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1. 发明公开

EP1711626A2 NUCLEIC ACID SEQUENCING BY RAMAN MONITORING OF UPTAKE OF NUCLEOTIDES DURING MOLECULAR REPLICATION 审中-公开
标题翻译：拉曼监测分子复制过程中核苷酸摄取的核酸序列分析
公开(公告)号：EP1711626A2
公开(公告)日：2006-10-18
申请号：EP04821053.8
申请日：2004-12-28
申请人： INTEL CORPORATION
发明人： BERLIN, Andrew , SU, Xing , CHAN, Selena , KOO, Tae-Woong , SUN, Lei , SUNDARARAJAN, Narayan
IPC分类号： C12Q1/68
CPC分类号： G01N21/658 , C12Q1/6869 , C12Q2565/632 , C12Q2533/101
摘要： The methods and apparatus disclosed herein are useful for detecting nucleotides, nucleosides, and bases and for nucleic acid sequence determination. The methods involve detection of a nucleotide, nucleoside, or base using surface enhanced Raman spectroscopy (SERS) or surface enhanced coherent anti-Stokes Raman spectroscopy (SECARS). The detection can be part of a nucleic acid sequencing reaction to detect uptake of a deoxynucleotide triphosphate during a nucleic acid polymerization reaction, such as a nucleic acid sequencing reaction. The nucleic acid sequence of a synthesized nascent strand, and the complementary sequence of the template strand, can be determined by tracking the order of incorporation of nucleotides during the polymerization reaction. Methods for enhancing the SERS signal of a nucleotide or nucleoside by cleaving the base from a sugar moiety are provided. Furthermore, methods for detecting single base repeats are provided.
摘要翻译：本文公开的方法和装置可用于检测核苷酸，核苷和碱基并用于核酸序列测定。该方法涉及使用表面增强拉曼光谱（SERS）或表面增强相干反斯托克斯拉曼光谱（SECARS）检测核苷酸，核苷或碱基。检测可以是核酸测序反应的一部分，以在核酸聚合反应（例如核酸测序反应）期间检测脱氧核苷酸三磷酸的摄取。合成的新生链的核酸序列和模板链的互补序列可以通过追踪聚合反应期间核苷酸掺入的顺序来确定。提供了通过从糖部分切割碱基来增强核苷酸或核苷的SERS信号的方法。此外，提供了检测单碱基重复的方法。

2. 发明公开

EP1711829A2 METHODS FOR USING RAMAN SPECTROSCOPY TO OBTAIN A PROTEIN PROFILE OF A BIOLOGICAL SAMPLE 审中-公开
标题翻译：用拉曼光谱对蛋白质的保护方法PROFILE生物样品
公开(公告)号：EP1711829A2
公开(公告)日：2006-10-18
申请号：EP04815772.1
申请日：2004-12-29
申请人： Intel Corporation
发明人： BERLIN, Andrew , SU, Xing , CHAN, Selena , KOO, Tae-Woong , SUN, Lei , SUNDARARAJAN, Narayan , YAMAKAWA, Mineo
IPC分类号： G01N33/58
CPC分类号： G01N21/658 , G01N33/6803 , G01N2021/653 , G01N2021/655 , G01N2021/656
摘要： The invention provides methods for analyzing the protein content of a biological sample, for example to obtain a protein profile of a sample provided by a particular individual. The proteins and protein fragments in the sample are separated on the basis of chemical and/or physical properties and maintained in a separated state at discrete locations on a solid substrate or within a stream of flowing liquid. Raman spectra are then detected as produced by the separated proteins or fragments at the discrete locations such that a spectrum from a discrete location provides information about the structure or identity of one or more particular proteins or fragments at the discrete location. The proteins or fragments at discrete locations can be coated with a metal, such as gold or silver, and/or the separated proteins can be contacted with a chemical enhancer to provide SERS spectra. Method and kits for practicing the invention are also provided.

3. 发明公开

EP1488002A2 METHODS TO INCREASE NUCLEOTIDE SIGNALS BY RAMAN SCATTERING 审中-公开
标题翻译：方法来增加拉曼NUKLEOTIDSIGNALEN溢油手段
公开(公告)号：EP1488002A2
公开(公告)日：2004-12-22
申请号：EP03719382.8
申请日：2003-03-11
申请人： INTEL CORPORATION
发明人： SU, Xing , BERLIN, Andrew , KOO, Tae-Woong , CHAN, Selena , SUNDARARAJAN, Narayan , YAMAKAWA, Mineo
IPC分类号： C12Q1/68 , C12P19/34 , C07H21/02 , G01N21/29
CPC分类号： C12Q1/6869 , C12Q1/6816 , C12Q1/6825 , C12Q1/6872 , C12Q2565/632 , C12Q2563/155 , C12Q2521/319
摘要： The methods and apparatus disclosed herein concern nucleic acid sequencing by enhanced Raman spectroscopy. In certain embodiments of the invention, nucleotides are covalently attached to Raman labels before incorporation into a nucleic acid (13). Exonuclease (15) treatment of the labeled nucleic acid (13) results in the release of labeled nucleotides (16, 130), which are detected by Raman spectroscopy. In alternative embodiments of the invention, nucleotides (16, 130) released from a nucleic acid (13) by exonuclease (15) treatment are covalently cross-linked to silver or gold nanoparticles (140) and detected by surface enhanced Raman spectroscopy (SERS), surface enhanced resonance Raman spectroscopy (SERRS) and/or coherent anti-Stokes Raman spectroscopy (CARS). Other embodiments of the invention concern apparatus (10, 100, 210) for nucleic acid sequencing.

4. 发明授权

EP1552531B1 DETECTION AND IDENTIFICATION OF BIOMOLECULES BY MEANS OF IMAGES CAPTURED BY SPM 有权
标题翻译：检测和生物分子的鉴定使用探测显微图像GRID
公开(公告)号：EP1552531B1
公开(公告)日：2013-05-01
申请号：EP03809156.7
申请日：2003-10-16
申请人： Intel Corporation
发明人： HAUSSECKER, Horst , BERLIN, Andrew , CHAN, Selena , HANNAH, Eric , SUNDARARAJAN, Narayan , YAMAKAWA, Mineo
IPC分类号： G01N27/00
CPC分类号： G01Q30/04

5. 发明公开

EP1664335A1 METHODS TO INCREASE NUCLEOTIDE SIGNALS BY RAMAN SCATTERING 审中-公开
标题翻译： VERFAHREN ZURVERSTÄRKUNGVON NUKLEOTIDSIGNALEN DURCH RAMANSTREUUNG
公开(公告)号：EP1664335A1
公开(公告)日：2006-06-07
申请号：EP03752462.6
申请日：2003-09-15
申请人： INTEL CORPORATION
发明人： SU, Xing , BERLIN, Andrew, A. , CHAN, Selena , KIRCH, Steven, J. , KOO, Tae-Woong , NEUBAUER, Gabi , RAO, Valluri , SUNDARARAJAN, Narayan , YAMAKAWA, Mineo
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6869 , C12Q2565/632 , C12Q2563/155 , C12Q2521/319
摘要： The methods and apparatus disclosed herein concern nucleic acid sequencing by enhanced Raman spectroscopy. In certain embodiments of the invention, nucleotides are covalently attached to Raman labels before incorporation into a nucleic acid. In other embodiments, unlabeled nucleic acids are used. Exonuclease treatment of the nucleic acid results in the release of labeled or unlabeled nucleotides that are detected by Raman spectroscopy. In alternative embodiments of the invention, nucleotides released from a nucleic acid by exonuclease treatment are covalently cross-linked to nanoparticles and detected by surface enhanced Raman spectroscopy (SERS), surface enhanced resonance Raman spectroscopy (SERRS) and/or coherent anti-Stokes Raman spectroscopy (CARS). Other embodiments of the invention concern apparatus for nucleic acid sequencing.
摘要翻译：本文公开的方法和装置涉及通过增强拉曼光谱进行的核酸测序。在本发明的某些实施方案中，核苷酸在引入核酸之前共价连接到拉曼标记上。在其它实施方案中，使用未标记的核酸。核酸外切核酸处理导致通过拉曼光谱法检测的标记或未标记的核苷酸的释放。在本发明的替代实施方案中，通过外切核酸酶处理从核酸释放的核苷酸与纳米颗粒共价交联，并通过表面增强拉曼光谱（SERS），表面增强共振拉曼光谱（SERRS）和/或相干反斯托克斯拉曼光谱学（CARS）。本发明的其它实施方案涉及核酸测序装置。

6. 发明公开

EP1552531A1 MODEL-BASED FUSION OF SCANNING PROBE MICROSCOPIC IMAGES FOR DETECTION AND IDENTIFICATION OF MOLECULAR STRUCTURES 有权
标题翻译：检测和生物分子的鉴定使用探测显微图像GRID
公开(公告)号：EP1552531A1
公开(公告)日：2005-07-13
申请号：EP03809156.7
申请日：2003-10-16
申请人： INTEL CORPORATION
发明人： HAUSSECKER, Horst , BERLIN, Andrew , CHAN, Selena , HANNAH, Eric , SUNDARARAJAN, Narayan , YAMAKAWA, Mineo
IPC分类号： G12B21/00 , G01N27/00
CPC分类号： G01Q30/04
摘要： In certain embodiments of the invention, a plurality of images of one or more subjects may be captured using different imaging techniques, such as different modalities of scanning probe microscopy. Parameters may be estimated from the plurality of images, using one or more models of known molecular structures to provide a model-based analysis. The estimated parameters may be fused, with further input from physical models of known molecular structures. The fused parameters may be used to characterize the subjects. Such characterization may include the detection and/or identification of specific molecular structures, such as proteins, peptides and/or nucleic acids of known sequence and/or structure. In some embodiments of the invention the structural characterizations may be used to identify previously unknown properties of a subject molecule.

7. 发明公开

EP1513950A1 APPLICATION OF CANTILEVERS IN NUCLEIC ACID SEQUENCING 审中-公开
标题翻译：悬挂剂在核酸测序中的应用
公开(公告)号：EP1513950A1
公开(公告)日：2005-03-16
申请号：EP03726388.6
申请日：2003-04-18
申请人： INTEL CORPORATION
发明人： SUNDARARAJAN, Narayan , BERLIN, Andrew , YAMAKAWA, Mineo , SU, Xing , CHAN, Selena , KOO, Tae-Woong
IPC分类号： C12Q1/68 , C12M1/34
CPC分类号： C12Q1/6825 , B82Y5/00 , B82Y15/00 , B82Y30/00 , C12Q1/6869 , C12Q2563/155 , C12Q2565/607
摘要： The present methods and apparatus 100 concern nucleic acid 214 sequencing by incorporation of nucleotides 218 into nucleic acid strands 220. The incorporation of nucleotides 218 is detected by changes in the mass and/or surface stress of the structure 116, 212. In some embodiments of the invention, the structure 116, 212 comprises one or more nanoscale or microsacle cantilevers. In certain embodiments of the invention, each different type of nucleotide 218 is distinguishably labeled with a bulky group and each incorporated nucleotide 218 is identified by the changes in mass and/or surface stress of the structure 116, 212 upon incorporation of the nucleotide 218. In alternative embodiments of the invention only one type of nucleotide 218 is exposed at a time to the nucleic acids 214, 220. Changes in the properties of the structure 116, 212 may be detected by a variety of methods, such as piezoelectric detection, shifts in resonant frequency of the structure 116, 212, and/or position sensitive photodetection.
摘要翻译：本发明的方法和设备100涉及通过将核苷酸218掺入核酸链220来进行核酸214测序。核苷酸218的掺入通过结构116,212的质量和/或表面应力的变化来检测。在一些实施方式中，本发明中，结构116,212包括一个或多个纳米级或微型悬臂梁。在本发明的某些实施方案中，每个不同类型的核苷酸218用庞大的基团可区分地标记，并且每个掺入的核苷酸218通过掺入核苷酸218后结构116,212的质量和/或表面应力的变化来鉴定。在本发明的可选实施方案中，一次只有一种类型的核苷酸218暴露于核酸214,220。结构116,212的性质的变化可以通过多种方法检测，诸如压电检测，偏移在结构116,212的谐振频率中，和/或位置敏感的光电检测。

8. 发明授权

EP1595120B1 METAL COATED NANOCRYSTALLINE SILICON AS AN ACTIVE SURFACE ENHANCED RAMAN SPECTROSCOPY (SERS) SUBSTRATE 有权
标题翻译：涂布金属纳米晶硅为活性基材表面增强拉曼光谱（SERS）
公开(公告)号：EP1595120B1
公开(公告)日：2009-12-30
申请号：EP03774634.4
申请日：2003-10-07
申请人： Intel Corporation
发明人： CHAN, Selena , BERLIN, Andrew , KWON, Sunghoon , SUNDARARAJAN, Narayan , YAMAKAWA, Mineo
IPC分类号： G01J3/44 , G01N21/65
CPC分类号： G01N21/658 , B01D67/0062 , B01D67/0086 , B01D67/0088 , B01D71/02 , B82Y15/00 , B82Y30/00 , C12Q1/6825 , G01J3/44 , G01N21/65 , G01N2021/6439 , G01N2021/655 , G01N2021/656 , C12Q2565/632 , C12Q2563/155
摘要： The disclosed methods and apparatus concern Raman spectroscopy using metal coated nanocrystalline porous silicon substrates. Porous silicon substrates may be formed by anodic etching in dilute hydrofluoric acid. A thin coating of a Raman active metal, such as gold or silver, may be coated onto the porous silicon by cathodic electromigration or any known technique. In certain alternatives, the metal coated porous silicon substrate comprises a plasma-oxidized, dip and decomposed porous silicon substrate. The metalcoated substrate provides an extensive, metal rich environment for SERS, SERBS, hyperRaman and/or CARS Raman spectroscopy. In certain alternatives, metal nanoparticles may be added to the metal-coated substrate to further enhance the Raman signals. Raman spectroscopy may be used to detect, identify and/or quantify a wide variety of analytes, using the disclosed methods and apparatus. In some disclosed methods, Raman spectroscopy may be used to detect nucleotides, purines or pyrimidines at the single molecule level.

9. 发明公开

EP1699938A2 METHODS OF PRODUCING CARBON NANOTUBES USING PEPTIDE OR NUCLEIC ACID MICROPATTERNING 审中-公开
标题翻译：工艺制造碳纳米管的使用肽或核酸MICRO图案的生产
公开(公告)号：EP1699938A2
公开(公告)日：2006-09-13
申请号：EP04818073.1
申请日：2004-12-24
申请人： INTEL CORPORATION
发明人： SU, Xing , SUNDARARAJAN, Narayan , YAMAKAWA, Mineo , BERLIN, Andrew , SUN, Lei , ZHANG, Yuegang
IPC分类号： C12Q1/68
CPC分类号： B82Y40/00 , B82Y10/00 , B82Y30/00 , C01B32/162 , C01B2202/08 , C01B2202/36 , D01F9/127 , H01L51/0048 , H01L51/0052
摘要： The methods, apparatus and systems disclosed herein concern ordered arrays of carbon nanotubes. In particular embodiments of the invention, the nanotube arrays are formed by a method comprising attaching catalyst nanoparticles (140, 230) to polymer (120, 210) molecules, attaching the polymer (120, 210) molecules to a substrate, removing the polymer (120, 210) molecules and producing carbon nanotubes on the catalyst nanoparticles (140, 230). The polymer (120, 210) molecules alignment techniques. The nanotube arrays can be attached to selected areas (110, 310) of the substrate. Within the selected areas (110, 310), the nanotubes are distributed non-randomly. Other embodiments disclosed herein concern apparatus that include ordered arrays of nanotubes attached to a substrate and systems that include ordered arrays of carbon nanotubes attached to a substrate, produced by the claimed methods. In certain embodiments, provided herein are methods for aligning a molecular wire, by ligating the molecular wire to a double stranded DNA molecule.

10. 发明公开

EP1595120A1 METAL COATED NANOCRYSTALLINE SILICON AS AN ACTIVE SURFACE ENHANCED RAMAN SPECTROSCOPY (SERS) SUBSTRATE 有权
标题翻译：金属制品纳米压片硅酸盐
公开(公告)号：EP1595120A1
公开(公告)日：2005-11-16
申请号：EP03774634.4
申请日：2003-10-07
申请人： INTEL CORPORATION
发明人： CHAN, Selena , BERLIN, Andrew , KWON, Sunghoon , SUNDARARAJAN, Narayan , YAMAKAWA, Mineo
IPC分类号： G01J3/44 , G01N21/65
CPC分类号： G01N21/658 , B01D67/0062 , B01D67/0086 , B01D67/0088 , B01D71/02 , B82Y15/00 , B82Y30/00 , C12Q1/6825 , G01J3/44 , G01N21/65 , G01N2021/6439 , G01N2021/655 , G01N2021/656 , C12Q2565/632 , C12Q2563/155
摘要： The disclosed methods and apparatus concern Raman spectroscopy using metal coated nanocrystalline porous silicon substrates. Porous silicon substrates may be formed by anodic etching in dilute hydrofluoric acid. A thin coating of a Raman active metal, such as gold or silver, may be coated onto the porous silicon by cathodic electromigration or any known technique. In certain alternatives, the metal coated porous silicon substrate comprises a plasma-oxidized, dip and decomposed porous silicon substrate. The metalcoated substrate provides an extensive, metal rich environment for SERS, SERBS, hyperRaman and/or CARS Raman spectroscopy. In certain alternatives, metal nanoparticles may be added to the metal-coated substrate to further enhance the Raman signals. Raman spectroscopy may be used to detect, identify and/or quantify a wide variety of analytes, using the disclosed methods and apparatus. In some disclosed methods, Raman spectroscopy may be used to detect nucleotides, purines or pyrimidines at the single molecule level.
摘要翻译：本文公开的方法，系统400和装置涉及金属150浸渍的多孔基材110,210。本发明的某些实施方案涉及用于制备金属涂覆的多孔硅基板110,210的方法，其显示出显着改善金属150沉积物的均匀性和深度的渗透。增加的均匀性和深度允许分析物的改进和更可重复的拉曼检测。在本发明的示例性实施例中，所述方法可包括多孔硅110的氧化，浸入金属盐溶液130中，干燥和热分解金属盐140以形成金属沉积物150.在本发明的其它示例性实施方案中，方法可以包括多孔硅衬底210与一种或多种金属盐溶液130的微流体浸渍。本发明的其它实施方案涉及用于分析物的拉曼检测的装置和/或系统400，包括金属涂覆的多孔硅衬底110,210，由公开的方法。

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