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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

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。

3. 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。

4. 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。

5. 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。

6. 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.

7. 发明授权

US08846378B2 Fluidics system for sequential delivery of reagents 有权
标题翻译：用于顺序递送试剂的流体系统
公开(公告)号：US08846378B2
公开(公告)日：2014-09-30
申请号：US13245649
申请日：2011-09-26
申请人： Jonathan Schultz , David Marran
发明人： Jonathan Schultz , David Marran
IPC分类号： C12M1/00 , C12M3/00 , C12M1/34 , B01L3/00 , G01N27/447 , C12Q1/68 , G01N35/10
CPC分类号： B01L3/502715 , B01J2219/00389 , B01J2219/00394 , B01L3/502 , B01L3/50273 , B01L3/502738 , B01L3/502746 , B01L3/502769 , B01L3/502776 , B01L3/52 , B01L2200/16 , B01L2300/0636 , B01L2300/0645 , B01L2300/0861 , B01L2300/0864 , B01L2300/0867 , B01L2300/0874 , B01L2300/0877 , B01L2400/0487 , C12Q1/6869 , G01N27/447 , G01N35/1002 , G01N35/1097 , Y10T137/0318 , Y10T137/0424 , Y10T137/85938 , C12Q2565/629 , C12Q2527/119
摘要： Fluidic circuits and methods of using same are provided herein. In some embodiments, the circuit can direct different fluids to a common volume, such as a reaction chamber or flow cell, without intermixing or cross contamination. The direction and rate of flow through junctions, nodes and passages of the fluidics circuit can be controlled, for example, by the states of upstream valves, differential fluid pressures at circuit inlets or upstream reservoirs, or flow path resistances. Free diffusion or leakage of fluids from unselected inlets into the common outlet or other inlets at junctions or nodes can be prevented by the flow of the selected inlet fluid, a portion of which can sweep by the inlets of unselected fluids and exit the fluidics circuit by waste ports.
摘要翻译：本文提供了流体电路及其使用方法。在一些实施例中，电路可以将不同的流体引导到公共体积，例如反应室或流动池，而不会混合或交叉污染。可通过例如上游阀的状态，电路入口或上游储存器处的差分流体压力或流动阻力来控制流过流体回路的结，节点和通道的流动方向和速率。可以通过所选择的入口流体的流动来防止流体从未选择的入口到共同出口或其他入口处的自由扩散或泄漏，其一部分可以被未选择的流体的入口扫过并且通过废物港口。

8. 发明授权

US08746984B2 Mechanism for mounting and dismounting bearing 有权
标题翻译：安装和拆卸轴承的机构
公开(公告)号：US08746984B2
公开(公告)日：2014-06-10
申请号：US13253476
申请日：2011-10-05
申请人： Daniel Putt , Jonathan Schultz
发明人： Daniel Putt , Jonathan Schultz
IPC分类号： F16C43/00
CPC分类号： F16D1/096 , F16C19/38 , F16C23/086 , F16C35/073 , Y10T29/49 , Y10T29/49636 , Y10T29/49696 , Y10T29/49698 , Y10T29/49947 , Y10T29/53104 , Y10T403/5793 , Y10T403/7069
摘要： A mechanism and method for locking a bearing to a shaft includes a split sleeve and a receptive flange adapted to be fixed to the bearing. A positioning flange is coupled to the split sleeve. A screw extends through the positioning flange and threadingly engages the receptive flange. Rotation of the screw in a first direction axially drives the sleeve into engagement with the bearing to collapse the split sleeve into engagement with the shaft.
摘要翻译：用于将轴承锁定到轴的机构和方法包括分开套筒和适于固定到轴承的容纳凸缘。定位凸缘与分开的套筒相连。螺钉延伸穿过定位凸缘并与接收凸缘螺纹接合。螺杆在第一方向的旋转轴向地驱动套筒与轴承接合，以使分开的套筒与轴接合。

9. 发明授权

US08524057B2 Methods and apparatus for measuring analytes using large scale FET arrays 有权
公开(公告)号：US08524057B2
公开(公告)日：2013-09-03
申请号：US13193128
申请日：2011-07-28
申请人： Jonathan M. Rothberg , Wolfgang Hinz , Kim L. Johnson , James M. Bustillo , John H. Leamon , Jonathan Schultz
发明人： Jonathan M. Rothberg , Wolfgang Hinz , Kim L. Johnson , James M. Bustillo , John H. Leamon , Jonathan Schultz
IPC分类号： G01N27/414
CPC分类号： C12Q1/6874 , B01L3/502761 , B01L2300/046 , B01L2300/0663 , B01L2300/0851 , B01L2400/086 , C12Q1/6869 , G01N27/4145 , G01N27/4148 , C12Q2565/607 , C12Q2565/301 , C12Q2565/629
摘要： Methods and apparatus relating to very large scale FET arrays for analyte measurements. ChemFET (e.g., ISFET) arrays may be fabricated using conventional CMOS processing techniques based on improved FET pixel and array designs that increase measurement sensitivity and accuracy, and at the same time facilitate significantly small pixel sizes and dense arrays. Improved array control techniques provide for rapid data acquisition from large and dense arrays. Such arrays may be employed to detect a presence and/or concentration changes of various analyte types in a wide variety of chemical and/or biological processes. In one example, chemFET arrays facilitate DNA sequencing techniques based on monitoring changes in the concentration of inorganic pyrophosphate (PPi), hydrogen ions, and nucleotide triphosphates.

10. 发明授权

US08546128B2 Fluidics system for sequential delivery of reagents 有权
标题翻译：用于顺序递送试剂的流体系统
公开(公告)号：US08546128B2
公开(公告)日：2013-10-01
申请号：US12785667
申请日：2010-05-24
申请人： Jonathan Schultz , David Marran
发明人： Jonathan Schultz , David Marran
IPC分类号： C12M1/00 , C12M3/00 , C12M1/34 , B01L3/00
CPC分类号： B01L3/502715 , B01J2219/00389 , B01J2219/00394 , B01L3/502 , B01L3/50273 , B01L3/502738 , B01L3/502746 , B01L3/502769 , B01L3/502776 , B01L3/52 , B01L2200/16 , B01L2300/0636 , B01L2300/0645 , B01L2300/0861 , B01L2300/0864 , B01L2300/0867 , B01L2300/0874 , B01L2300/0877 , B01L2400/0487 , C12Q1/6869 , G01N27/447 , G01N35/1002 , G01N35/1097 , Y10T137/0318 , Y10T137/0424 , Y10T137/85938 , C12Q2565/629 , C12Q2527/119
摘要： The invention provides a passive fluidics circuit for directing different fluids to a common volume, such as a reaction chamber or flow cell, without intermixing or cross contamination. The direction and rate of flow through junctions, nodes and passages of the fluidics circuit are controlled by the states of upstream valves (e.g. opened or closed), differential fluid pressures at circuit inlets or upstream reservoirs, flow path resistances, and the like. Free diffusion or leakage of fluids from unselected inlets into the common outlet or other inlets at junctions or nodes is prevented by the flow of the selected inlet fluid, a portion of which sweeps by the inlets of unselected fluids and exits the fluidics circuit by waste ports, thereby creating a barrier against undesired intermixing with the outlet flow through leakage or diffusion. The invention is particularly advantageous in apparatus for performing sensitive multistep reactions, such as pH-based DNA sequencing reactions.
摘要翻译：本发明提供了一种用于将不同流体引导到公共体积（例如反应室或流动池）的无源流体回路，而不会混合或交叉污染。通过流体回路的连接点，节点和通道的流动方向和流速由上游阀（例如打开或关闭）的状态，电路入口或上游储存器处的差分流体压力，流动阻力等来控制。通过所选择的入口流体的流动防止流体从未选择的入口到共同的出口或其他入口处的自由扩散或泄漏，其一部分由未选择的流体的入口扫过并且通过废物端口离开流体回路，从而产生阻止与出口流通过泄漏或扩散的不期望的混合的屏障。本发明在用于进行灵敏多步反应（例如基于pH的DNA测序反应）的装置中特别有利。

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