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1. 发明授权

US06573044B1 Methods of using chemical libraries to search for new kinase inhibitors 失效
标题翻译：使用化学文库搜索新的激酶抑制剂的方法
公开(公告)号：US06573044B1
公开(公告)日：2003-06-03
申请号：US09221406
申请日：1998-12-22
申请人： Nathanael S. Gray , Peter Schultz , Lisa Wodicka , Laurent Meijer , David J. Lockhart
发明人： Nathanael S. Gray , Peter Schultz , Lisa Wodicka , Laurent Meijer , David J. Lockhart
IPC分类号： C12Q168
CPC分类号： A61K31/52 , C07D473/16
摘要： The generation of selective inhibitors for specific protein kinases would provide new tools for analyzing signal transduction pathways and possibly new therapeutic agents. We have invented an approach to the development of selective protein kinase inhibitors based on the unexpected binding mode of 2,6,9-trisubstituted purines to the ATP binding site of human CDK2. The most potent inhibitor, purvalanol B (IC50=6 nM), binds with a 30-fold greater affinity than the known CDK2 inhibitor, flavopiridol. The cellular effects of this class of compounds were examined and compared to those of flavopiridol by monitoring changes in mRNA expression levels for all genes in treated cells of Saccharomyces cerevisiae using high-density oligonucleotide probe arrays.
摘要翻译：产生特异性蛋白激酶的选择性抑制剂将为分析信号转导途径和可能的新治疗剂提供新的工具。我们已经发明了一种基于26,9-三取代嘌呤到人CDK2的ATP结合位点的意想不到的结合模式来开发选择性蛋白激酶抑制剂的方法。最有效的抑制剂，纯丙醇B（IC50 = 6nM）以比已知的CDK2抑制剂flavopiridol高30倍的亲和力结合。通过使用高密度寡核苷酸探针阵列监测酿酒酵母的处理细胞中所有基因的mRNA表达水平的变化来检查这类化合物的细胞效应，并与黄曲妥替尔的细胞效应进行比较。

2. 发明授权

US06333155B1 Exploiting genomics in the search for new drugs 有权
标题翻译：利用基因组学寻找新药
公开(公告)号：US06333155B1
公开(公告)日：2001-12-25
申请号：US09215207
申请日：1998-12-18
申请人： David J. Lockhart , Lisa Wodicka , Ming Hsiu Ho
发明人： David J. Lockhart , Lisa Wodicka , Ming Hsiu Ho
IPC分类号： C12Q168
CPC分类号： C12Q1/6883 , C12Q1/6809 , C12Q1/6837 , C12Q1/6876 , C12Q2600/156 , C12Q2600/158
摘要： The cellular effects of potentially therapeutic compounds are characterized in mammalian cells and yeast. In the latter case the effects can be characterized on a genome-wide scale by monitoring changes in messenger RNA levels in treated cells with high-density oligonucleotide probe arrays.
摘要翻译：潜在治疗性化合物的细胞效应在哺乳动物细胞和酵母中表征。在后一种情况下，通过用高密度寡核苷酸探针阵列监测处理的细胞中的信使RNA水平的变化，可以在全基因组范围内表征效应。

3. 发明授权

US06344316B1 Nucleic acid analysis techniques 失效
标题翻译：核酸分析技术
公开(公告)号：US06344316B1
公开(公告)日：2002-02-05
申请号：US08882649
申请日：1997-06-25
申请人： David J. Lockhart , Mark Chee , Kevin Gunderson , Lai Chaoqiang , Lisa Wodicka , Maureen T. Cronin , Danny Lee , Huu M. Tran , Hajime Matsuzaki
发明人： David J. Lockhart , Mark Chee , Kevin Gunderson , Lai Chaoqiang , Lisa Wodicka , Maureen T. Cronin , Danny Lee , Huu M. Tran , Hajime Matsuzaki
IPC分类号： C12Q168
CPC分类号： C07H19/052 , C07H19/12 , C07H21/00 , C12Q1/6809 , C12Q1/6837 , C12Q2600/156 , C40B40/00 , G06F19/20 , G06F19/22 , C12Q2525/161 , C12Q2565/501 , C12Q2561/125
摘要： The present invention provides a simplified method for identifying differences in nucleic acid abundances (e.g., expression levels) between two or more samples. The methods involve providing an array containing a large number (e.g. greater than 1,000) of arbitrarily selected different oligonucleotide probes where the sequence and location of each different probe is known. Nucleic acid samples (e.g. mRNA) from two or more samples are hybridized to the probe arrays and the pattern of hybridization is detected. Differences in the hybridization patterns between the samples indicates differences in expression of various genes between those samples. This invention also provides a method of end-labeling a nucleic acid. In one embodiment, the method involves providing a nucleic acid, providing a labeled oligonucleotide and then enzymatically ligating the oligonucleotide to the nucleic acid. Thus, for example, where the nucleic acid is an RNA, a labeled oligoribonucleotide can be ligated using an RNA ligase. In another embodiment, the end labeling can be accomplished by providing a nucleic acid, providing labeled nucleoside triphosphates, and attaching the nucleoside triphosphates to the nucleic acid using a terminal transferase.
摘要翻译：本发明提供用于鉴定两个或多个样品之间的核酸丰度差异（例如，表达水平）的简化方法。所述方法包括提供包含大量（例如大于1,000个）任意选择的不同寡核苷酸探针的阵列，其中每个不同探针的序列和位置是已知的。来自两个或更多个样品的核酸样品（例如mRNA）与探针阵列杂交，并检测杂交模式。样本之间的杂交模式的差异表明这些样品之间各种基因的表达差异。本发明还提供了一种终止标记核酸的方法。在一个实施方案中，该方法包括提供核酸，提供标记的寡核苷酸，然后将寡核苷酸酶连接到核酸上。因此，例如，当核酸是RNA时，可以使用RNA连接酶连接标记的寡核糖核苷酸。在另一个实施方案中，末端标记可以通过提供核酸，提供标记的核苷三磷酸和使用末端转移酶将核苷三磷酸与核酸连接来实现。

4. 发明授权

US06524800B2 Exploiting genomics in the search for new drugs 有权
公开(公告)号：US06524800B2
公开(公告)日：2003-02-25
申请号：US09900845
申请日：2001-07-06
申请人： David J. Lockhart , Lisa Wodicka , Ming Hsiu Ho
发明人： David J. Lockhart , Lisa Wodicka , Ming Hsiu Ho
IPC分类号： C12Q168
CPC分类号： C12Q1/6883 , C12Q1/6809 , C12Q1/6837 , C12Q1/6876 , C12Q2600/156 , C12Q2600/158
摘要： The cellular effects of potentially therapeutic compounds are characterized in mammalian cells and yeast. In the latter case the effects can be characterized on a genome-wide scale by monitoring changes in messenger RNA levels in treated cells with high-density oligonucleotide probe arrays.

5. 发明授权

US08084197B2 Identification of molecular sequence signatures and methods involving the same 有权
标题翻译：鉴定分子序列特征及涉及相同的方法
公开(公告)号：US08084197B2
公开(公告)日：2011-12-27
申请号：US11745987
申请日：2007-05-08
申请人： David J. Lockhart , Gordon G. Wong , Pennina Langer-Safer
发明人： David J. Lockhart , Gordon G. Wong , Pennina Langer-Safer
IPC分类号： C12Q1/68 , C07H21/00 , C07H21/02 , C07H21/04
CPC分类号： C12Q1/6827 , B01J2219/00608 , B01J2219/0061 , B01J2219/00612 , B01J2219/00617 , B01J2219/00626 , B01J2219/00637 , B01J2219/00641 , B01J2219/00659 , B01J2219/00689 , B01J2219/00702 , B01J2219/00711 , B01J2219/00722 , B82Y30/00 , C12Q1/6837 , C40B40/06 , C12Q2565/515
摘要： Novel means and methods for analyzing hybridization data derived from hybridization assays between a target nucleic acid and differently sequenced polynucleotide probes involve selecting probe sets that define reference sequences for sequence signatures and deriving useful data about the nature of the target nucleic acid molecule based on its hybridization to the probes. The methods are useful for determining whether the target contains a nucleic acid or polypeptide sequence signature, whether the target encodes a member of a gene family, or whether the target is derived from one of any number of genes.
摘要翻译：用于分析衍生自靶核酸和不同序列多核苷酸探针之间的杂交测定的杂交数据的新颖方法和方法涉及选择定义用于序列特征的参考序列的探针组，并且基于其杂交获得关于靶核酸分子的性质的有用数据到探头。所述方法对于确定靶是否含有核酸或多肽序列特征，靶是否编码基因家族的成员，或者靶是否衍生自任何数量的基因之一是有用的。

6. 发明申请

US20100106473A1 MULTIPLE COMPARTMENT DOSING MODEL 有权
标题翻译：多个舱室配料模型
公开(公告)号：US20100106473A1
公开(公告)日：2010-04-29
申请号：US12604855
申请日：2009-10-23
申请人： Daniel J. Lockhart , David J. Lockhart
发明人： Daniel J. Lockhart , David J. Lockhart
IPC分类号： G06F17/10
CPC分类号： G06F19/12
摘要： The method for modeling a dosing regimen for a medicament includes providing a system having at least two biocompartments. The method determines steady state levels in each of the biocompartments. After that, the method provides for modifying values to calculate an amount of at least one protein in one of the biocompartments to which the protein is being transported. Next, the method calculates and integrates a weighted value of the protein to find a weighted area under the curve. Then, the method calculates and integrates a non-drug value of the protein to find a non-drug area under the curve. Finally, the method evaluates one or more dosing regimens by comparing the weighted area under the curve and the non-drug area under the curve of the protein to determine a net effect of the drug over the time period.
摘要翻译：用于建模用于药物的给药方案的方法包括提供具有至少两个生物隔离物的系统。该方法确定每个生物隔离物中的稳态水平。之后，该方法提供修饰值以计算蛋白质正在运输到的一个生物隔离物中的至少一种蛋白质的量。接下来，该方法计算并积分蛋白质的加权值以找到曲线下的加权面积。然后，该方法计算并整合蛋白质的非药物值，找出曲线下的非药物区域。最后，该方法通过比较曲线下的加权面积和蛋白质曲线下的非药物面积来评估一种或多种给药方案，以确定药物在该时间段内的净效应。

7. 发明授权

US07135285B2 Identification of molecular sequence signatures and methods involving the same 有权
公开(公告)号：US07135285B2
公开(公告)日：2006-11-14
申请号：US10099442
申请日：2002-03-14
申请人： David J. Lockhart , Gordon G. Wong , Pennina Langer-Safer
发明人： David J. Lockhart , Gordon G. Wong , Pennina Langer-Safer
IPC分类号： C12Q1/68 , C07H21/02 , C07H21/04
CPC分类号： C12Q1/6827 , B01J2219/00608 , B01J2219/0061 , B01J2219/00612 , B01J2219/00617 , B01J2219/00626 , B01J2219/00637 , B01J2219/00641 , B01J2219/00659 , B01J2219/00689 , B01J2219/00702 , B01J2219/00711 , B01J2219/00722 , B82Y30/00 , C12Q1/6837 , C40B40/06 , C12Q2565/515
摘要： Novel means and methods for analyzing hybridization data derived from hybridization assays between a target nucleic acid and differently sequenced polynucleotide probes involve selecting probe sets that define reference sequences for sequence signatures and deriving useful data about the nature of the target nucleic acid molecule based on its hybridization to the probes. The methods are useful for determining whether the target contains a nucleic acid or polypeptide sequence signature, whether the target encodes a member of a gene family, or whether the target is derived from one of any number of genes.

8. 发明授权

US07060443B2 Methods for testing oligonucleotide arrays 失效
公开(公告)号：US07060443B2
公开(公告)日：2006-06-13
申请号：US10457994
申请日：2003-06-10
申请人： Glenn McGall , Anthony D. Barone , Martin Diggelmann , David J. Lockhart , Ann Maria Caviani Pease , Mark Chee
发明人： Glenn McGall , Anthony D. Barone , Martin Diggelmann , David J. Lockhart , Ann Maria Caviani Pease , Mark Chee
IPC分类号： C12Q1/68 , G01N33/553 , G01N33/552 , G01N33/544 , G01N33/53
CPC分类号： B82Y30/00 , B01J2219/00432 , B01J2219/00527 , B01J2219/00585 , B01J2219/0059 , B01J2219/00605 , B01J2219/0061 , B01J2219/00612 , B01J2219/00626 , B01J2219/00637 , B01J2219/00641 , B01J2219/00659 , B01J2219/00693 , B01J2219/00711 , B01J2219/00722 , C12Q1/6837 , C40B40/06 , C40B60/14 , Y10S435/807
摘要： Methods for testing oligonucleotide arrays are disclosed including methods for testing the efficiency of nucleotide coupling; methods for testing amounts of deprotected oligonucleotides; methods for determining amounts of depurinated oligonucleotides; and methods of detecting the presence of cleavable structural features, such as double-stranded nucleic acids.

9. 发明授权

US06974666B1 Methods of enzymatic discrimination enhancement and surface-bound double-stranded DNA 失效
标题翻译：酶鉴别增强方法和表面结合双链DNA
公开(公告)号：US06974666B1
公开(公告)日：2005-12-13
申请号：US08533582
申请日：1995-10-18
申请人： David J. Lockhart , Mark S. Chee , Dirk Vetter , Martin Digglemann
发明人： David J. Lockhart , Mark S. Chee , Dirk Vetter , Martin Digglemann
IPC分类号： B01J19/00 , C07B61/00 , C07H21/00 , C12N15/10 , C12Q1/68 , C40B40/06 , G01N33/53 , G01N33/551 , C07H21/02 , C12P19/34
CPC分类号： C12N15/1093 , B01J19/0046 , B01J2219/00529 , B01J2219/00608 , B01J2219/00612 , B01J2219/00626 , B01J2219/0063 , B01J2219/00659 , B01J2219/00722 , C07B2200/11 , C07H21/00 , C12Q1/6827 , C12Q1/683 , C12Q1/6837 , C12Q1/6874 , C40B40/06 , C40B80/00 , G01N33/5308 , G01N33/551
摘要： Methods for discriminating between fully complementary hybrids and those that differ by one or more base pairs and libraries of unimolecular, double-stranded oligonucleotides on a solid support. In one embodiment, the present invention provides methods of using nuclease treatment to improve the quality of hybridization signals on high density oligonucleotide arrays. In another embodiment, the present invention provides methods of using ligation reactions to improve the quality of hybridization signals on high density oligonucleotide arrays. In yet another embodiment, the present invention provides libraries of unimolecular or intermolecular, double-stranded oligonucleotides on a solid support. These libraries are useful in pharmaceutical discovery for the screening of numerous biological samples for specific interactions between the double-stranded oligonucleotides, and peptides, proteins, drugs and RNA. In a related aspect, the present invention provides libraries of conformationally restricted probes on a solid support. The probes are restricted in their movement and flexibility using double-stranded oligonucleotides as scaffolding. The probes are also useful in various screening procedures associated with drug discovery and diagnosis. The present invention further provides methods for the preparation and screening of the above libraries.
摘要翻译：用于区分完全互补的杂交体与通过一个或多个碱基对不同的那些的方法和在固体支持物上的单分子双链寡核苷酸的文库。在一个实施方案中，本发明提供了使用核酸酶处理来提高高密度寡核苷酸阵列上杂交信号质量的方法。在另一个实施方案中，本发明提供了使用连接反应来提高高密度寡核苷酸阵列上杂交信号质量的方法。在另一个实施方案中，本发明提供了在固体支持物上的单分子或分子间双链寡核苷酸的文库。这些文库在药物发现中可用于筛选许多生物样品，用于双链寡核苷酸与肽，蛋白质，药物和RNA之间的特异性相互作用。在相关方面，本发明提供了在固体支持物上的构象限制探针的文库。使用双链寡核苷酸作为脚手架，探针的运动和灵活性受到限制。探针也可用于与药物发现和诊断相关的各种筛选程序。本发明还提供了制备和筛选上述文库的方法。

10. 发明授权

US06600996B2 Computer-aided techniques for analyzing biological sequences 失效
公开(公告)号：US06600996B2
公开(公告)日：2003-07-29
申请号：US08828952
申请日：1997-03-28
申请人： Teresa A. Webster , MacDonald S. Morris , Michael P. Mittmann , David J. Lockhart , Ming-Hsiu Ho , Derek Bernhart , Luis C. Jevons
发明人： Teresa A. Webster , MacDonald S. Morris , Michael P. Mittmann , David J. Lockhart , Ming-Hsiu Ho , Derek Bernhart , Luis C. Jevons
IPC分类号： G01N3348
CPC分类号： C12Q1/6816 , G01N15/1475 , G06F19/20
摘要： Computer-aided techniques for analyzing biological sequences like nucleic acids are provided. The computer system may analyze hybridization intensities indicating hybridization affinity between nucleic acid probes and a sample nucleic acid sequence in order to call bases in the sample sequence. Multiple base calls may be combined to form a single base call. Additionally, the computer system may analyze hybridization intensities in order to monitor gene expression or the change in gene expression as compared to a baseline.

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