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51. 发明申请

US20020062072A1 Enhanced biologically based chronotropic biosensing 失效
标题翻译：增强生物学基于时间的生物传感
公开(公告)号：US20020062072A1
公开(公告)日：2002-05-23
申请号：US09848064
申请日：2001-05-03
发明人： Jay M. Edelberg , David J. Christini
IPC分类号： A61B005/05 , A61B005/00
CPC分类号： A61L27/383 , A61L27/3604 , A61L27/3826 , Y10S977/853
摘要： The present invention provides implantable physiological or pathophysiological biosensors. The subject biosensors comprise tissue or cells capable of carrying out a physiological or pathophysiological function, which can be used to monitor a chemical, physiological or pathophysiological variable associated with the physiological or pathophysiological function. In one embodiment, the tissue or cells are coupled via an electrical interface to an electronic measuring device or an electronic amplifying device. In another embodiment, the tissue or cells are coupled via an electrical interface to endogenous tissue or cells, including the blood. Preferably, the tissue or cells are excitable tissue or cells such as cardiac tissue or cells and neuronal tissue or cells. The subject biosensors may be placed, inserted or implanted in any animal including but not limited to a mouse, rat, rabbit, pig, cat, dog, cattle, horse, sheep or human. The present invention also provides various methods which employ a biosensor of the present invention. Such methods include a method of monitoring physiological or pathophysiological function, a method of regulating output of a signal to a subject, and a method for controlling heart function.
摘要翻译：本发明提供可植入的生理或病理生物传感器。受试者生物传感器包括能够进行生理或病理生理功能的组织或细胞，其可用于监测与生理或病理生理功能相关的化学，生理或病理生理学变量。在一个实施例中，组织或细胞通过电接口耦合到电子测量装置或电子放大装置。在另一个实施方案中，经由电接口将组织或细胞偶联至内源性组织或细胞，包括血液。优选地，组织或细胞是可兴奋的组织或细胞，例如心脏组织或细胞和神经元组织或细胞。主题生物传感器可以放置，插入或植入任何动物，包括但不限于小鼠，大鼠，兔，猪，猫，狗，牛，马，绵羊或人。本发明还提供采用本发明的生物传感器的各种方法。这样的方法包括监测生理或病理生理功能的方法，调节对受试者的信号输出的方法以及用于控制心脏功能的方法。

52. 发明授权

US06287765B1 Methods for detecting and identifying single molecules 失效
标题翻译：检测和识别单分子的方法
公开(公告)号：US06287765B1
公开(公告)日：2001-09-11
申请号：US09081930
申请日：1998-05-20
申请人： Roger S. Cubicciotti
发明人： Roger S. Cubicciotti
IPC分类号： C12Q108
CPC分类号： C07H21/00 , Y10S977/853
摘要： Multimolecular devices and drug delivery systems prepared from synthetic heteropolymers, heteropolymeric discrete structures, multivalent heteropolymeric hybrid structures, aptameric multimolecular devices, multivalent imprints, tethered specific recognition devices, paired specific recognition devices, nonaptameric multimolecular devices and immobilized multimolecular structures are provided, including molecular adsorbents and multimolecular adherents, adhesives, transducers, switches, sensors and delivery systems. Methods for selecting single synthetic nucleotides, shape-specific probes and specifically attractive surfaces for use in these multimolecular devices are also provided. In addition, paired nucleotide-nonnucleotide mapping libraries for transposition of selected populations of selected nonoligonucleotide molecules into selected populations of replicatable nucleotide sequences are described.
摘要翻译：提供了由合成杂聚物，异聚分子结构，多价杂聚杂合结构，适体多分子装置，多价印记，系留特异性识别装置，配对特异性识别装置，非多聚多分子装置和固定化多分子结构制备的多分子装置和药物递送系统，包括分子吸附剂和多分子粘附剂，粘合剂，换能器，开关，传感器和输送系统。还提供了用于选择单个合成核苷酸，形状特异性探针和用于这些多分子装置的特别有吸引力的表面的方法。此外，描述了用于将选定的非寡核苷酸分子的选定群体转移到选择的可复制核苷酸序列群体中的配对核苷酸 - 非核苷酸映射文库。

53. 发明授权

US5992226A Apparatus and method for measuring intermolecular interactions by atomic force microscopy 失效
标题翻译：用原子力显微镜测量分子间相互作用的装置和方法
公开(公告)号：US5992226A
公开(公告)日：1999-11-30
申请号：US74541
申请日：1998-05-08
申请人： John-Bruce DeVault Green , Gil U Lee
发明人： John-Bruce DeVault Green , Gil U Lee
IPC分类号： G01B21/30 , G01B5/00 , G01B5/30 , G01Q30/02 , G01Q60/24 , G01Q60/42 , G01N27/00
CPC分类号： G01Q60/42 , B82Y35/00 , Y10S977/849 , Y10S977/851 , Y10S977/853 , Y10S977/863
摘要： A sample support member for atomic force microscopy of intermolecular interactions includes a sample support base having a plurality of protrusions, each protrusion having an apical substrate region or tip that has been chemically modified by the immobilization thereon of a sample compound or of a linking compound that is capable of binding a sample compound. A reference compound support member has a surface region having at least one reference compound immobilized thereon.The relative position and orientation of the reference compound support member and the substrate support member are controlled to select a particular protrusion and to cause an interaction between a reference compound immobilized on the surface region of the free end of the cantilever and the sample compound immobilized on the apical substrate area of the selected protrusion. A physical parameter associated with the interaction between the reference compound and the sample compound can be measured.
摘要翻译：用于分子间相互作用的原子力显微镜的样品支撑构件包括具有多个突起的样品支撑基底，每个突起具有通过其上固定化样品化合物或连接化合物进行化学修饰的顶端基底区域或尖端，能够结合样品化合物。参考化合物支撑构件具有固定有至少一个参考化合物的表面区域。控制参考化合物支撑构件和基板支撑构件的相对位置和取向以选择特定的突起并且使固定在悬臂自由端的表面区域上的参考化合物与固定在悬臂梁上的样品化合物之间的相互作用所选突起的顶端基底面积。可以测量与参考化合物和样品化合物之间的相互作用相关的物理参数。

54. 发明授权

US5958701A Method for measuring intramolecular forces by atomic force 失效
标题翻译：用原子力测量分子内力的方法
公开(公告)号：US5958701A
公开(公告)日：1999-09-28
申请号：US272733
申请日：1999-01-27
申请人： John-Bruce De Vault Green , Alexey Novoradovsky , Gil U. Lee
发明人： John-Bruce De Vault Green , Alexey Novoradovsky , Gil U. Lee
IPC分类号： C12Q1/68 , G01Q30/20 , G01Q60/24
CPC分类号： G01Q60/42 , B82Y35/00 , Y10S977/853 , Y10S977/863 , Y10S977/873 , Y10S977/881 , Y10S977/924
摘要： A method is disclosed for measuring intramolecular forces within a sample compound by providing an atomic force microscope that includes a sample support member and a cantilever. The sample support member has a plurality of protrusions, and each protrusion has an apical substrate region that has been chemically modified to have a sample compound immobilized thereon. The cantilever has a fixed end and a free end, the free end having a surface region that has been chemically modified to have a grasping compound immobilized thereon. To measure intramolecular forces within the sample compound, the relative position and orientation of the cantilever and the sample support member are controlled to select a particular protrusion and to allow a molecule of the grasping compound to bind with a molecule of the sample compound. Then, the relative position and orientation of the cantilever and the sample support member are controlled to vary the distance between the cantilever and the sample support member so that the forces exerted on the cantilever as the distance between the cantilever and the sample support member is varied and as the molecule of the sample compound is stretched between the cantilever and the sample support member can be measured.
摘要翻译：公开了一种用于通过提供包括样品支撑构件和悬臂的原子力显微镜来测量样品化合物内的分子内力的方法。样品支撑构件具有多个突起，并且每个突起具有经化学修饰以固定其上的样品化合物的顶端基底区域。悬臂具有固定端和自由端，自由端具有经化学修饰以具有固定在其上的抓握化合物的表面区域。为了测量样品化合物内的分子内力，控制悬臂和样品支撑构件的相对位置和取向以选择特定的突起并使得抓握化合物的分子与样品化合物的分子结合。然后，控制悬臂和样品支撑构件的相对位置和取向以改变悬臂和样品支撑构件之间的距离，使得当悬臂与样品支撑构件之间的距离变化时施加在悬臂上的力并且可以测量样品化合物的分子在悬臂和样品支撑构件之间的拉伸。

55. 发明授权

US5363697A Scanning probe microscope, molecular processing method using the scanning probe microscope and DNA base arrangement detecting method 失效
标题翻译：扫描探针显微镜，使用扫描探针显微镜的分子加工方法和DNA碱基排列检测方法
公开(公告)号：US5363697A
公开(公告)日：1994-11-15
申请号：US875694
申请日：1992-04-29
申请人： Tohru Nakagawa
发明人： Tohru Nakagawa
IPC分类号： C12M1/34 , C12M1/40 , C12Q1/68 , G01B7/34 , G01B21/30 , G01N27/416 , G01Q60/10 , G01Q60/24 , G01Q60/38 , G01Q60/42 , G01Q60/44 , G01Q70/00 , G01B5/28
CPC分类号： G01Q60/60 , B82Y35/00 , G01Q60/42 , B82Y30/00 , Y10S977/728 , Y10S977/849 , Y10S977/852 , Y10S977/853 , Y10S977/86 , Y10S977/877 , Y10S977/879 , Y10S977/881 , Y10S977/924 , Y10S977/958
摘要： This invention relates to a scanning probe microscope which examines or processes directly the structure of substance surfaces at the molecular or atomic level, and a method for processing molecules using a scanning probe microscope and a method for detecting DNA base arrangement. A scanning probe microscope has a probe approaching or contacting the substance surface to detect a physical quantity between the substance surface and the probe, wherein the physical quantity is what is interacted or chemically reacted between the substance surface and the molecules or atom groups which act as a sensor and are fixed on the probe, scanning at an atomic level of precision. Therefore, surface structure within a microscopic region can be examined or processed at the molecular or atomic level. A method for detecting DNA base arrangement with any one of three or four kinds of probes fixed with any one of four different kinds of molecules interacting four kinds of bases consisting of DNA, by approaching single stranded DNA fixed on a substrate, measuring the force and scanning by an atomic force microscope at an atomic level of precision.
摘要翻译：本发明涉及一种扫描探针显微镜，该扫描探针显微镜直接检查分子或原子水平的物质表面的结构，以及使用扫描探针显微镜处理分子的方法和检测DNA碱基排列的方法。扫描探针显微镜具有接近或接触物质表面的探针以检测物质表面和探针之间的物理量，其中物理量是物质表面与作为的物质表面和分子或原子团之间的相互作用或化学反应的物质传感器并固定在探头上，以原子级精度扫描。因此，微观区域内的表面结构可以在分子或原子水平进行检查或处理。用四种不同种类的分子中的任何一种分离的任何一种探针中的任何一种探测DNA的检测方法，其通过接近固定在基底上的单链DNA，测量力和与用原子力显微镜以原子精度扫描。

56. 发明授权

US5314829A Method for imaging informational biological molecules on a semiconductor substrate 失效
标题翻译：在半导体衬底上成像信息生物分子的方法
公开(公告)号：US5314829A
公开(公告)日：1994-05-24
申请号：US992601
申请日：1992-12-18
申请人： L. Stephen Coles
发明人： L. Stephen Coles
IPC分类号： B01L3/00 , C07B61/00 , C07K1/04 , C40B70/00 , G01N33/48 , G01N35/00 , G01Q30/20 , G01Q70/14 , G01N21/03
CPC分类号： B01L3/508 , B01L3/502761 , B01L9/50 , C07K1/047 , B01J2219/00547 , B01J2219/00549 , B01J2219/00608 , B01J2219/00612 , B01J2219/00621 , B01J2219/00659 , B01L2200/0663 , B01L2200/0668 , B01L2300/021 , B01L2300/0803 , B01L2300/0819 , B01L2300/0893 , B01L2400/0415 , B01L2400/0472 , B82Y15/00 , C40B70/00 , G01N2035/00237 , Y10S977/853 , Y10T436/13 , Y10T436/143333
摘要： Imaging biological molecules such as DNA at rates several times faster than conventional imaging techniques is carried out using a patterned silicon wafer having nano-machined grooves which hold individual molecular strands and periodically spaced unique bar codes permitting repeatably locating all images. The strands are coaxed into the grooves preferably using gravity and pulsed electric fields which induce electric charge attraction to the molecular strands in the bottom surfaces of the grooves. Differential imaging removes substrate artifacts.
摘要翻译：使用具有纳米加工凹槽的图案化硅晶片，以比传统成像技术快几倍的速率成像生物分子，例如DNA，其保持单独的分子链，并且周期性地间隔开独特的条形码，可重复定位所有图像。绞线优选地使用重力和脉冲电场哄骗，这些电场引起对槽的底表面中的分子线的电荷吸引。差分成像消除了底物伪影。

57. 发明授权

US08574892B2 Methods and apparatus for nucleic acid sequencing by signal stretching and data integration 有权
标题翻译：通过信号拉伸和数据整合进行核酸测序的方法和装置
公开(公告)号：US08574892B2
公开(公告)日：2013-11-05
申请号：US11233933
申请日：2005-09-22
申请人： Xing Su
发明人： Xing Su
IPC分类号： C12M1/34 , C12M3/00 , C12Q1/68 , C07H21/04 , G01N33/48
CPC分类号： C12Q1/6869 , B82Y5/00 , Y10S977/853 , C12Q2565/631
摘要： The methods and apparatus 100 disclosed herein concern DNA sequencing. In some embodiments of the invention, the methods comprise measuring the distance between labeled nucleotides 220, such as nucleotides labeled with bulky groups. The methods may further comprise placing identical template DNA 200 into four reaction chambers 110, 120, 130, 140, each containing a different labeled nucleotide precursor, synthesizing complementary strands 230, 240, 250 and detecting labeled nucleotides 220. The distances between labeled nucleotides 220 may be used to construct 450 distance maps 310, 320, 330, 340 for each type of labeled nucleotide 220. The distance maps 310, 320, 330, 340 may be aligned 520 to obtain a nucleic acid sequence 210. Overlapping data analysis and frequency analysis may be used to construct 450 the distance maps 310, 320, 330, 340 and non-overlapping data analysis may be used to align 520 the distance maps into a sequence 210.
摘要翻译：本文公开的方法和装置100涉及DNA测序。在本发明的一些实施方案中，所述方法包括测量标记的核苷酸220之间的距离，例如用大体积标记的核苷酸。所述方法还可以包括将相同的模板DNA 200置于四个反应室110,120,130,140中，每个反应室含有不同的标记的核苷酸前体，合成互补链230,240,250和检测标记的核苷酸220.标记的核苷酸220之间的距离可以用于为每种类型的标记核苷酸220构建450个距离图310,320,330,340。距离图310,320,330,340可以对齐520以获得核酸序列210.重叠的数据分析和频率可以使用分析来构建距离映射310,320,330,340，并且可以使用不重叠的数据分析来将距离映射映射到序列210中。

58. 发明授权

US08187673B2 Methods utilizing scanning probe microscope tips and products thereof or produced thereby 有权
标题翻译：使用扫描探针显微镜尖端及其产品或由其制造的方法
公开(公告)号：US08187673B2
公开(公告)日：2012-05-29
申请号：US11933251
申请日：2007-10-31
申请人： Chad A. Mirkin , Richard Piner , Seunghun Hong
发明人： Chad A. Mirkin , Richard Piner , Seunghun Hong
IPC分类号： B05D3/00
CPC分类号： B82B3/00 , B05D1/007 , B05D1/185 , B05D1/26 , G01Q80/00 , G03F7/0002 , G03F7/165 , Y10S977/849 , Y10S977/853 , Y10S977/854 , Y10S977/855 , Y10S977/856 , Y10S977/857 , Y10S977/86 , Y10S977/88 , Y10S977/884 , Y10S977/885 , Y10S977/886 , Y10S977/895 , Y10T428/24802
摘要： The invention provides a lithographic method referred to as “dip pen” nanolithography (DPN). DPN utilizes a scanning probe microscope (SPM) tip (e.g., an atomic force microscope (AFM) tip) as a “pen,” a solid-state substrate (e.g., gold) as “paper,” and molecules with a chemical affinity for the solid-state substrate as “ink.” Capillary transport of molecules from the SPM tip to the solid substrate is used in DPN to directly write patterns consisting of a relatively small collection of molecules in submicrometer dimensions, making DPN useful in the fabrication of a variety of microscale and nanoscale devices. The invention also provides substrates patterned by DPN, including submicrometer combinatorial arrays, and kits, devices and software for performing DPN. The invention further provides a method of performing AFM imaging in air. The method comprises coating an AFM tip with a hydrophobic compound, the hydrophobic compound being selected so that AFM imaging performed using the coated AFM tip is improved compared to AFM imaging performed using an uncoated AFM tip. Finally, the invention provides AFM tips coated with the hydrophobic compounds.
摘要翻译：本发明提供了称为“浸笔”纳米光刻（DPN）的光刻方法。 DPN使用扫描探针显微镜（SPM）尖端（例如，原子力显微镜（AFM）尖端）作为“笔”，固态基底（例如，金）作为“纸”，并且具有化学亲和力的分子固体底物作为“墨水”。DPN中使用分子从SPM尖端到固体基质的毛细管转运，以直接写入由亚微米尺寸的相对小的分子集合组成的图案，使得DPN可用于制造各种微米级和纳米级器件。本发明还提供由DPN图案化的衬底，包括亚微米组合阵列，以及用于执行DPN的试剂盒，装置和软件。本发明还提供了一种在空气中进行AFM成像的方法。该方法包括用疏水性化合物涂覆AFM尖端，选择疏水性化合物，使得与使用未涂覆的AFM尖端进行的AFM成像相比，使用涂覆的AFM尖端进行的AFM成像得到改善。最后，本发明提供涂覆有疏水化合物的AFM尖端。

59. 发明授权

US07507957B2 Probe microscope system suitable for observing sample of long body 有权
标题翻译：探头显微镜系统适用于长时间观察样品
公开(公告)号：US07507957B2
公开(公告)日：2009-03-24
申请号：US11216389
申请日：2005-08-31
申请人： Masamichi Fujihira , Masatoshi Yasutake , Tatsuaki Ataka
发明人： Masamichi Fujihira , Masatoshi Yasutake , Tatsuaki Ataka
IPC分类号： G01N23/00
CPC分类号： G01Q30/14 , G01Q10/06 , Y10S977/853 , Y10S977/86 , Y10S977/862 , Y10S977/869 , Y10S977/871
摘要： A problem to be resolved by the invention resides in providing a multifunction analyzing apparatus for detecting a shape with high resolution and physical property information capable of not only successively reading a base arrangement from end to end but also specifying a position hybridized by known RNA with regard to a single piece of DNA elongated in one direction on a board. A microscope system of the invention is provided with a fluorescence microscope, a scanning near field microscope and a scanning probe microscope as a detecting system, the microscopes are fixed to a switching mechanism and can be moved to a position at which the various microscopes can observe the same portion of a sample by switching operation of the mechanism. The microscope system of the invention is provided with a function capable of directly detecting a shape and physical property information of one piece of DNA by the scanning probe microscope by multifunction scanning.
摘要翻译：本发明要解决的问题在于提供一种用于检测具有高分辨率和物理属性信息的形状的多功能分析装置，其不仅能够从一端到另一端连续读取基本排列，而且还指定与已知RNA杂交的位置到在板上沿一个方向伸长的单个DNA。本发明的显微镜系统设置有荧光显微镜，扫描型近场显微镜和扫描探针显微镜作为检测系统，将显微镜固定在切换机构上，并可移动到各种显微镜可以观察到的位置通过切换机构的操作来获取样品的相同部分。本发明的显微镜系统具有能够通过扫描探针显微镜通过多功能扫描直接检测一片DNA的形状和物理性质信息的功能。

60. 发明申请

US20070231795A1 Methods and apparatus for nucleic acid sequencing by signal stretching and data integration 有权
标题翻译：通过信号拉伸和数据整合进行核酸测序的方法和装置
公开(公告)号：US20070231795A1
公开(公告)日：2007-10-04
申请号：US11233933
申请日：2005-09-22
申请人： Xing Su
发明人： Xing Su
IPC分类号： C12Q1/68 , G06F19/00
CPC分类号： C12Q1/6869 , B82Y5/00 , Y10S977/853 , C12Q2565/631
摘要： The methods and apparatus 100 disclosed herein concern DNA sequencing. In some embodiments of the invention, the methods comprise measuring the distance between labeled nucleotides 220, such as nucleotides labeled with bulky groups. The methods may further comprise placing identical template DNA 200 into four reaction chambers 110, 120, 130, 140, each containing a different labeled nucleotide precursor, synthesizing complementary strands 230, 240, 250 and detecting labeled nucleotides 220. The distances between labeled nucleotides 220 may be used to construct 450 distance maps 310, 320, 330, 340 for each type of labeled nucleotide 220. The distance maps 310, 320, 330, 340 may be aligned 520 to obtain a nucleic acid sequence 210. Overlapping data analysis and frequency analysis may be used to construct 450 the distance maps 310, 320, 330, 340 and non-overlapping data analysis may be used to align 520 the distance maps into a sequence 210.
摘要翻译：本文公开的方法和装置100涉及DNA测序。在本发明的一些实施方案中，所述方法包括测量标记的核苷酸220之间的距离，例如用大体积标记的核苷酸。所述方法可以进一步包括将相同的模板DNA 200置于四个反应室110,120,130,140中，每个反应室含有不同的标记的核苷酸前体，合成互补链230,240,250和检测标记的核苷酸220。标记的核苷酸220之间的距离可用于为每种类型的标记核苷酸220构建450个距离图310,320,330,340。距离图310,320,330,340可以对齐520以获得核酸序列210。可以使用重叠数据分析和频率分析来构造距离映射310,320,330,340，并且可以使用不重叠的数据分析来将距离图对准520到序列210中。

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