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1. 发明申请

WO1996035810A1 APPARATUS AND METHOD FOR THE GENERATION, SEPARATION, DETECTION, AND RECOGNITION OF BIOPOLYMER FRAGMENTS 审中-公开
标题翻译：生物聚合物碎片的生成，分离，检测和识别的装置和方法
公开(公告)号：WO1996035810A1
公开(公告)日：1996-11-14
申请号：PCT/US1996006579
申请日：1996-05-09
申请人： CURAGEN CORPORATION
发明人： CURAGEN CORPORATION , SIMPSON, John, W. , ROTHBERG, Jonathan, M. , WENT, Gregory, T.
IPC分类号： C12Q01/68
CPC分类号： B01J19/0093 , B01J2219/00783 , B01J2219/00828 , B01J2219/00831 , B01J2219/00833 , B01J2219/00873 , B01J2219/00995 , G01N27/44708 , G01N27/44721 , G01N27/44782 , G01N27/44791 , Y10S436/80 , Y10T436/143333
摘要： This invention is an integrated instrument for the high capacity electrophoretic analysis of biopolymer samples. It comprises a specialized high-voltage, electrophoretic module in which migration lanes are formed between a bottom plate (446) and a plurality of etched grooves in a top plate (438), the module permitting concurrent separation of 80 or more separate samples. In thermal contact with the bottom plate (446) is a thermal control module incorporating a plurality of Peltier heat transfer devices for the control of temperature and gradients in the electrophoretic medium. Fragments are detected by a transmission imaging spectrograph which simultaneously spatially focuses and spectrally resolves the detection region of all the migration lanes. The spectrograph comprises a transmission dispersion element and a CCD array to detect signals. Signal analysis comprises the steps of noise filtering, comparison in a configuration space with signal prototypes, and selection of the best prototype. Optionally post-processing is done by a Monte-Carlo simulated annealing algorithm to improve results. Optionally, an array of micro-reactors can be integrated into the instrument for the generation of sequencing reaction fragments directly from crude DNA samples.
摘要翻译：本发明是用于生物聚合物样品的高容量电泳分析的集成仪器。它包括专门的高压电泳模块，其中在底板（446）和顶板（438）中的多个蚀刻凹槽之间形成迁移通道，该模块允许同时分离80个或更多个单独的样品。与底板（446）热接触是一个热控制模块，其包含多个用于控制电泳介质中的温度和梯度的珀尔帖传热装置。通过透射成像光谱仪检测片段，其同时空间聚焦并光谱地解析所有迁移通道的检测区域。该光谱仪包括用于检测信号的透射色散元件和CCD阵列。信号分析包括噪声滤波，配置空间与信号原型的比较以及最佳原型的选择的步骤。可选地，后处理通过蒙特卡罗模拟退火算法完成以改善结果。任选地，可以将微反应器阵列整合到仪器中，以直接从粗DNA样品产生测序反应片段。

2. 发明申请

WO2002077287A1 APPARATUS AND METHOD FOR SEQUENCING A NUCLEIC ACID 审中-公开
标题翻译：用于测序核酸的装置和方法
公开(公告)号：WO2002077287A1
公开(公告)日：2002-10-03
申请号：PCT/US2002/008700
申请日：2002-03-21
申请人： CURAGEN CORPORATION , ROTHBERG, Jonathan, M. , BADER, Joel, S. , DEWELL, Scott, B. , MCDADE, Keith , SIMPSON, John, W. , BERKA, Jane , COLANGELO, Christopher, M. , WEINER, Michael, Philip
发明人： ROTHBERG, Jonathan, M. , BADER, Joel, S. , DEWELL, Scott, B. , MCDADE, Keith , SIMPSON, John, W. , BERKA, Jane , COLANGELO, Christopher, M. , WEINER, Michael, Philip
IPC分类号： C12Q1/68
CPC分类号： G01N21/6452 , B01L3/5027 , B01L3/502715 , B01L9/527 , B01L2300/0636 , B01L2300/0654 , B01L2300/0816 , B01L2300/0819 , B01L2300/0822 , B01L2300/0877 , B01L2300/0893 , B82Y15/00 , B82Y30/00 , C12P19/34 , C12Q1/6827 , C12Q1/6837 , C12Q1/6869 , C12Q1/6874 , G01N21/0303 , G01N21/7703 , C12Q2565/519 , C12Q2533/101 , C12Q2531/125 , C12Q2535/101 , C12Q2565/301 , C12Q2565/107 , C12Q2525/307
摘要： Disclosed herein are methods and apparatus for sequencing a nucleic acid. These methods permit a very large number of independent sequencing reactions to be arrayed in parallel, permitting simultaneous sequencing of a very large number (>10,000) of different oligonucleotides.
摘要翻译：本文公开了用于测序核酸的方法和装置。这些方法允许非常大量的独立测序反应并行排列，允许非常大数量（> 10,000）不同寡核苷酸的同时测序。

3. 发明申请

WO1997036171A1 SEPARATION OF CHARGED PARTICLES BY A SPATIALLY AND TEMPORALLY VARYING ELECTRIC FIELD 审中-公开
标题翻译：通过空间和时间变化的电场分离充电颗粒
公开(公告)号：WO1997036171A1
公开(公告)日：1997-10-02
申请号：PCT/US1997005172
申请日：1997-03-26
申请人： CURAGEN CORPORATION
发明人： CURAGEN CORPORATION , BADER, Joel, S. , ROTHBERG, Jonathan, M. , DEEM, Michael, W. , MULHERN, Gregory, T. , WENT, Gregory, T.
IPC分类号： G01N27/26
CPC分类号： B82Y30/00 , G01N27/44773
摘要： A device for separating charged particles comprising: an upper substate (11); a lower substrate (12); separation lanes (15) defined on the upper substrate, a first plurality of electrodes (21, 22...); a first pad (18), said first plurality of electrodes connected to said first pad (13); second plurality of electrodes (21, 23...); a second pad (14), said second plurality of electrodes connected to said second pad; said pads and electrodes deposited on the lower substrate; and said first plurality of electrodes and said second plurality of electrodes are interdigitated. During the operation of the device, charged particles are subjected to an electric potential that is cycled between an off-state and one or more on states, in which the potential is preferably spatially periodic with a plurality of eccentrically shaped stationary potential wells.
摘要翻译：一种用于分离带电粒子的装置，包括：上部基底（11）; 下基板（12）; 限定在上基板上的分离通道（15），第一多个电极（21,22 ...）; 第一焊盘（18），所述第一多个电极连接到所述第一焊盘（13）; 第二多个电极（21,23 ...）; 第二焊盘（14），所述第二多个电极连接到所述第二焊盘; 所述焊盘和电极沉积在下基板上; 并且所述第一多个电极和所述第二多个电极是交叉的。在装置的操作期间，带电粒子经受在断开状态和一个或多个导通状态之间循环的电位，其中电势优选地与多个偏心形状的固定势阱在空间周期性。

4. 发明申请

WO1997015690A1 METHOD AND APPARATUS FOR IDENTIFYING, CLASSIFYING, OR QUANTIFYING DNA SEQUENCES IN A SAMPLE WITHOUT SEQUENCING 审中-公开
标题翻译：用于在没有序列的情况下识别，分类或定量样品中的DNA序列的方法和装置
公开(公告)号：WO1997015690A1
公开(公告)日：1997-05-01
申请号：PCT/US1996017159
申请日：1996-10-24
申请人： CURAGEN CORPORATION
发明人： CURAGEN CORPORATION , ROTHBERG, Jonathan, M. , DEEM, Michael, W. , SIMPSON, John, W.
IPC分类号： C12Q01/68
CPC分类号： C12Q1/6855 , C12N15/10 , C12N15/1034 , C12Q1/68 , C12Q1/6809 , G06F19/22 , G06F19/24 , Y10S977/728 , Y10S977/924 , Y10T436/143333
摘要： This invention provides methods by which biologically derived DNA sequences in a mixed sample or in an arrayed single sequence clone can be determined and classified without sequencing. The methods make use of information on the presence of carefully chosen target subsequences, typically of length from 4 to 8 base pairs, and preferably the length between target subsequences in a sample DNA sequence together with DNA sequence databases containing lists of sequences likely to be present in the sample to determine a sample sequence. The preferred method uses restriction endonucleases to recognize target subsequences and cut the sample sequence. Then carefully chosen recognition moieties are ligated to the cut fragments, the fragments amplified, and the experimental observation made. Polymerase chain reaction (PCR) is the preferred method of amplification. Several alternative embodiments are described which are capable of increased discrimination and which use TypeIIS restriction endonucleases, various capture moieties, or samples of specially synthesized cDNA. Another embodiment of the invention uses information on the presence or absence of carefully chosen target subsequences in a single sequence clone together with DNA sequence databases to determine the clone sequence. Computer implemented methods are provided to analyze the experimental results and to determine the sample sequences in question and to carefully choose target subsequences in order that experiments yield a maximum amount of information.
摘要翻译：本发明提供了可以在不测序的情况下确定和分类混合样品或排列单序列克隆中的生物衍生DNA序列的方法。这些方法利用关于精心选择的目标子序列的存在的信息，通常长度为4至8个碱基对，优选样品DNA序列中靶序列之间的长度以及含有可能存在的序列的DNA序列数据库在样品中确定样品序列。优选的方法使用限制性内切核酸酶识别目标子序列并切割样品序列。然后仔细选择识别部分连接到切割片段，扩增片段，并进行实验观察。聚合酶链反应（PCR）是优选的扩增方法。描述了能够增加鉴别和使用TypeIIS限制性内切核酸酶，各种捕获部分或特别合成的cDNA的样品的几种备选实施方案。本发明的另一个实施方案使用关于单个序列克隆中仔细选择的目标子序列存在或不存在的信息以及DNA序列数据库来确定克隆序列。提供计算机实现的方法来分析实验结果并确定所讨论的样本序列，并仔细选择目标子序列，以便实验产生最大量的信息。

5. 发明申请

WO2002018661A3 METHODS FOR IDENTIFYING NOVEL THERAPEUTIC AGENTS 审中-公开
公开(公告)号：WO2002018661A3
公开(公告)日：2002-03-07
申请号：PCT/US2001/041982
申请日：2001-09-04
申请人： CURAGEN CORPORATION , HERRMANN, John, L. , RASTELLI, Luca , BURGESS, Catherine, E. , GOULD-ROTHBERG, Bonnie, E. , ROTHBERG, Jonathan, M. , SHIMKETS, Richard, A.
发明人： HERRMANN, John, L. , RASTELLI, Luca , BURGESS, Catherine, E. , GOULD-ROTHBERG, Bonnie, E. , ROTHBERG, Jonathan, M. , SHIMKETS, Richard, A.
IPC分类号： C12Q1/68
摘要： The invention provides a method for identifying a therapeutic agent. The method includes detecting a nucleic acid in a test sample, e.g. cells, cell lines or tissue, which contains a plurality of nucleic acid species, determining if the detected nucleic acid contributes to a disease state and is thus a qualified therapeutic target, and establishing if the qualified therapeutic target plays a role in disease progress and is thus a verified therapeutic candidate that can function as a therapeutic agent.

6. 发明申请

WO2001038580A3 NUCLEIC ACID PROBE ARRAYS 审中-公开
公开(公告)号：WO2001038580A3
公开(公告)日：2001-05-31
申请号：PCT/US2000/032131
申请日：2000-11-27
申请人： CURAGEN CORPORATION , ROTHBERG, Jonathan, M. , BADER, Joel, S.
发明人： ROTHBERG, Jonathan, M. , BADER, Joel, S.
IPC分类号： C12Q1/68
摘要： Disclosed are nucleic acid probe arrays and methods of identifying and sequencing nucleic acids in a population of nucleic acids using the arrays. The method is preferably performed by annealing a nucleic acid template to an anchor primer attached to a durface of the array. At least one anchor in the array has a sequence complementary to sequences at the 5' and 3' termini of a target nucleic acid.The annealed linear target nucleic acid is circularized using one or two ligation reactions. In one embodiment, one liggation is issued. Annealing of of the linear nucleic acid results in juxtaposition of the 5' and 3' termini of the target nucleic acid on the anchor primer. Addition of a ligase results in circulization of the target nucleic acid. This circularized nucleic acid is a template for extension of the anchor primer in a rolling circle amplification reaction. An extended anchor primer containing multiple copies of a sequence complementary to the circular mucleic acid is also referred to herein as a anchor primer nucleid acid-nucleic acid concatamer. The presence of multiple copies of the complementary sequence facilitates detection of the nucleic acid. Thus, the method provides for a highly sensitive method of detecting a desired nucleic acid attached at a discrete location on the array.

7. 发明申请

WO1997047763A1 IDENTIFICATION AND COMPARISON OF PROTEIN-PROTEIN INTERACTIONS AND INHIBITORS THEREOF 审中-公开
标题翻译：蛋白质与蛋白质相互作用及其抑制剂的鉴别与比较
公开(公告)号：WO1997047763A1
公开(公告)日：1997-12-18
申请号：PCT/US1997010392
申请日：1997-06-13
申请人： CURAGEN CORPORATION
发明人： CURAGEN CORPORATION , NANDABALAN, Krishnan , ROTHBERG, Jonathan, M. , YANG, Meijia , KNIGHT, James, R. , KALBFLEISCH, Theodore, S.
IPC分类号： C12P21/06
CPC分类号： C40B30/04 , B01J2219/00605 , B01J2219/0061 , B01J2219/00659 , B01J2219/00677 , B01J2219/00689 , B01J2219/00695 , B82Y30/00 , C12N15/1055 , C12N15/81 , G01N33/6845 , G06F19/22
摘要： Disclosed are methods of detecting protein-protein interactions among two populations of proteins, wherein each protein population has a complexity of at least 1,000. Fusion proteins of each population are expressed in yeast cells of opposite mating types. The fusion protein populations are made by fusing to one population a DNA-binding domain of a transcriptional activator and fusing to the other population at the activation domain of a transcriptional activator. When the yeast cells of opposite mating type are mated, productive interactions between members of each protein population functionally reconstitute the two domains of the transcriptional activator and result in reporter gene expression. The disclosed methods allow identification and characterization of new protein-protein interactions that may be relevant to a particular tissue or disease stage. Inhibitors of the identified protein-protein interactions can also be identified by screening for the ability to reverse expression of reporter gene. This inhibitor screening method can be performed in multiplex. Other aspects of the invention include information processing methods and systems. The methods and systems provide for assembling and processing of a unified database of sequences and identifying sequences that may be involved in protein-protein interactions.
摘要翻译：公开了检测两个蛋白质群体之间的蛋白质 - 蛋白质相互作用的方法，其中每个蛋白质群体的复杂度至少为1,000。每个群体的融合蛋白在相反交配型的酵母细胞中表达。通过将转录激活物的DNA结合结构域融合到一个群体并在转录激活子的活化域处与其它群体融合来制备融合蛋白质群体。当相互交配型的酵母细胞交配时，每个蛋白质群体的成员之间的生产性相互作用功能地重建转录激活因子的两个结构域并导致报道基因表达。所公开的方法允许鉴定和表征可能与特定组织或疾病阶段相关的新的蛋白质 - 蛋白质相互作用。鉴定的蛋白质 - 蛋白质相互作用的抑制剂也可以通过筛选报告基因逆转表达的能力来鉴定。该抑制剂筛选方法可以多重进行。本发明的其它方面包括信息处理方法和系统。该方法和系统提供组合和处理序列的统一数据库并鉴定可能参与蛋白质 - 蛋白质相互作用的序列。

8. 发明申请

WO1996030849A1 CONSENSUS CONFIGURATIONAL BIAS MONTE CARLO METHOD AND SYSTEM FOR PHARMACOPHORE STRUCTURE DETERMINATION 审中-公开
标题翻译：共同配置偏倚蒙特卡罗方法和系统用于药物结构测定
公开(公告)号：WO1996030849A1
公开(公告)日：1996-10-03
申请号：PCT/US1996004229
申请日：1996-03-27
申请人： CURAGEN CORPORATION
发明人： CURAGEN CORPORATION , DEEM, Michael, W. , ROTHBERG, Jonathan, M. , WENT, Gregory, T.
IPC分类号： G06F17/50
CPC分类号： G01N33/6803 , B01J2219/007 , C07K1/00 , C40B40/10 , G01N33/542 , G01N33/54326 , G01N33/5748 , Y10S977/808 , Y10S977/839 , Y10S977/906 , Y10S977/953 , Y10T436/24
摘要： In a specific embodiment, this invention comprises a method for selecting highly targeted lead compounds for design of a drug that binds to a target molecule. The method comprises screening a diversity library against the target molecule of interest to pick the selectively binding members. Next the structure of the selected members is examined and a candidate pharmacophore responsible for the binding to the target molecule is determined. Next, preferably by REDOR nuclear magnetic resonance, several highly accurate interatomic distances are determined in certain of the selected members which are related to the candidate pharmacophore. A highly accurate consensus, configurational bias, Monte Carlo method determination of the structure of the candidate pharmacophore is made using the structure of the selected members and incorporating as constraints the shared selected members and incorporating as constraints the shared candidate phamacophore and the several measured distances. This determination is adapted to efficiently examine only relatively low energy configurations while respecting any structural constraints present in the organic diversity library. If the diversity library contains short peptides, the determination respects the known degrees of freedom of peptides as well as any internal constraints, such as those imposed by disulfide bridges. Finally, the highly accurate pharmacophore so determined is used to select lead organics for drug development targeted at the initial target molecule.
摘要翻译：在具体实施方案中，本发明包括用于选择高靶向铅化合物以设计与靶分子结合的药物的方法。该方法包括筛选针对目的靶分子的多样性文库以选择性结合成员。接下来，检查所选成员的结构，确定负责与靶分子结合的候选药效团。接下来，优选地通过REDOR核磁共振，在与候选药效团相关的某些选定的成员中确定几个高度准确的原子间距离。使用所选择的成员的结构并且将共同选定的成员并入作为约束条件并且作为约束条件并入共享的候选候选植物体和几个测量的距离来进行候选药效团的结构的高度准确的一致性，构型偏差，蒙特卡罗方法确定候选药效团的结构。该确定适于在尊重有机分集库中存在的任何结构约束的同时仅有效地检查相对较低的能量构型。如果多样性文库包含短肽，则确定方面取决于肽的已知自由度以及任何内部约束，例如由二硫键施加的约束。最后，如此确定的高度精确的药效团用于选择靶向初始靶分子的药物开发的铅有机物。

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