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1. 发明授权

US08592153B1 Methods for manufacturing high capacitance microwell structures of chemically-sensitive sensors 有权
标题翻译：用于制造化学敏感传感器的高电容微孔结构的方法
公开(公告)号：US08592153B1
公开(公告)日：2013-11-26
申请号：US13603631
申请日：2012-09-05
申请人： James Bustillo , Jonathan Schultz , Todd Rearick , Mark Milgrew
发明人： James Bustillo , Jonathan Schultz , Todd Rearick , Mark Milgrew
IPC分类号： C12Q1/68 , C12M1/34 , C12M3/00 , G01N27/403
CPC分类号： G01N27/4145 , C12Q1/6869 , C12Q1/6874 , G01N27/27 , G01N27/414 , Y10T29/49002
摘要： Methods and apparatus relating to FET arrays for monitoring chemical and/or biological reactions such as nucleic acid sequencing-by-synthesis reactions. Some methods provided herein relate to improving signal (and also signal to noise ratio) from released hydrogen ions during nucleic acid sequencing reactions.
摘要翻译：与用于监测化学和/或生物反应的FET阵列相关的方法和装置，例如核酸序列合成反应。本文提供的一些方法涉及在核酸测序反应期间从释放的氢离子改进信号（以及信噪比）。

2. 发明授权

US08673627B2 Apparatus and methods for performing electrochemical reactions 有权
标题翻译：用于进行电化学反应的装置和方法
公开(公告)号：US08673627B2
公开(公告)日：2014-03-18
申请号：US12785716
申请日：2010-05-24
申请人： John Nobile , Thomas Roth , Todd Rearick , Jonathan Schultz , Jonathan Rothberg , David Marran
发明人： John Nobile , Thomas Roth , Todd Rearick , Jonathan Schultz , Jonathan Rothberg , David Marran
IPC分类号： C12M1/34 , C12M3/00 , C12M1/00 , C12Q1/68 , G01N27/403
CPC分类号： G01N27/301 , B01J2219/00315 , B01J2219/00317 , B01J2219/005 , B01J2219/00653 , B01J2219/00722 , B01L3/502761 , B01L2200/0668 , B01L2300/0636 , B01L2300/0645 , B01L2300/0877 , G01N27/4145
摘要： The invention is directed to apparatus and methods for delivering multiple reagents to, and monitoring, a plurality of analytical reactions carried out on a large-scale array of electronic sensors underminimal noise conditions. In one aspect, the invention provides method of improving signal-to-noise ratios of output signals from the electronic sensors sensing analytes or reaction byproducts by subtracting an average of output signals measured from neighboring sensors where analyte or reaction byproducts are absent. In other aspects, the invention provides an array of electronic sensors integrated with a microwell array for confining analytes and/or particles for analytical reactions and a method for identifying microwells containing analytes and/or particles by passing a sensor-active reagent over the array and correlating sensor response times to the presence or absence of analytes or particles. Such detection of analyte- or particle-containing microwells may be used as a step in additional noise reduction methods.
摘要翻译：本发明涉及用于在最小噪声条件下向多个电子传感器阵列上进行的多个分析反应的多个试剂的输送和监测的装置和方法。一方面，本发明提供了通过减去从相邻传感器测得的输出信号的平均值来提高来自电子传感器感测分析物或反应副产物的输出信号的信噪比的方法，其中分析物或反应副产物不存在。在其它方面，本发明提供了与微孔阵列集成的电子传感器阵列，用于限制用于分析反应的分析物和/或颗粒，以及通过使传感器活性试剂通过阵列而识别含有分析物和/或颗粒的微孔的方法，以及将传感器响应时间与分析物或颗粒的存在或不存在相关联。含有分析物或含微粒微孔的这种检测可以用作额外的降噪方法中的步骤。

3. 发明申请

US20110263463A1 INTEGRATED SENSOR ARRAYS FOR BIOLOGICAL AND CHEMICAL ANALYSIS 有权
标题翻译：用于生物和化学分析的集成传感器阵列
公开(公告)号：US20110263463A1
公开(公告)日：2011-10-27
申请号：US13125133
申请日：2009-10-22
申请人： Jonathan M. Rothberg , James Bustillo , Mark Milgrew , Jonathan Schultz , David Marran , Todd Rearick , Kim Johnson
发明人： Jonathan M. Rothberg , James Bustillo , Mark Milgrew , Jonathan Schultz , David Marran , Todd Rearick , Kim Johnson
IPC分类号： C40B60/12 , B82Y15/00
CPC分类号： G01N27/4145 , C12Q1/6869 , C12Q1/6874 , G01N27/4148 , H01L21/82 , C12Q2565/607
摘要： The invention is directed to apparatus and chips comprising a large scale chemical field effect transistor arrays that include an array of sample-retaining regions capable of retaining a chemical or biological sample from a sample fluid for analysis. In one aspect such transistor arrays have a pitch of 10 μm or less and each sample-retaining region is positioned on at least one chemical field effect transistor which is configured to generate at least one output signal related to a characteristic of a chemical or biological sample in such sample-retaining region. In one embodiment, the characteristic of said chemical or biological sample is a concentration of a charged species and wherein each of said chemical field effect transistors is an ion-sensitive field effect transistor having a floating gate with a dielectric layer on a surface thereof, the dielectric layer contacting said sample fluid and being capable of accumulating charge in proportion to a concentration of the charged species in said sample fluid. In one embodiment such charged species is a hydrogen ion such that the sensors measure changes in pH of the sample fluid in or adjacent to the sample-retaining region thereof. Apparatus and chips of the invention may be adapted for large scale pH-based DNA sequencing and other bioscience and biomedical applications.
摘要翻译：本发明涉及包括大规模化学场效应晶体管阵列的装置和芯片，其包括能够保留来自样品流体的化学或生物样品用于分析的样品保持区阵列。在一个方面，这种晶体管阵列具有10μm或更小的间距，并且每个采样保持区域位于至少一个化学场效应晶体管上，该晶体管被配置为产生与化学或生物样品的特性相关的至少一个输出信号在这样的样品保留区域中。在一个实施方案中，所述化学或生物样品的特征是带电物质的浓度，并且其中每个所述化学场效应晶体管是离子敏感场效应晶体管，其具有在其表面上具有介电层的浮置栅极，电介质层与所述样品流体接触并且能够与所述样品流体中的带电物质的浓度成比例地积累电荷。在一个实施方案中，这种带电物质是氢离子，使得传感器测量样品流体在其样品保持区域中或其附近的pH值的变化。本发明的装置和芯片可适用于大规模的基于pH的DNA测序和其他生物科学和生物医学应用。

4. 发明申请

US20100300895A1 APPARATUS AND METHODS FOR PERFORMING ELECTROCHEMICAL REACTIONS 有权
标题翻译：用于执行电化学反应的装置和方法
公开(公告)号：US20100300895A1
公开(公告)日：2010-12-02
申请号：US12785716
申请日：2010-05-24
申请人： John Nobile , Thomas Roth , Todd Rearick , Jonathan Schultz , Jonathan Rothberg , David Marran
发明人： John Nobile , Thomas Roth , Todd Rearick , Jonathan Schultz , Jonathan Rothberg , David Marran
IPC分类号： G01N27/26
CPC分类号： G01N27/301 , B01J2219/00315 , B01J2219/00317 , B01J2219/005 , B01J2219/00653 , B01J2219/00722 , B01L3/502761 , B01L2200/0668 , B01L2300/0636 , B01L2300/0645 , B01L2300/0877 , G01N27/4145
摘要： The invention is directed to apparatus and methods for delivering multiple reagents to, and monitoring, a plurality of analytical reactions carried out on a large-scale array of electronic sensors underminimal noise conditions. In one aspect, the invention provides method of improving signal-to-noise ratios of output signals from the electronic sensors sensing analytes or reaction byproducts by subtracting an average of output signals measured from neighboring sensors where analyte or reaction byproducts are absent. In other aspects, the invention provides an array of electronic sensors integrated with a microwell array for confining analytes and/or particles for analytical reactions and a method for identifying microwells containing analytes and/or particles by passing a sensor-active reagent over the array and correlating sensor response times to the presence or absence of analytes or particles. Such detection of analyte- or particle-containing microwells may be used as a step in additional noise reduction methods.
摘要翻译：本发明涉及用于在最小噪声条件下向多个电子传感器阵列上进行的多个分析反应的多个试剂的输送和监测的装置和方法。一方面，本发明提供了通过减去从相邻传感器测得的输出信号的平均值来提高来自电子传感器感测分析物或反应副产物的输出信号的信噪比的方法，其中分析物或反应副产物不存在。在其它方面，本发明提供了与微孔阵列集成的电子传感器阵列，用于限制用于分析反应的分析物和/或颗粒，以及通过使传感器活性试剂通过阵列而识别含有分析物和/或颗粒的微孔的方法，以及将传感器响应时间与分析物或颗粒的存在或不存在相关联。含有分析物或含微粒微孔的这种检测可以用作额外的降噪方法中的步骤。

5. 发明授权

US08936763B2 Integrated sensor arrays for biological and chemical analysis 有权
标题翻译：用于生物和化学分析的集成传感器阵列
公开(公告)号：US08936763B2
公开(公告)日：2015-01-20
申请号：US13125133
申请日：2009-10-22
申请人： Jonathan Rothberg , James Bustillo , Mark Milgrew , Jonathan Schultz , David Marran , Todd Rearick , Kim Johnson
发明人： Jonathan Rothberg , James Bustillo , Mark Milgrew , Jonathan Schultz , David Marran , Todd Rearick , Kim Johnson
IPC分类号： G01N27/403 , G01N27/414 , C12Q1/68 , H01L21/82
CPC分类号： G01N27/4145 , C12Q1/6869 , C12Q1/6874 , G01N27/4148 , H01L21/82 , C12Q2565/607
摘要： The invention is directed to apparatus and chips comprising a large scale chemical field effect transistor arrays that include an array of sample-retaining regions capable of retaining a chemical or biological sample from a sample fluid for analysis. In one aspect such transistor arrays have a pitch of 10 μm or less and each sample-retaining region is positioned on at least one chemical field effect transistor which is configured to generate at least one output signal related to a characteristic of a chemical or biological sample in such sample-retaining region. In one embodiment, the characteristic of said chemical or biological sample is a concentration of a charged species and wherein each of said chemical field effect transistors is an ion-sensitive field effect transistor having a floating gate with a dielectric layer on a surface thereof, the dielectric layer contacting said sample fluid and being capable of accumulating charge in proportion to a concentration of the charged species in said sample fluid. In one embodiment such charged species is a hydrogen ion such that the sensors measure changes in pH of the sample fluid in or adjacent to the sample-retaining region thereof. Apparatus and chips of the invention may be adapted for large scale pH-based DNA sequencing and other bioscience and biomedical applications.
摘要翻译：本发明涉及包括大规模化学场效应晶体管阵列的装置和芯片，其包括能够保留来自样品流体的化学或生物样品用于分析的样品保持区阵列。在一个方面，这种晶体管阵列具有10μm或更小的间距，并且每个采样保持区域位于至少一个化学场效应晶体管上，该晶体管被配置为产生与化学或生物样品的特性相关的至少一个输出信号在这样的样品保留区域中。在一个实施方案中，所述化学或生物样品的特征是带电物质的浓度，并且其中每个所述化学场效应晶体管是离子敏感场效应晶体管，其具有在其表面上具有介电层的浮置栅极，电介质层与所述样品流体接触并且能够与所述样品流体中的带电物质的浓度成比例地积累电荷。在一个实施方案中，这种带电物质是氢离子，使得传感器测量样品流体在其样品保持区域中或其附近的pH值的变化。本发明的装置和芯片可适用于大规模的基于pH的DNA测序和其他生物科学和生物医学应用。

6. 发明申请

US20130302932A1 METHODS FOR MANUFACTURING HIGH CAPACITANCE MICROWELL STRUCTURES OF CHEMICALLY-SENSITIVE SENSORS 有权
标题翻译：化学敏感传感器的高电容微结构的制造方法
公开(公告)号：US20130302932A1
公开(公告)日：2013-11-14
申请号：US13603631
申请日：2012-09-05
申请人： James Bustillo , Jonathan SCHULTZ , Todd Rearick , Mark Milgrew
发明人： James Bustillo , Jonathan SCHULTZ , Todd Rearick , Mark Milgrew
IPC分类号： G01N27/414
CPC分类号： G01N27/4145 , C12Q1/6869 , C12Q1/6874 , G01N27/27 , G01N27/414 , Y10T29/49002
摘要： Methods and apparatus relating to FET arrays for monitoring chemical and/or biological reactions such as nucleic acid sequencing-by-synthesis reactions. Some methods provided herein relate to improving signal (and also signal to noise ratio) from released hydrogen ions during nucleic acid sequencing reactions.
摘要翻译：与用于监测化学和/或生物反应的FET阵列相关的方法和装置，例如核酸序列合成反应。本文提供的一些方法涉及在核酸测序反应期间从释放的氢离子改进信号（以及信噪比）。

7. 发明授权

US10146906B2 Models for analyzing data from sequencing-by-synthesis operations 有权
公开(公告)号：US10146906B2
公开(公告)日：2018-12-04
申请号：US13339846
申请日：2011-12-29
申请人： Todd Rearick , Jonathan Schultz
发明人： Todd Rearick , Jonathan Schultz
IPC分类号： G06F19/24 , C12Q1/6869
摘要： Mathematical models for the analysis of signal data generated by sequencing of a polynucleotide strand using a pH-based method of detecting nucleotide incorporation(s). In an embodiment, the measured output signal from the reaction confinement region of a reactor array is mathematically modeled. The output signal may be modeled as a linear combination of one or more signal components, including a background signal component. This model is solved to determine the nucleotide incorporation signal. In another embodiment, the incorporation signal from the reaction confinement region of a reactor array is mathematically modeled.

8. 发明授权

US09494951B2 Temperature control of chemical detection system 有权
标题翻译：化学检测系统温度控制
公开(公告)号：US09494951B2
公开(公告)日：2016-11-15
申请号：US13216008
申请日：2011-08-23
申请人： Todd Rearick , Jeremy Jordan , John Nobile , William Julian Mileski , Chun Heen Ho
发明人： Todd Rearick , Jeremy Jordan , John Nobile , William Julian Mileski , Chun Heen Ho
IPC分类号： G01N33/48 , G01N27/26 , G05D23/19 , G01N31/20
CPC分类号： G01N27/4145 , B01L3/502 , B01L3/52 , B01L7/00 , B01L2200/0605 , B01L2200/147 , B01L2200/16 , B01L2300/0627 , B01L2300/0829 , B01L2300/1805 , B01L2300/1894 , B01L2400/0487 , B01L2400/0622 , G01N27/414 , G01N31/20 , G05D23/19 , G05D23/1931
摘要： An apparatus for detecting chemical reactions may be provided. The apparatus may comprise a chemical detection device. The chemical detection device may include a chemical sensor, which may be mounted on the chemical detection device. The apparatus may further comprise a valve block. The valve block may fluidly couple a plurality of reagent containers to the chemical detection device. The apparatus may further comprise a heat exchanger and a controller. The controller may control a fluid connection between the valve block and the chemical detection device. The controller may be also configured to adjust a temperature of a selected reagent from the plurality of reagent containers via the heat exchanger. The temperature of the selected reagent may be adjusted prior to the reagent entering the chemical detection device.
摘要翻译：可以提供用于检测化学反应的装置。该装置可以包括化学检测装置。化学检测装置可以包括可安装在化学检测装置上的化学传感器。该装置还可以包括阀块。阀块可以将多个试剂容器流体耦合到化学检测装置。该装置还可以包括热交换器和控制器。控制器可以控制阀块和化学检测装置之间的流体连接。控制器还可以被配置为经由热交换器从多个试剂容器调节所选择的试剂的温度。可以在试剂进入化学检测装置之前调整所选择的试剂的温度。

9. 发明申请

US20120261274A1 METHODS AND APPARATUS FOR MEASURING ANALYTES 审中-公开
标题翻译：测量分析仪的方法和装置
公开(公告)号：US20120261274A1
公开(公告)日：2012-10-18
申请号：US13334747
申请日：2011-12-22
申请人： Todd Rearick , Mark Beauchemin
发明人： Todd Rearick , Mark Beauchemin
IPC分类号： G01N27/414
CPC分类号： G01N27/4145 , C12Q1/6869 , G01N27/27 , G01N27/4148 , G16B30/00
摘要： A method is provided to sample a sensor array. The method can include measuring a waveform associated with a chemical event occurring on the sensor array. The waveform can include at least one region associated with expected measured values and at least one region associated with unpredictable measured values. The method can also include applying a first frame averaging to the at least one region associated with the expected measured values. Here, a first number of frames can be included in the first frame averaging. Further, the method can include applying a second frame averaging to the at least one region associated with the unpredictable measured values, where a second number of frames can be included in the second frame averaging. The second number of frames can be less than the first number of frames.
摘要翻译：提供了一种对传感器阵列进行采样的方法。该方法可以包括测量与传感器阵列上发生的化学事件相关联的波形。波形可以包括与预期测量值相关联的至少一个区域和与不可预测的测量值相关联的至少一个区域。该方法还可以包括将第一帧平均应用于与预期测量值相关联的至少一个区域。这里，可以在第一帧平均中包括第一数量的帧。此外，该方法可以包括将第二帧平均应用于与不可预测的测量值相关联的至少一个区域，其中可以在第二帧平均中包括第二数量的帧。第二帧数可以小于第一帧数。

10. 发明申请

US20130017642A1 CHEMICALLY-SENSITIVE FIELD EFFECT TRANSISTOR BASED PIXEL ARRAY WITH PROTECTION DIODES 审中-公开
标题翻译：具有保护二极管的基于化学敏感场效应晶体管的像素阵列
公开(公告)号：US20130017642A1
公开(公告)日：2013-01-17
申请号：US13607128
申请日：2012-09-07
申请人： Mark Milgrew , James BUSTILLO , Todd Rearick
发明人： Mark Milgrew , James BUSTILLO , Todd Rearick
IPC分类号： H01L21/336
CPC分类号： G01N27/4145 , C12Q1/6869 , C12Q1/6874 , G01N27/27 , G01N27/414 , Y10T29/49002
摘要： Methods and apparatus relating to FET arrays for monitoring chemical and/or biological reactions such as nucleic acid sequencing-by-synthesis reactions. Some methods provided herein relate to improving signal (and also signal to noise ratio) from released hydrogen ions during nucleic acid sequencing reactions.
摘要翻译：与用于监测化学和/或生物反应的FET阵列相关的方法和装置，例如核酸序列合成反应。本文提供的一些方法涉及在核酸测序反应期间从释放的氢离子改进信号（以及信噪比）。

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