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91. 发明申请

US20120142101A1 OLIGONUCLEOTIDE END CAPS 有权
公开(公告)号：US20120142101A1
公开(公告)日：2012-06-07
申请号：US13382353
申请日：2010-07-07
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev
IPC分类号： C12N5/02 , C12N15/113
CPC分类号： C12N15/113 , C07H21/02 , C07H21/04 , C12N2310/14 , C12N2310/344
摘要： Modified nucleic acids are described herein, including pharmaceutical compositions comprising the modified nucleic acids, and methods of using the modified nucleic acids.
摘要翻译：本文描述了修饰的核酸，包括包含修饰的核酸的药物组合物，以及使用经修饰的核酸的方法。

92. 发明申请

US20110313144A1 iRNA Agents Targeting CCR5 Expressing Cells And Uses Thereof 审中-公开
标题翻译：靶向CCR5表达细胞的iRNA试剂及其用途
公开(公告)号：US20110313144A1
公开(公告)日：2011-12-22
申请号：US13216110
申请日：2011-08-23
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev
IPC分类号： C07H21/00 , C07H21/04
CPC分类号： C07D401/14 , C07D211/24 , C07D211/58 , C07D211/96 , C07D309/14 , C07D401/12 , C07D405/12 , C07D407/12 , C07D409/12 , C07D471/10 , C07H21/00
摘要： The invention relates to iRNA agents that preferably include a modification that targets CC chemokine receptor 5 (CCR5). The invention also relates to methods of making and using such modified iRNA agents.
摘要翻译：本发明涉及优选包括靶向CC趋化因子受体5（CCR5）的修饰的iRNA试剂。本发明还涉及制备和使用这种修饰的iRNA试剂的方法。

93. 发明授权

US08063198B2 Processes and reagents for desilylation of oligonucleotides 有权
标题翻译：寡核苷酸脱乙酰化的方法和试剂
公开(公告)号：US08063198B2
公开(公告)日：2011-11-22
申请号：US12050633
申请日：2008-03-18
申请人： Muthiah Manoharan , Michael E. Jung , Kallanthottathil G. Rajeev , Rajendra K. Pandey , Gang Wang
发明人： Muthiah Manoharan , Michael E. Jung , Kallanthottathil G. Rajeev , Rajendra K. Pandey , Gang Wang
IPC分类号： C07H21/00 , C07C17/07
CPC分类号： C07H21/00 , C07H21/04 , Y02P20/55
摘要： The present invention relates to processes and reagents for oligonucleotide synthesis and purification. One aspect of the present invention relates to compounds useful for activating phosphoramidites in oligonucleotide synthesis. Another aspect of the present invention relates to a method of preparing oligonucleotides via the phosphoramidite method using an activator of the invention. Another aspect of the present invention relates to sulfur-transfer agents. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to a method of preparing a phosphorothioate by treating a phosphite with a sulfur-transfer reagent of the invention. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to compounds that scavenge acrylonitrile produced during the deprotection of phosphate groups bearing ethylnitrile protecting groups. In a preferred embodiment, the acrylonitrile scavenger is a polymer-bound thiol. Another aspect of the present invention relates to agents used to oxidize a phosphite to a phosphate. In a preferred embodiment, the oxidizing agent is sodium chlorite, chloroamine, or pyridine-N-oxide. Another aspect of the present invention relates to methods of purifying an oligonucleotide by annealing a first single-stranded oligonucleotide and second single-stranded oligonucleotide to form a double-stranded oligonucleotide; and subjecting the double-stranded oligonucleotide to chromatographic purification. In a preferred embodiment, the chromatographic purification is high-performance liquid chromatography.
摘要翻译：本发明涉及用于寡核苷酸合成和纯化的方法和试剂。本发明的一个方面涉及可用于在寡核苷酸合成中活化亚磷酰胺的化合物。本发明的另一方面涉及使用本发明的活化剂通过亚磷酰胺方法制备寡核苷酸的方法。本发明的另一方面涉及硫转移剂。在优选的实施方案中，硫转移剂是3-氨基-1,2,4-二噻唑烷-5-酮。本发明的另一方面涉及通过用本发明的硫转移试剂处理亚磷酸酯制备硫代磷酸酯的方法。在优选的实施方案中，硫转移剂是3-氨基-1,2,4-二噻唑烷-5-酮。本发明的另一方面涉及清除在带有乙腈基保护基团的磷酸酯基团去保护过程中产生的丙烯腈的化合物。在优选的实施方案中，丙烯腈清除剂是聚合物结合的硫醇。本发明的另一方面涉及用于将亚磷酸盐氧化成磷酸盐的试剂。在优选的实施方案中，氧化剂是亚氯酸钠，氯胺或吡啶-N-氧化物。本发明的另一方面涉及通过退火第一单链寡核苷酸和第二单链寡核苷酸来纯化寡核苷酸以形成双链寡核苷酸的方法; 并对双链寡核苷酸进行色谱纯化。在优选的实施方案中，色谱纯化是高效液相色谱法。

94. 发明授权

US08017762B2 Modified iRNA agents 有权
标题翻译：修饰的iRNA试剂
公开(公告)号：US08017762B2
公开(公告)日：2011-09-13
申请号：US12510050
申请日：2009-07-27
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev , Meena
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev , Meena
IPC分类号： C07H21/04 , A61K31/70
CPC分类号： C07H21/02
摘要： The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose that further includes a tether having one or more linking groups, in which at least one of the linking groups is a cleavable linking group. The tether in turn can be connected to a selected moiety, e.g., a ligand, e.g., a targeting or delivery moiety, or a moiety which alters a physical property. The cleavable linking group is one which is sufficiently stable outside the cell such that it allows targeting of a therapeutically beneficial amount of an iRNA agent (e.g., a single stranded or double stranded iRNA agent), coupled by way of the cleavable linking group to a targeting agent—to targets cells, but which upon entry into a target cell is cleaved to release the iRNA agent from the targeting agent.The inclusion of such a monomer can allow for modulation of a property of the iRNA agent into which it is incorporated, e.g., by using the non-ribose moiety as a point to which a ligand or other entity, e.g., a lipophilic moiety. e.g., cholesterol, is directly, or indirectly, tethered. The invention also relates to methods of making and using such modified iRNA agents.
摘要翻译：本发明涉及iRNA试剂，其优选包括其中核糖部分已被核糖替代的单体，其进一步包括具有一个或多个连接基团的系链，其中至少一个连接基团是可切割的连接组。系链又可以连接到所选择的部分，例如配体，例如靶向或递送部分，或改变物理性质的部分。可切割连接基团是在细胞外部足够稳定的连接基团，使得其允许靶向治疗有益量的iRNA试剂（例如，单链或双链iRNA试剂），其通过可切割连接基团连接至靶向细胞靶向细胞，但是在进入靶细胞时被切割以从靶向剂释放iRNA试剂。包含这样的单体可以允许调节掺入其中的iRNA试剂的性质，例如通过使用非核糖部分作为配体或其它实体例如亲油部分的点。例如胆固醇是直接或间接的系链。本发明还涉及制备和使用这种修饰的iRNA试剂的方法。

95. 发明申请

US20110118339A1 CHEMICALLY MODIFIED OLIGONUCLEOTIDES AND USES THEREOF 审中-公开
标题翻译：化学修饰的寡核苷酸及其用途
公开(公告)号：US20110118339A1
公开(公告)日：2011-05-19
申请号：US12863359
申请日：2009-01-16
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev
IPC分类号： A61K31/7105 , A61P35/00
CPC分类号： A61K31/7115 , C12N15/113 , C12N2310/14 , C12N2310/141 , C12N2310/315 , C12N2310/322
摘要： This invention relates generally to chemically modified oligonuceotides useful for augmenting activity of microRNAs and pre-microRNAs. E.g., the invention relates to single stranded chemically modified oligonuceotides for augmenting microRNA and pre-microRNA expression and to methods of making and using the modified oligonucleotides.
摘要翻译：本发明一般涉及可用于增强微小RNA和前微小RNA的活性的化学修饰的寡核苷酸。例如，本发明涉及用于增加microRNA和pre-microRNA表达的单链化学修饰的寡核苷酸以及制备和使用修饰的寡核苷酸的方法。

96. 发明授权

US07919473B2 IRNA agents targeting VEGF 有权
标题翻译：靶向VEGF的IRNA试剂
公开(公告)号：US07919473B2
公开(公告)日：2011-04-05
申请号：US11340080
申请日：2006-01-25
申请人： Antonin De Fougerolles , Maria Frank-Kamenetsky , Muthiah Manoharan , Kallanthottathil G. Rajeev , Philipp Hadwiger
发明人： Antonin De Fougerolles , Maria Frank-Kamenetsky , Muthiah Manoharan , Kallanthottathil G. Rajeev , Philipp Hadwiger
IPC分类号： A61K31/70 , C07H21/04
CPC分类号： C12N15/1136 , A61K9/0019 , A61K31/7088 , A61K31/712 , A61K31/713 , A61K47/02 , A61K47/10 , A61K47/12 , A61K47/549 , A61K47/551 , A61K47/60 , A61K48/00 , C07K14/475 , C12N2310/14 , C12N2310/3515 , C12N2310/533 , C12N2320/30 , C12N2320/32
摘要： The features of the present invention relate to compounds, compositions and methods useful for modulating the expression of vascular endothelial growth factor (VEGF), such as by the mechanism of RNA interference (RNAi). The compounds and compositions include iRNA agents that can be unmodified or chemically-modified.
摘要翻译：本发明的特征涉及用于调节血管内皮生长因子（VEGF）表达的化合物，组合物和方法，例如通过RNA干扰（RNAi）机制。化合物和组合物包括可以未修饰或化学修饰的iRNA试剂。

97. 发明授权

US07745608B2 Modified iRNA agents 有权
标题翻译：修饰的iRNA试剂
公开(公告)号：US07745608B2
公开(公告)日：2010-06-29
申请号：US10916185
申请日：2004-08-10
申请人： Muthiah Manoharan , Venkitasamy Kesavan , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Venkitasamy Kesavan , Kallanthottathil G. Rajeev
IPC分类号： C07H21/04 , A61K31/70
CPC分类号： C12N15/111 , A61K47/554 , C12N2310/14 , C12N2310/323 , C12N2310/344 , C12N2310/3515 , C12N2320/51
摘要： The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose. The inclusion of such a monomer can allow for modulation of a property of the iRNA agent into which it is incorporated, e.g., by using the non-ribose moiety as a point to which a ligand or other entity, e.g., a lipophilic moiety. e.g., cholesterol, is directly, or indirectly, tethered. The invention also relates to methods of making and using such modified iRNA agents.
摘要翻译：本发明涉及iRNA试剂，其优选包括其中核糖部分被除核糖以外的部分替代的单体。包含这样的单体可以允许调节掺入其中的iRNA试剂的性质，例如通过使用非核糖部分作为配体或其它实体例如亲油部分的点。例如胆固醇是直接或间接的系链。本发明还涉及制备和使用这种修饰的iRNA试剂的方法。

98. 发明授权

US07674778B2 Oligonucleotides comprising a conjugate group linked through a C5-modified pyrimidine 有权
标题翻译：包含通过C5-修饰的嘧啶连接的共轭基团的寡核苷酸
公开(公告)号：US07674778B2
公开(公告)日：2010-03-09
申请号：US11119533
申请日：2005-04-29
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev
IPC分类号： A61K31/70 , C07H21/04
CPC分类号： C07H21/00 , C07H21/02 , C12N15/111 , C12N15/113 , C12N15/1135 , C12N15/1136 , C12N2310/14 , C12N2310/33 , C12N2310/351 , C12N2310/3515 , C12N2320/51 , C12N2330/30
摘要： One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one ligand. In certain embodiments, a ligand is bound to only one of the two oligonucleotide strands comprising the double-stranded oligonucleotide. In certain embodiments, both of the oligonucleotide strands of the double-stranded oligonucleotide independently comprise a bound ligand. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. In certain embodiments, a phosphate linkage in one or both of the strands of the oligonucleotide has been replaced with a phosphorothioate or phosphorodithioate linkage. In a preferred embodiment, the ligand is cholesterol or 5β-cholanic acid. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one ligand. In certain embodiments, the oligonucleotide comprises at least one modified sugar moiety. In certain embodiments, a phosphate linkage of the oligonucleotide has been replaced with a phosphorothioate or phosphorodithioate linkage. In a preferred embodiment, the ligand is cholesterol or 5β-cholanic acid. The ligand improves the pharmacokinetic properties of the oligonucleotide.
摘要翻译：本发明的一个方面涉及包含至少一种配体的双链寡核苷酸。在某些实施方案中，配体仅与包含双链寡核苷酸的两条寡核苷酸链中的一条结合。在某些实施方案中，双链寡核苷酸的两个寡核苷酸链都独立地包含结合的配体。在某些实施方案中，寡核苷酸链包含至少一个修饰的糖部分。在某些实施方案中，寡核苷酸的一条或两条链中的磷酸键被硫代磷酸酯或二硫代磷酸酯键取代。在优选的实施方案中，配体是胆固醇或5'-胆碱。本发明的另一方面涉及包含至少一种配体的单链寡核苷酸。在某些实施方案中，寡核苷酸包含至少一个修饰的糖部分。在某些实施方案中，寡核苷酸的磷酸键被硫代磷酸酯或二硫代磷酸酯键取代。在优选的实施方案中，配体是胆固醇或5'-胆碱。该配体改善寡核苷酸的药代动力学性质。

99. 发明授权

US07626014B2 Single-stranded and double-stranded oligonucleotides comprising a 2-arylpropyl moiety 有权
标题翻译：包含2-芳基丙基部分的单链和双链寡核苷酸
公开(公告)号：US07626014B2
公开(公告)日：2009-12-01
申请号：US11115989
申请日：2005-04-27
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev , Venkitasamy Kesavan
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev , Venkitasamy Kesavan
IPC分类号： C07H21/04 , A61K31/70
CPC分类号： C07H21/04 , C07H21/02 , C12N15/111 , C12N2310/14 , C12N2310/351 , C12N2320/51
摘要： The present invention provides single-stranded and double-stranded oligonucleotides comprising at least one aralkyl ligand that improves the pharmacokinetic properties of the oligonucleotides. The aralkyl ligands of the present invention include naproxen, ibuprofen and derivatives thereof. The present invention also provides methods for modulating gene expression using the modified oligonucleotide compounds and compositions comprising those modified oligonucleotides.
摘要翻译：本发明提供了包含改善寡核苷酸的药代动力学性质的至少一种芳烷基配体的单链和双链寡核苷酸。本发明的芳烷基配体包括萘普生，布洛芬及其衍生物。本发明还提供了使用修饰的寡核苷酸化合物和包含那些经修饰的寡核苷酸的组合物调节基因表达的方法。

100. 发明申请

US20080213891A1 RNAi Agents Comprising Universal Nucleobases 审中-公开
标题翻译：包含通用核碱基的RNAi试剂
公开(公告)号：US20080213891A1
公开(公告)日：2008-09-04
申请号：US11834140
申请日：2007-08-06
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev
IPC分类号： C12N5/02 , C07H21/00
CPC分类号： C07F9/65515 , C07F9/65586 , C07F9/6561 , C07H21/02 , C12N15/111 , C12N2310/14 , C12N2310/331 , C12N2320/34
摘要： One aspect of the present invention relates to an oligonucleotide agent comprising at least one universal nucleobase. In certain embodiments, the universal nucleobase is difluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl. In a preferred embodiment, the universal nucleobase is difluorotolyl. In certain embodiments, the oligonucleotide is double-stranded. In certain embodiments, the oligonucleotide is single-stranded. Another aspect of the present invention relates to a method of altering the expression level of a target in the presence of target sequence polymorphism. In a preferred embodiment, the oligonucleotide agent alters the expression of different alleles of a gene. In another preferred embodiment, the oligonucleotide agent alters the expression level of two or more genes. In another embodiment, the oligonucleotide agent alters the expression level of a viral gene from different strains of the virus. In another embodiment, the oligonucleotide agent alters the expression level of genes from different species.
摘要翻译：本发明的一个方面涉及包含至少一种通用核碱基的寡核苷酸试剂。在某些实施方案中，通用核碱基是二氟苯甲酰基，硝基吲哚基，硝基吡咯基或硝基咪唑基。在优选的实施方案中，通用核碱基是二氟甲苯基。在某些实施方案中，寡核苷酸是双链的。在某些实施方案中，寡核苷酸是单链的。本发明的另一方面涉及在存在靶序列多态性的情况下改变靶的表达水平的方法。在优选的实施方案中，寡核苷酸试剂改变基因的不同等位基因的表达。在另一个优选的实施方案中，寡核苷酸试剂改变两个或多个基因的表达水平。在另一个实施方案中，寡核苷酸试剂改变来自不同病毒株的病毒基因的表达水平。在另一个实施方案中，寡核苷酸试剂改变来自不同物种的基因的表达水平。

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