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公开(公告)号：US20130018085A1
公开(公告)日：2013-01-17
申请号：US13620212
申请日：2012-09-14
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： A61K31/713 , A61P35/00 , A61P27/02 , C12N5/071 , C07H21/02
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.
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公开(公告)号：US08344125B2
公开(公告)日：2013-01-01
申请号：US12619382
申请日：2009-11-16
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摘要： The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose.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 carbohydrate; or a steroid, e.g., cholesterol, which is optionally substituted with at least one carbohydrate. 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其引入其中的iRNA试剂的性质，例如通过使用非核糖部分作为配体或其他实体例如碳水化合物的点; 或类固醇，例如胆固醇，其任选被至少一种碳水化合物取代。 是直接或间接地束缚着。 本发明还涉及制备和使用这种修饰的iRNA试剂的方法。
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公开(公告)号：US08324366B2
公开(公告)日：2012-12-04
申请号：US12432192
申请日：2009-04-29
申请人： Akin Akinc , Tomoko Nakayama , Muthiah Manoharan , Markus Stoffel
发明人： Akin Akinc , Tomoko Nakayama , Muthiah Manoharan , Markus Stoffel
CPC分类号： C12N15/111 , A61K47/554 , A61K47/6919 , C12N2310/14 , C12N2310/315 , C12N2310/321 , C12N2310/322 , C12N2310/3515 , C12N2320/32 , C12N2310/3521 , C12N2310/3533
摘要： This invention relates to new compositions comprising at least one of a single or double stranded oligonucleotide, where said oligonucleotide has been conjugated to a lipophile and to which the conjugated oligonucleotide has been preassembled with lipoproteins. These compositions are effectively in delivering oligonucleotides to mammalian tissue where they effect gene silencing.
摘要翻译： 本发明涉及包含单链或双链寡核苷酸中的至少一种的新组合物，其中所述寡核苷酸已经与亲脂体缀合并且缀合的寡核苷酸已经与脂蛋白预组装。 这些组合物有效地将哺乳动物组织中的寡核苷酸递送到基因沉默中。
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公开(公告)号：US20120220761A1
公开(公告)日：2012-08-30
申请号：US13393851
申请日：2009-12-22
IPC分类号： C07H1/04
CPC分类号： C07H21/00 , C12N15/117 , C12N2310/17 , C12N2310/321 , C12N2310/3521
摘要： The present invention describes simple, efficient, and enzyme-free method of making oligonucleotides with 5′-triphosphate. This invention presents novel process for synthesizing triphosphate oligonucleotides using a diaryl phosphonate as reagent. The process of the present invention is amenable to large-scale, economic 5′-triphosphate oligonucleotide synthesis.
摘要翻译： 本发明描述了制备具有5'-三磷酸的寡核苷酸的简单，有效和无酶的方法。 本发明提出了使用二芳基膦酸盐作为试剂合成三磷酸酯寡核苷酸的新方法。 本发明的方法适用于大规模，经济的5'-三磷酸寡核苷酸合成。
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公开(公告)号：US20120157511A1
公开(公告)日：2012-06-21
申请号：US13382346
申请日：2010-07-07
IPC分类号： A61K31/7088 , C07H19/11 , C12N5/071 , C07H19/073 , C07H21/00 , C07H21/02 , C07H19/04 , C07H19/10
CPC分类号： C12N15/113 , C07H19/10 , C07H19/11 , C07H19/20 , C07H19/213 , C12N2310/11
摘要： The present invention provides nucleosides and oligonucleotides comprising a 5′ phosphate mimics of formula (IVc) or (Vc). One aspect of the present invention relates to modified nucleosides and oligonucleotides comprising such dinucleotide of formula (Ia). Another aspect of the invention relates to a method of inhibiting the expression of a gene in call, the method comprising (a) contacting an oligonucleotide of the invention with the cell; and (b) maintaining the cell from step (a) for a time sufficient to obtain degradation of the mRNA of the target gene.
摘要翻译： 本发明提供了包含式（IVc）或（Vc）的5'磷酸酯模拟物的核苷和寡核苷酸。 本发明的一个方面涉及包含式（Ia）的二核苷酸的修饰核苷和寡核苷酸。 本发明的另一方面涉及一种抑制基因表达的方法，所述方法包括（a）使本发明的寡核苷酸与细胞接触; 和（b）将来自步骤（a）的细胞维持足以获得靶基因的mRNA降解的时间。
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公开(公告)号：US20110311583A1
公开(公告)日：2011-12-22
申请号：US13128287
申请日：2009-11-10
申请人： Muthiah Manoharan , kallanthottathil G. Rajeev , Muthusamy Jayaraman , David Butler , Jayaprakash K. Narayanannair , Martin Maier , Laxman Eltepu
发明人： Muthiah Manoharan , kallanthottathil G. Rajeev , Muthusamy Jayaraman , David Butler , Jayaprakash K. Narayanannair , Martin Maier , Laxman Eltepu
IPC分类号： A61K39/12 , A61K47/08 , C07J41/00 , A61K47/28 , C07C211/22 , A61K47/16 , C07C211/21 , C07D211/72 , A61K47/22 , C07C251/78 , C07C279/12 , C07C271/12 , A61K48/00 , A61K31/713 , C12N5/00 , A61K39/39 , A61K39/00 , A61K39/02 , A61P37/04 , A61P31/12 , A61P31/04 , A61P33/00 , C07C49/203
CPC分类号： A61K47/44 , A61K9/1272 , A61K31/7088 , A61K31/713 , A61K39/00 , A61K39/39 , A61K47/10 , A61K47/18 , A61K47/20 , A61K47/28 , A61K2039/55555 , A61K2039/55561 , C07C229/08 , C07C229/30 , C07C237/16 , C07C251/38 , C07C251/78 , C07C271/12 , C07C271/20 , C07C323/25 , C07D203/10 , C07D317/28 , C07D317/44 , C07D317/46 , C07D317/72 , C07D319/06 , C07D405/12 , C07D491/056 , C07D491/113 , C12N15/111 , C12N15/113 , C12N2310/14 , C12N2310/3515 , C12N2320/32 , Y02A50/464
摘要： (A1) Translate this text The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure (I) wherein R1 and R2 are each independently for each occurrence optionally substituted C10-C30 alkyl, optionally substituted C10-C30 alkenyl, optionally substituted C10-C30 alkynyl, optionally substituted C10-C30 acyl, or -linker-ligand; R3 is H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ?-aminoalkyls, ?-(substituted)aminoalkyls, ?-phosphoalkyls, ?-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; E is O, S, N(Q), C(O), N(Q)C(O), C(0)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O)2N(Q), S(O)2, N(Q)S(O)2, SS, O═N, aryl, heteroaryl, cyclic or heterocycle; and, Q is H, alkyl, ?-aminoalkyl, ?-(substituted)aminoalky, ?-phosphoalkyl or ?-thiophosphoalkyl.
摘要翻译： （A1）翻译本发明本发明提供有利地用于脂质颗粒以用于体内递送治疗剂至细胞的脂质。 特别地，本发明提供具有以下结构（I）的脂质，其中R1和R2各自独立地为任何取代的C 10 -C 30烷基，任选取代的C 10 -C 30烯基，任选取代的C 10 -C 30炔基，任选取代的C 10 -C 30 酰基或 - 连接子 - 配体; R 3是H，任选取代的C 1 -C 10烷基，任选取代的C 2 -C 10烯基，任选取代的C 2 -C 10炔基，烷基硫代磷酸烷基酯，硫代磷酸烷基酯，磷酸二烷基酯，烷基膦酸酯，烷基胺，羟烷基，α-氨基烷基， 任选取代的聚乙二醇（PEG，mw 100-40K），任选取代的mPEG（mw 120-40K），杂芳基，杂环或连接基 - 配体; E是O，S，N（Q），C（O），N（Q）C（O），C（O）N（Q），（Q） ），S（O），NS（O）2N（Q），S（O）2，N（Q）S（O）2，SS，O = N，芳基，杂芳基，环状或杂环; Q为H，烷基，α-氨基烷基，β-（取代）氨基烷基，α-磷酸烷基或α-硫代磷酰烷基。
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公开(公告)号：US08058448B2
公开(公告)日：2011-11-15
申请号：US12351605
申请日：2009-01-09
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： C07D285/01 , C07H21/00
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, chloramine, 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。
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公开(公告)号：US20110251257A1
公开(公告)日：2011-10-13
申请号：US12901458
申请日：2010-10-08
申请人： Muthiah Manoharan , Neil Aronin
发明人： Muthiah Manoharan , Neil Aronin
IPC分类号： A61K31/713 , A61P25/16 , A61P25/28 , C12N5/079 , A61P25/00
CPC分类号： C12N15/113 , A61K31/7088 , A61K47/554 , C12N15/111 , C12N2310/14 , C12N2310/315 , C12N2310/321 , C12N2310/3515 , C12N2320/32 , C12Q1/6883 , C12Q2600/136 , C12Q2600/158 , C12Q2600/178
摘要： This invention relates to methods and compositions for treating neurological disease, and more particularly to methods of delivering iRNA agents to neural cells for the treatment of neurological diseases.
摘要翻译： 本发明涉及用于治疗神经疾病的方法和组合物，更具体地涉及将iRNA试剂递送至神经细胞用于治疗神经疾病的方法。
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公开(公告)号：US08034921B2
公开(公告)日：2011-10-11
申请号：US11944227
申请日：2007-11-21
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。
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公开(公告)号：US08017763B2
公开(公告)日：2011-09-13
申请号：US12561529
申请日：2009-09-17
CPC分类号： C12N15/113 , A61K31/7088 , A61K31/713 , A61K47/54 , A61K47/543 , A61K47/551 , A61K47/554 , C07F9/06 , C12N15/111 , C12N15/87 , C12N2310/113 , C12N2310/14 , C12N2310/351 , C12N2310/3515 , C12N2320/32 , C12N2320/51
摘要： This invention relates composition and methods for making and using chemically modified oligonucleotides agents for inhibiting gene expression.
摘要翻译： 本发明涉及用于制备和使用化学修饰的寡核苷酸抑制基因表达的组合物和方法。
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