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71. 发明授权

US07893224B2 Oligonucleotides comprising a ligand tethered to a modified or non-natural nucleobase 有权
标题翻译：包含与修饰或非天然核碱基连接的配体的寡核苷酸
公开(公告)号：US07893224B2
公开(公告)日：2011-02-22
申请号：US12533710
申请日：2009-07-31
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev , Jie Xia
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev , Jie Xia
IPC分类号： C07G3/00 , C07H21/04 , C12Q1/68
CPC分类号： C07H21/00 , A61K31/7115 , C07F9/6561 , C07H21/02 , C12Q1/6883 , Y02A50/385 , Y02A50/387 , Y02A50/393 , Y02A50/395 , Y02A50/411 , Y02A50/463 , Y02A50/465 , Y02A50/467
摘要： One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one ligand tethered to an altered or non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitropyrrolyl, or nitroimidazolyl. In certain embodiments, the ligand is a steroid or aromatic compound. In certain embodiments, only one of the two oligonucleotide strands comprising the double-stranded oligonucleotide contains a ligand tethered to an altered or non-natural nucleobase. In certain embodiments, both of the oligonucleotide strands comprising the double-stranded oligonucleotide independently contain a ligand tethered to an altered or non-natural nucleobase. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one ligand tethered to an altered or non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitropyrrolyl, or nitroimidazolyl. In certain embodiments, the ligand is a steroid or aromatic compound. In certain embodiments, the ribose sugar moiety that occurs naturally in nucleosides is replaced with a hexose sugar, polycyclic heteroalkyl ring, or cyclohexenyl group. In certain embodiments, at least one phosphate linkage in the oligonucleotide has been replaced with a phosphorothioate linkage.
摘要翻译：本发明的一个方面涉及包含至少一个与改变的或非天然核碱基连接的配体的双链寡核苷酸。在某些实施方案中，非天然核碱基是二氟苯甲酰基，硝基吡咯基或硝基咪唑基。在某些实施方案中，配体是类固醇或芳族化合物。在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链中只有一条含有与改变的或非天然核碱基连接的配体。在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链都独立地包含与改变的或非天然核碱基连接的配体。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。本发明的另一方面涉及包含至少一个与改变的或非天然核碱基连接的配体的单链寡核苷酸。在某些实施方案中，非天然核碱基是二氟苯甲酰基，硝基吡咯基或硝基咪唑基。在某些实施方案中，配体是类固醇或芳族化合物。在某些实施方案中，在核苷中天然存在的核糖部分被己糖，多环杂烷基环或环己烯基取代。在某些实施方案中，寡核苷酸中的至少一个磷酸键被硫代磷酸酯键取代。

72. 发明授权

US07772387B2 Oligonucleotides comprising a modified or non-natural nucleobase 有权
标题翻译：包含修饰或非天然核碱基的寡核苷酸
公开(公告)号：US07772387B2
公开(公告)日：2010-08-10
申请号：US12495932
申请日：2009-07-01
申请人： Muthiah Manoharan , Jie Xia , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Jie Xia , Kallanthottathil G. Rajeev
IPC分类号： C07H21/02 , C07H21/04 , C12Q1/68
CPC分类号： C07H21/00 , A61K31/7115 , C07F9/65515 , C07F9/65586 , C07F9/6561 , C07H21/02 , Y02A50/385 , Y02A50/387 , Y02A50/393 , Y02A50/395 , Y02A50/411 , Y02A50/463 , Y02A50/465 , Y02A50/467
摘要： One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl. In a preferred embodiment, the non-natural nucleobase is difluorotolyl. In certain embodiments, only one of the two oligonucleotide strands comprising the double-stranded oligonucleotide contains a non-natural nucleobase. In certain embodiments, both of the oligonucleotide strands comprising the double-stranded oligonucleotide independently contain a non-natural nucleobase. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one non-natural nucleobase. In a preferred embodiment, the non-natural nucleobase is difluorotolyl. In certain embodiments, the ribose sugar moiety that occurs naturally in nucleosides is replaced with a hexose sugar, polycyclic heteroalkyl ring, or cyclohexenyl group. In certain embodiments, at least one phosphate linkage in the oligonucleotide has been replaced with a phosphorothioate linkage.
摘要翻译：本发明的一个方面涉及包含至少一种非天然核碱基的双链寡核苷酸。在某些实施方案中，非天然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，非天然核碱基是二氟苯甲酰基。在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链中只有一条含有非天然核碱基。在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链都独立地含有非天然核碱基。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。本发明的另一方面涉及包含至少一种非天然核碱基的单链寡核苷酸。在优选的实施方案中，非天然核碱基是二氟苯甲酰基。在某些实施方案中，在核苷中天然存在的核糖部分被己糖，多环杂烷基环或环己烯基取代。在某些实施方案中，寡核苷酸中的至少一个磷酸键被硫代磷酸酯键取代。

73. 发明授权

US07723509B2 IRNA agents with biocleavable tethers 有权
标题翻译：具有生物可清除系绳的IRNA试剂
公开(公告)号：US07723509B2
公开(公告)日：2010-05-25
申请号：US10985426
申请日：2004-11-09
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev
IPC分类号： C07H21/04 , A61K31/70
CPC分类号： C12N15/113 , C12N15/111 , C12N2310/14 , C12N2310/323 , C12N2310/3511 , 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 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.
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。

74. 发明授权

US07579451B2 Oligonucleotides comprising a modified or non-natural nucleobase 有权
标题翻译：包含修饰或非天然核碱基的寡核苷酸
公开(公告)号：US07579451B2
公开(公告)日：2009-08-25
申请号：US11186915
申请日：2005-07-21
申请人： Muthiah Manoharan , Jie Xia , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Jie Xia , Kallanthottathil G. Rajeev
IPC分类号： C07H21/00 , C07H21/02 , C07H21/04 , C12Q1/68
CPC分类号： C07H21/00 , A61K31/7115 , C07F9/65515 , C07F9/65586 , C07F9/6561 , C07H21/02 , Y02A50/385 , Y02A50/387 , Y02A50/393 , Y02A50/395 , Y02A50/411 , Y02A50/463 , Y02A50/465 , Y02A50/467
摘要： One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl. In a preferred embodiment, the non-natural nucleobase is difluorotolyl. In certain embodiments, only one of the two oligonucleotide strands comprising the double-stranded oligonucleotide contains a non-natural nucleobase. In certain embodiments, both of the oligonucleotide strands comprising the double-stranded oligonucleotide independently contain a non-natural nucleobase. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one non-natural nucleobase. In a preferred embodiment, the non-natural nucleobase is difluorotolyl. In certain embodiments, the ribose sugar moiety that occurs naturally in nucleosides is replaced with a hexose sugar, polycyclic heteroalkyl ring, or cyclohexenyl group. In certain embodiments, at least one phosphate linkage in the oligonucleotide has been replaced with a phosphorothioate linkage.
摘要翻译：本发明的一个方面涉及包含至少一种非天然核碱基的双链寡核苷酸。在某些实施方案中，非天然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，非天然核碱基是二氟苯甲酰基。在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链中只有一条含有非天然核碱基。在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链都独立地含有非天然核碱基。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。本发明的另一方面涉及包含至少一种非天然核碱基的单链寡核苷酸。在优选的实施方案中，非天然核碱基是二氟苯甲酰基。在某些实施方案中，在核苷中天然存在的核糖部分被己糖，多环杂烷基环或环己烯基取代。在某些实施方案中，寡核苷酸中的至少一个磷酸键被硫代磷酸酯键取代。

75. 发明申请

US20090005549A1 Processes and Reagents for Desilylation of Oligonucleotides 有权
标题翻译：寡核苷酸脱甲酰化的方法和试剂
公开(公告)号：US20090005549A1
公开(公告)日：2009-01-01
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： C07H19/00
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。

76. 发明授权

US09290760B2 Modified iRNA agents 有权
标题翻译：修饰的iRNA试剂
公开(公告)号：US09290760B2
公开(公告)日：2016-03-22
申请号：US13822441
申请日：2011-09-14
申请人： Kallanthottathil G. Rajeev , Tracy Zimmermann , Muthiah Manoharan , Martin Maier , Kevin Fitzgerald
发明人： Kallanthottathil G. Rajeev , Tracy Zimmermann , Muthiah Manoharan , Martin Maier , Kevin Fitzgerald
IPC分类号： C12N15/113 , C12N15/11
CPC分类号： C12N15/113 , C12N15/111 , C12N2310/14 , C12N2310/315 , C12N2310/322 , C12N2310/343 , C12N2310/346 , C12N2310/351 , C12N2310/3515 , C12N2320/32 , C12N2320/52 , C12N2310/3533
摘要： The present invention provides effective motifs for RNA agents conjugated to at least one ligand, which are advantageous for the in vivo delivery of iRNA duplex agents. Additionally, the present invention provides methods of making these compositions, as well as methods of introducing these iRNA duplex agents into cells using these compositions, e.g., for the treatment of various disease conditions.
摘要翻译：本发明提供了与至少一种配体缀合的RNA试剂的有效基序，其有利于iRNA双链体的体内递送。此外，本发明提供了制备这些组合物的方法，以及使用这些组合物将这些iRNA双链体引入细胞的方法，例如用于治疗各种疾病状况。

77. 发明申请

US20130323836A1 5'-END DERIVATIVES 有权
标题翻译： 5'-END衍生物
公开(公告)号：US20130323836A1
公开(公告)日：2013-12-05
申请号：US13696796
申请日：2011-04-22
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev , Ivan Zlatev , Eric E. Swayze , Thazha P. Prakash , Walter F. Lima
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev , Ivan Zlatev , Eric E. Swayze , Thazha P. Prakash , Walter F. Lima
IPC分类号： C07H17/02 , C12N15/113
CPC分类号： C07H17/02 , C07H19/067 , C07H21/02 , C12N15/113 , C12N15/1137 , C12N2310/14 , C12N2310/315 , C12N2310/321 , C12N2310/322 , C12N2310/344 , C12N2310/3521 , C12N2310/3525
摘要： The present invention provides compounds of formula (1). 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：本发明提供式（1）的化合物。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。

78. 发明申请

US20130236968A1 MULTIFUNCTIONAL COPOLYMERS FOR NUCLEIC ACID DELIVERY 审中-公开
标题翻译：用于核酸交付的多官能共聚物
公开(公告)号：US20130236968A1
公开(公告)日：2013-09-12
申请号：US13805991
申请日：2011-06-20
申请人： Muthiah Manoharan , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Kallanthottathil G. Rajeev
IPC分类号： C12N15/113 , C08F222/38 , C08F224/00 , C08F228/06 , C08F226/06
CPC分类号： C12N15/113 , A61K47/58 , C08F220/58 , C08F2220/603
摘要： The present invention relates to multifunctional polymers represented by the following formula: The invention further provides methods for their preparation and methods for site-specific delivery of nucleic acids by combining them with targeting ligands, endosomolytic ligands and/or PK modulator ligands.
摘要翻译：本发明涉及由下式表示的多官能聚合物：本发明进一步提供了它们的制备方法和通过将其与靶配体，内体分解配体和/或PK调节剂配体组合来进行核酸的位点特异性递送的方法。

79. 发明授权

US08507661B2 Modified iRNA agents 有权
标题翻译：修饰的iRNA试剂
公开(公告)号：US08507661B2
公开(公告)日：2013-08-13
申请号：US12714298
申请日：2010-02-26
申请人： Muthiah Manoharan , Venkitasamy Kesavan , Kallanthottathil G. Rajeev
发明人： Muthiah Manoharan , Venkitasamy Kesavan , Kallanthottathil G. Rajeev
IPC分类号： C07H15/00 , C07H17/00 , C07H17/02
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。

80. 发明申请

US20130203836A1 2' AND 5' MODIFIED MONOMERS AND OLIGONUCLEOTIDES 有权
标题翻译： 2'和5'改性单体和寡核苷酸
公开(公告)号：US20130203836A1
公开(公告)日：2013-08-08
申请号：US13638891
申请日：2011-03-31
申请人： Kallanthottathil G. Rajeev , Muthiah Manoharan , Eric E. Swayze , Thazha P. Prakash
发明人： Kallanthottathil G. Rajeev , Muthiah Manoharan , Eric E. Swayze , Thazha P. Prakash
IPC分类号： C12N15/113 , C07H19/16 , A61K48/00 , C07H19/06
CPC分类号： C12N15/113 , A61K48/00 , C07H19/06 , C07H19/067 , C07H19/16
摘要： The present invention provides nucleosides of formula (1) and oligonucleotides comprising at least on nucleoside of formula (2):Formula (1) and Formula (2). 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：本发明提供式（1）的核苷和至少包含式（2）核苷的寡核苷酸：式（1）和式（2）。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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