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1. 发明授权

US06673536B1 Methods of ranking oligonucleotides for specificity using wash dissociation histories 失效
标题翻译：使用洗涤解离历史对特异性的寡核苷酸进行排序的方法
公开(公告)号：US06673536B1
公开(公告)日：2004-01-06
申请号：US09408582
申请日：1999-09-29
申请人： Roland Stoughton , Julja Burchard , Stephen H. Friend
发明人： Roland Stoughton , Julja Burchard , Stephen H. Friend
IPC分类号： C12Q168
CPC分类号： G06F19/22 , C12Q1/6832 , C12Q2565/107
摘要： The present invention provides methods and systems, particularly computer systems, for determining the relative specificity with which a particular polynucleotide molecule hybridizes to a polynucleotide probe. For example, the methods and systems of the invention enable a user to compare the specificity with which different polynucleotides hybridize to a given probe and/or rank these polynucleotides according to their specificity to that probe. The methods and systems of the invention also enable a user to compare the specificity with which a particular polynucleotide hybridizes to different probes, and/or rank those different probes according to their specificity for that particular polynucleotide.
摘要翻译：本发明提供了用于确定特定多核苷酸分子与多核苷酸探针杂交的相对特异性的方法和系统，特别是计算机系统。例如，本发明的方法和系统使用户能够根据其对该探针的特异性，比较不同多核苷酸与给定探针杂交的特异性和/或对这些多核苷酸进行排序。本发明的方法和系统还使用户能够根据其对特定多核苷酸的特异性，比较特定多核苷酸与不同探针杂交的特异性和/或对这些不同探针进行排序。

2. 发明授权

US06171794B2 Methods for determining cross-hybridization 失效
标题翻译：确定交叉杂交的方法
公开(公告)号：US06171794B2
公开(公告)日：2001-01-09
申请号：US09335971
申请日：1999-06-18
申请人： Julja Burchard , Roland Stoughton , Stephen H. Friend
发明人： Julja Burchard , Roland Stoughton , Stephen H. Friend
IPC分类号： C12Q168
CPC分类号： C12Q1/6832 , C07B2200/11 , C12Q2527/107
摘要： The present invention provides methods for distinguishing the fractions of polynucleotide sequences which hybridize to any given probe, including probes on microarrays such as those described herein. In particular, the present invention enables users to identify the fraction of sequences which are perfectly complementary to a probe, thereby correcting for effects of cross hybridization in a hybridization assay. The methods of the invention work by monitoring the kinetics of dissociation of sequences from the probe so that a resulting “dissociation curve” may be compared to a combination of the individual “dissociation profiles” for each sequence which hybridizes. In alternative embodiments, the invention also provides computer systems for performing the present methods, as well as databases of the dissociation profiles.
摘要翻译：本发明提供了用于区分与任何给定探针杂交的多核苷酸序列的级分的方法，包括在诸如本文所述的微阵列之类的微阵列上的探针。特别地，本发明使得用户能够鉴定与探针完全互补的序列部分，从而在杂交测定中校正交叉杂交的作用。本发明的方法通过监测序列从探针中解离的动力学来起作用，从而可将所得到的“解离曲线”与杂交的每个序列的单独“解离曲线”的组合进行比较。在替代实施例中，本发明还提供用于执行本方法的计算机系统以及解离曲线的数据库。

3. 发明授权

US07013221B1 Iterative probe design and detailed expression profiling with flexible in-situ synthesis arrays 有权
标题翻译：迭代探针设计和具有灵活原位合成阵列的详细表达谱
公开(公告)号：US07013221B1
公开(公告)日：2006-03-14
申请号：US09561487
申请日：2000-04-28
申请人： Stephen H. Friend , Roland Stoughton , Peter S. Linsley , Julja Burchard
发明人： Stephen H. Friend , Roland Stoughton , Peter S. Linsley , Julja Burchard
IPC分类号： G01N33/48 , C12Q1/68
CPC分类号： G06F19/20
摘要： Methods and compositions are provided that are useful for detecting and reporting a plurality of different target polynucleotide sequences in a sample, such as polynucleotides corresponding to a plurality of different genes expressed by a cell or cells. In particular, the invention provides methods for screening a plurality of candidate polynucleotide probes to evaluate both the sensitivity and the specificity with which each candidate probe hybridizes to a target polynucleoide sequence. Candidate polynucleotide probes can then be ranked according to both their sensitivity and specificity, and probes that have optimal sensitivity and specificity for a target polynucleotide sequence can be selected. In one embodiment, polynucleotide probes can be selected according to the methods described herein to prepare “screening chips” wherein a large number of target polynucleotide sequences are detected using a single microarray have a few (e.g., 1–5) probes for each target polynucleotide sequence. In a particularly preferred embodiment, the invention provides a screening chip that can detect genetic transcripts from the entire genome of an organism. In an alternative embodiment, polynucleotide probes can be selected according to the methods described herein to prepare “signature chips” to more accurately detect certain selected “signature genes” using several polynucleotide probes (e.g., 10–20) for each signature gene. The invention additionally provides microarrays containing polynucleotide probes for a large number of genes expressed by a cell or organism. Further, methods for detecting a plurality of polynucleotide molecules, including a large number of genes expressed by a cell or organism, are also provided.
摘要翻译：提供了可用于检测和报告样品中多个不同靶多核苷酸序列的方法和组合物，例如对应于由细胞或细胞表达的多种不同基因的多核苷酸。特别地，本发明提供了筛选多个候选多核苷酸探针以评估每个候选探针与目标多核苷酸序列杂交的灵敏度和特异性的方法。然后可以根据其灵敏度和特异性对候选多核苷酸探针进行排序，并且可以选择对靶多核苷酸序列具有最佳敏感性和特异性的探针。在一个实施方案中，可以根据本文所述的方法选择多核苷酸探针以制备“筛选芯片”，其中使用单个微阵列检测大量目标多核苷酸序列，其中每个靶多核苷酸具有少量（例如1-5）探针序列。在一个特别优选的实施方案中，本发明提供了可以检测来自生物体的整个基因组的遗传转录物的筛选芯片。在替代实施方案中，可以根据本文所述的方法选择多核苷酸探针以通过使用每个特征基因的多个多核苷酸探针（例如10-20）来制备“签名芯片”以更精确地检测某些所选择的“特征基因”。本发明另外提供含有由细胞或生物表达的大量基因的多核苷酸探针的微阵列。此外，还提供了用于检测多个多核苷酸分子的方法，包括由细胞或生物体表达的大量基因。

4. 发明授权

US06859735B1 Computer systems for identifying pathways of drug action 失效
标题翻译：用于识别药物作用途径的计算机系统
公开(公告)号：US06859735B1
公开(公告)日：2005-02-22
申请号：US09374565
申请日：1999-08-13
申请人： Roland Stoughton , Stephen H. Friend
发明人： Roland Stoughton , Stephen H. Friend
IPC分类号： G01N33/53 , C12N15/09 , C12Q1/02 , C12Q1/04 , C12Q1/68 , G06F19/12 , G01N33/48 , C12P21/06 , G06G7/48
CPC分类号： G06F19/12 , C12Q1/025 , G01N33/5041
摘要： The present invention provides methods and computer systems for identifying and representing the biological pathways of drug action on a cell The present invention also provides methods and computer systems for assessing the significance of the identified representation and for verifying that the identified pathways are actual pathway of drug action. The present invention also provides methods and computer systems for drug development based on the methods for identifying biological pathways of drug action, and methods and computer systems for representing the biological pathways involved in the effect of an environmental change upon a cell.
摘要翻译：本发明提供用于鉴定和表示药物作用于细胞的生物学途径的方法和计算机系统本发明还提供了用于评估所鉴定的表现的重要性并用于验证所鉴定的途径是药物的实际途径的方法和计算机系统行动。本发明还提供了用于鉴定药物作用的生物学途径的方法的用于药物开发的方法和计算机系统，以及用于表示涉及环境变化对细胞的影响的生物学途径的方法和计算机系统。

5. 发明授权

US06801859B1 Methods of characterizing drug activities using consensus profiles 有权
标题翻译：使用共识的形式表征药物活动的方法
公开(公告)号：US06801859B1
公开(公告)日：2004-10-05
申请号：US09220142
申请日：1998-12-23
申请人： Stephen H. Friend , Roland Stoughton , Yudong He
发明人： Stephen H. Friend , Roland Stoughton , Yudong He
IPC分类号： G01N3348
CPC分类号： G06F19/24 , G06F19/20
摘要： The present invention provides methods for enhanced detection of biological response profiles. In particular, the methods of this invention allow for the detection of biological response patterns, such as gene expression patterns, in response to different drug treatments. The methods of the invention also allow the determination of a “consensus profile” which describes a particular class or type of biological response. In certain embodiments the consensus profile may describe the biological response of a particular group or class of drugs. In other embodiments, the consensus profile may describe an “ideal” biological response such as one associated with a desired therapeutic effect. The methods of the present invention also allow for the comparison of different biological responses. Thus, the methods of the invention may be used, e.g., to identify and/or study new drugs.
摘要翻译：本发明提供用于增强生物反应曲线检测的方法。特别地，本发明的方法允许响应于不同的药物治疗来检测生物反应模式，如基因表达模式。本发明的方法还允许确定描述特定类别或类型的生物反应的“共有概况”。在某些实施方案中，共有概况可以描述特定组或一类药物的生物反应。在其它实施方案中，共有概况可以描述“理想”生物反应，例如与期望的治疗效果相关联的生物反应。本发明的方法还允许比较不同的生物反应。因此，本发明的方法可以用于例如鉴定和/或研究新的药物。

6. 发明授权

US08019552B2 Classification of breast cancer patients using a combination of clinical criteria and informative genesets 失效
标题翻译：乳腺癌患者使用临床标准和信息基因组合的分类
公开(公告)号：US08019552B2
公开(公告)日：2011-09-13
申请号：US10591800
申请日：2005-03-07
申请人： Hongyue Dai , Laura J. Van't Veer , John Lamb , Roland Stoughton , Stephen H. Friend , Yudong He
发明人： Hongyue Dai , Laura J. Van't Veer , John Lamb , Roland Stoughton , Stephen H. Friend , Yudong He
IPC分类号： G01N33/48 , G01N33/50
CPC分类号： G01N33/57415 , C12Q1/6886 , C12Q2600/106 , C12Q2600/112 , C12Q2600/118 , Y10T436/143333
摘要： The present invention provides prognostic methods for conditions such as cancer, for example, breast cancer, comprising classifying an individual by a plurality of phenotypic, genotypic or clinical characteristics of the condition into a plurality of patient subsets, and analyzing the pattern of expression of prognosis-informative genes identified for that subset in a sample from the individual. The present invention also provides methods for constructing such patient subsets and of identifying prognosis-informative genesets for such subsets. The invention further provides methods of assigning a therapeutic regimen to an individual, microarrays useful for performing prognosis, kits comprising these microarrays, and computer systems and programs for implementing the methods of the invention.
摘要翻译：本发明提供了诸如癌症例如乳腺癌的病症的预后方法，包括将个体的多个表型，基因型或临床特征分类为多个患者子集，并分析预后表达模式在来自个体的样品中识别该子集的信息基因。本发明还提供了用于构建这样的患者子集以及鉴定这样的子集的预后信息性基因组的方法。本发明进一步提供了将个体的治疗方案分配给用于进行预后的微阵列，包括这些微阵列的试剂盒以及用于实施本发明的方法的计算机系统和程序的方法。

7. 发明申请

US20080187909A1 Classification of Breast Cancer Patients Using a Combination of Clinical Criteria and Informative Genesets 失效
标题翻译：乳腺癌患者使用临床标准和信息基因组合的分类
公开(公告)号：US20080187909A1
公开(公告)日：2008-08-07
申请号：US10591800
申请日：2005-03-07
申请人： Hongyue Dai , Laura J. Van't Veer , John Lamb , Roland Stoughton , Stephen H. Friend , Yudong He
发明人： Hongyue Dai , Laura J. Van't Veer , John Lamb , Roland Stoughton , Stephen H. Friend , Yudong He
IPC分类号： C12Q1/68 , C40B40/06
CPC分类号： G01N33/57415 , C12Q1/6886 , C12Q2600/106 , C12Q2600/112 , C12Q2600/118 , Y10T436/143333
摘要： The present invention provides prognostic methods for conditions such as cancer, for example, breast cancer, comprising classifying an individual by a plurality of phenotypic, genotypic or clinical characteristics of the condition into a plurality of patient subsets, and analyzing the pattern of expression of prognosis-informative genes identified for that subset in a sample from the individual. The present invention also provides methods for constructing such patient subsets and of identifying prognosis-informative genesets for such subsets. The invention further provides methods of assigning a therapeutic regimen to an individual, microarrays useful for performing prognosis, kits comprising these microarrays, and computer systems and programs for implementing the methods of the invention.
摘要翻译：本发明提供了诸如癌症例如乳腺癌的病症的预后方法，包括将个体的多个表型，基因型或临床特征分类为多个患者子集，并分析预后表达模式在来自个体的样品中识别该子集的信息基因。本发明还提供了用于构建这样的患者子集以及鉴定这样的子集的预后信息性基因组的方法。本发明进一步提供了将个体的治疗方案分配给用于进行预后的微阵列，包括这些微阵列的试剂盒以及用于实施本发明的方法的计算机系统和程序的方法。

8. 发明授权

US06973388B2 Methods of diagnosing disease states using gene expression profiles 失效
标题翻译：使用基因表达谱诊断疾病状态的方法
公开(公告)号：US06973388B2
公开(公告)日：2005-12-06
申请号：US09783474
申请日：2001-02-14
申请人： Stephen H. Friend , Roland Stoughton
发明人： Stephen H. Friend , Roland Stoughton
IPC分类号： G01D1/16 , A01N43/04 , A01N61/00 , C07H21/04 , C12M20060101 , C12M1/34 , C12M3/00 , C12N15/09 , C12P21/06 , C12Q1/02 , C12Q1/68 , G01N33/48 , G01N33/53 , G01N37/00 , G06G7/48
CPC分类号： C12Q1/6886 , C12Q2600/156 , C12Q2600/158
摘要： The present invention provides methods for monitoring disease states in a subject, as well as methods for monitoring the levels of effect of therapies upon a subject having one or more disease states. The methods involve: (i) measuring abundances of cellular constituents in a cell from a subject to obtain a diagnostic profile, (ii) measuring abundances of cellular constituents in a cell of one or more analogous subjects to obtain perturbation response profiles which correlate to a particular disease or therapy, and (iii) determining the interpolated perturbation response profile or profiles which best fit the diagnostic profile. In other aspects, the invention also provides a computer system capable of performing the methods of the invention, databases comprising perturbation response profiles for one or more diseases and/or therapies, and kits for determining levels of disease states and/or therapeutic effects according to the methods of the invention.
摘要翻译：本发明提供了用于监测受试者的疾病状态的方法，以及用于监测治疗对具有一种或多种疾病状态的受试者的疗效水平的方法。所述方法包括：（i）测量来自受试者的细胞中的细胞成分的丰度以获得诊断特征，（ii）测量一个或多个类似受试者的细胞中细胞成分的丰度，以获得与a相关的扰动反应曲线特定疾病或治疗，以及（iii）确定最适合诊断特征的内插扰动响应曲线或轮廓。在其他方面，本发明还提供一种能够执行本发明的方法的计算机系统，包括用于一种或多种疾病和/或治疗的扰动反应概况的数据库，以及用于确定根据本发明的疾病状态和/或治疗效果水平的试剂盒本发明的方法。

9. 发明授权

US06468476B1 Methods for using-co-regulated genesets to enhance detection and classification of gene expression patterns 失效
标题翻译：使用共同调控的基因组的方法来增强基因表达模式的检测和分类
公开(公告)号：US06468476B1
公开(公告)日：2002-10-22
申请号：US09428427
申请日：1999-10-27
申请人： Stephen H. Friend , Roland Stoughton , Yudong He
发明人： Stephen H. Friend , Roland Stoughton , Yudong He
IPC分类号： G01N1500
CPC分类号： G06F19/24 , C12Q1/6809 , C12Q1/6834 , G01N33/6803 , G06F19/20
摘要： The present invention provides methods for enhanced detection of biological response patterns. In one embodiment of the invention, genes are grouped into basis genesets according to the co-regulation of their expression. Expression of individual genes within a geneset is indicated with a single gene expression value for the geneset by a projection process. The expression values of genesets, rather than the expression of individual genes, are then used as the basis for comparison and detection of biological response with greatly enhanced sensitivity. In another embodiment of the invention, biological responses are grouped according to the similarity of their biological profile. The methods of the invention have many useful applications, particularly in the fields of drug development and discovery. For example, the methods of the invention may be used to compare biological responses with greatly enhanced sensitivity. The biological responses that may be compared according to these methods include responses to single perturbations, such as a biological response to a mutation or temperature change, as well as graded perturbations such as titration with a particular drug. The methods are also useful to identify cellular constituents, particularly genes, associated with a particular type of biological response. Further, the methods may also be used to identify perturbations, such as novel drugs or mutations, which effect one or more particular genesets. The methods may still further be used to remove experimental artifacts in biological response data.
摘要翻译：本发明提供了用于增强生物反应模式检测的方法。在本发明的一个实施方案中，根据其表达的共调节将基因分组成基因基因组。个体基因在基因组中的表达用投影过程的基因表达值表示。然后将基因的表达值，而不是单个基因的表达值作为比较和检测生物反应的基础，大大提高敏感性。在本发明的另一个实施方案中，生物反应根据其生物学特征的相似性进行分组。本发明的方法具有许多有用的应用，特别是在药物开发和发现领域。例如，本发明的方法可用于比较具有极大增强的灵敏度的生物反应。可以根据这些方法比较的生物反应包括对单一扰动的反应，例如对突变或温度变化的生物反应，以及分级扰动，例如用特定药物滴定。所述方法还可用于鉴定与特定类型的生物反应相关的细胞成分，特别是基因。此外，所述方法还可用于鉴定影响一个或多个特定基因组的扰动，例如新型药物或突变。这些方法还可以进一步用于去除生物反应数据中的实验伪影。

10. 发明授权

US06324479B1 Methods of determining protein activity levels using gene expression profiles 失效
标题翻译：使用基因表达谱确定蛋白质活性水平的方法
公开(公告)号：US06324479B1
公开(公告)日：2001-11-27
申请号：US09303082
申请日：1999-04-30
申请人： Stephen H. Friend , Roland Stoughton
发明人： Stephen H. Friend , Roland Stoughton
IPC分类号： G01N3348
CPC分类号： C07K14/4702 , A61K38/00
摘要： The present invention provides methods for determining the level of protein activity in a cell by: (i) measuring abundances of cellular constituents in a cell in which the activity of a specific protein is to be determined so that a diagnostic profile is thus obtained; (ii) measuring abundances of cellular constituents that occur in a cell in response to perturbations in the activity of said protein to obtain response profiles and interpolating said response profiles to generate response curves; and (iii) determining a protein activity level at which the response profile extracted from the response curves best fits the measured diagnostic profile, according to some objective measure. In alternative embodiments, the present invention also provides methods for identifying individuals having genetic mutations or polymorphisms that disrupt protein activity, and methods for identifying drug activity in vivo by determining the activity levels of proteins which interact with said drugs.
摘要翻译：本发明提供了通过以下步骤确定细胞中蛋白质活性水平的方法：（i）测量要确定特定蛋白质的活性的细胞中细胞成分的丰度，从而获得诊断特征; （ii）测量在细胞中发生的细胞成分的丰度以响应所述蛋白质的活动中的扰动以获得反应谱并内插所述响应谱以产生响应曲线; 和（iii）根据一些客观的测定，确定从响应曲线提取的反应曲线最适合测量的诊断谱的蛋白质活性水平。在替代实施方案中，本发明还提供了用于鉴定具有破坏蛋白质活性的遗传突变或多态性的个体的方法，以及通过测定与所述药物相互作用的蛋白质的活性水平来鉴定体内药物活性的方法。

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