmann-La Roche Ag|Computer-implemented method to operate an automated sample work cell|

---

US20110300033A1|2010-06-07|2011-12-08|Chemence Medical, Inc.|Pipette Holder and Applicator Apparatus|

---

CN103555558B|2010-07-23|2016-09-28|贝克曼考尔特公司|Container for real-time PCR|

---

WO2012036296A1|2010-09-17|2012-03-22|ユニバーサル・バイオ・リサーチ株式会社|Cartridge and automatic analysis device|

---

WO2012142516A1|2011-04-15|2012-10-18|Becton, Dickinson And Company|Scanning real-time microfluidic thermo-cycler and methods for synchronized thermocycling and scanning optical detection|

---

USD692162S1|2011-09-30|2013-10-22|Becton, Dickinson And Company|Single piece reagent holder|

---

EP2761305B1|2011-09-30|2017-08-16|Becton, Dickinson and Company|Unitized reagent strip|

---

WO2013055963A1|2011-10-14|2013-04-18|Becton, Dickinson And Company|Square wave thermal cycling|

---

CN104040238B|2011-11-04|2017-06-27|汉迪拉布公司|Polynucleotides sample preparation apparatus|

---

RU2658773C2|2012-02-03|2018-06-22|Бектон, Дикинсон Энд Компани|System and method of implementation of automated assays on plurality of biological samples|

---

BR112014025384B1|2012-04-13|2022-01-25|Becton, Dickinson And Company|System and methods for performing automated assay and reflective testing on samples from the respective specimens|

---

USD686749S1|2012-04-20|2013-07-23|Stratec Biomedical Ag|Rack for holding sheaths|

---

USD702854S1|2012-05-18|2014-04-15|Yoko Nakahana|Micro tube array container|

---

USD687567S1|2012-10-22|2013-08-06|Qiagen Gaithersburg, Inc.|Tube strip for automated processing systems|

---

USD710024S1|2013-03-14|2014-07-29|Bio-Rad Laboratories, Inc.|Microplate|

---

CN112831410A|2013-03-15|2021-05-25|伯克顿迪金森公司|Process tube and carrier tray|

---

CN110082550A|2013-03-16|2019-08-02|莱斯利·唐·罗伯茨|Integrated Modularity analysis cylinder and can layout reagent delivery system|

---

KR102043320B1|2013-08-08|2019-11-11|일루미나, 인코포레이티드|Fluidic system for reagent delivery to a flow cell|

---

CH709054A1|2013-12-20|2015-06-30|Tecan Trading Ag|Spacer for stacked pipette tip support.|

---

USD729404S1|2014-06-02|2015-05-12|Seahorse Bioscience|Carrier|

---

WO2016037000A1|2014-09-04|2016-03-10|Miodx|Method of multivariate molecule analysis|

---

AU2017269556A1|2016-05-23|2018-11-29|Becton, Dickinson And Company|Liquid dispenser with manifold mount for modular independently-actuated pipette channels|US6692700B2|2001-02-14|2004-02-17|Handylab, Inc.|Heat-reduction methods and systems related to microfluidic devices|

---

US7010391B2|2001-03-28|2006-03-07|Handylab, Inc.|Methods and systems for control of microfluidic devices|

---

US8895311B1|2001-03-28|2014-11-25|Handylab, Inc.|Methods and systems for control of general purpose microfluidic devices|

---

US7829025B2|2001-03-28|2010-11-09|Venture Lending & Leasing Iv, Inc.|Systems and methods for thermal actuation of microfluidic devices|

---

EP2402089A1|2003-07-31|2012-01-04|Handylab, Inc.|Processing particle-containing samples|

---

US8852862B2|2004-05-03|2014-10-07|Handylab, Inc.|Method for processing polynucleotide-containing samples|

---

US8883490B2|2006-03-24|2014-11-11|Handylab, Inc.|Fluorescence detector for microfluidic diagnostic system|

---

WO2007112114A2|2006-03-24|2007-10-04|Handylab, Inc.|Integrated system for processing microfluidic samples, and method of using same|

---

US8133671B2|2007-07-13|2012-03-13|Handylab, Inc.|Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples|

---

US8105783B2|2007-07-13|2012-01-31|Handylab, Inc.|Microfluidic cartridge|

---

US9186677B2|2007-07-13|2015-11-17|Handylab, Inc.|Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples|

---

US7998708B2|2006-03-24|2011-08-16|Handylab, Inc.|Microfluidic system for amplifying and detecting polynucleotides in parallel|

---

US10900066B2|2006-03-24|2021-01-26|Handylab, Inc.|Microfluidic system for amplifying and detecting polynucleotides in parallel|

---

WO2008061165A2|2006-11-14|2008-05-22|Handylab, Inc.|Microfluidic cartridge and method of making same|

---

EP3741869A1|2007-07-13|2020-11-25|Handylab, Inc.|Polynucleotide capture materials and methods of using same|

---

US9618139B2|2007-07-13|2017-04-11|Handylab, Inc.|Integrated heater and magnetic separator|

---

US8287820B2|2007-07-13|2012-10-16|Handylab, Inc.|Automated pipetting apparatus having a combined liquid pump and pipette head system|

---

US8182763B2|2007-07-13|2012-05-22|Handylab, Inc.|Rack for sample tubes and reagent holders|

---

USD787087S1|2008-07-14|2017-05-16|Handylab, Inc.|Housing|

---

WO2012142516A1|2011-04-15|2012-10-18|Becton, Dickinson And Company|Scanning real-time microfluidic thermo-cycler and methods for synchronized thermocycling and scanning optical detection|

---

USD692162S1|2011-09-30|2013-10-22|Becton, Dickinson And Company|Single piece reagent holder|

---

EP2761305B1|2011-09-30|2017-08-16|Becton, Dickinson and Company|Unitized reagent strip|

---

RU2658773C2|2012-02-03|2018-06-22|Бектон, Дикинсон Энд Компани|System and method of implementation of automated assays on plurality of biological samples|

---

CN103048157B|2012-11-30|2015-06-24|刘小欣|Automatic pathological paraffin specimen recognition machine, detection trolley adopting same and control method for same|

---

US20150093786A1|2013-09-27|2015-04-02|Eppendorf Ag|Laboratory apparatus and method of using a laboratory apparatus|

---

AU2014332126B2|2013-10-07|2019-10-31|Agdia Inc.|Portable testing device for analyzing biological samples|

---

US20170089836A1|2014-04-03|2017-03-30|Hitachi High-Technologies Corporation|Analysis Device|

---

GB201506992D0|2014-11-14|2015-06-10|Nplex Pty Ltd|A portable in-vitro diagnostic detector|

---

US10012590B2|2015-02-06|2018-07-03|Life Technolgies Corporation|Methods and systems for biological instrument calibration|

---

US9623405B2|2015-03-03|2017-04-18|HighRes Biosolutions, Inc.|Pipettor system|

---

USD784549S1|2015-04-28|2017-04-18|Streck, Inc.|Laboratory analysis device housing|

---

CN107921399B|2015-07-30|2021-07-27|加利福尼亚大学董事会|Optical cavity PCR|

---

CN105400691A|2015-12-11|2016-03-16|舟山医院|A multifunctional PCR instrument|

---

WO2017160979A1|2016-03-15|2017-09-21|Abbott Laboratories|Methods and systems of multi-assay processing and analysis|

---

JP2019521850A|2016-06-27|2019-08-08|アバクシス， インコーポレイテッド|Device with modified conduit|

---

DE102016225817B4|2016-12-21|2019-07-04|Bayer Pharma Aktiengesellschaft|Method and system for measurements in high-throughput screening with high time resolution|

---

USD871611S1|2017-03-31|2019-12-31|Qiagen Healthcare Biotechnologies Systems Limited|Magazine for holding flat cards|

---

JP2020519859A|2017-04-21|2020-07-02|アバキス・インコーポレーテッド|Systems, devices and methods for microfluidic analysis|

---

JP2018196365A|2017-05-25|2018-12-13|パナソニックＩｐマネジメント株式会社|Nucleic acid amplifier|

---

US10859505B2|2018-01-26|2020-12-08|Gemological Institute Of America, Inc. |Fluorescence box for gemological applications|

---

TWI657138B|2018-02-13|2019-04-21|光鼎生物科技股份有限公司|Thermal cycler|

---

CN109182117A|2018-09-19|2019-01-11|基蛋生物科技股份有限公司|Nucleic acid amplification detection device and diagnositc analyser|

---

WO2020174918A1|2019-02-27|2020-09-03|Ｐｈｃホールディングス株式会社|Nucleic acid amplification device|

---

WO2021080567A1|2019-10-22|2021-04-29|Hewlett-Packard Development Company, L.P.|Fluidic die with a suppressible clock circuit|

---

JP2021139784A|2020-03-06|2021-09-16|株式会社日立ハイテク|Autoanalyzer|

---

DE102020106865A1|2020-03-12|2021-09-16|Analytik Jena Gmbh|Arrangement and method for PCR with multi-channel fluorescence measurement for spatially distributed samples|

---

ES2885648A1|2020-06-10|2021-12-14|Advanced Mechatronic Systems S L U|MECHATRONIC MACHINE AND MASS PROCESSING PROCEDURE OF PCR TEST|

法律状态:
2019-12-03| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2020-06-09| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-12-01| B09A| Decision: intention to grant|

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2021-02-09| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 13/04/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161476167P| true| 2011-04-15|2011-04-15|

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US201161476175P| true| 2011-04-15|2011-04-15|

---

US61/476,167|2011-04-15|

---

US61/476,175|2011-04-15|

---

PCT/US2012/033667|WO2012142516A1|2011-04-15|2012-04-13|Scanning real-time microfluidic thermo-cycler and methods for synchronized thermocycling and scanning optical detection|

---