公开(公告)号：WO2015188197A2

公开(公告)日：2015-12-10

申请号：PCT/US2015034749

申请日：2015-06-08

Applicant: SOLSTICE BIOLOG LTD ,  BRADSHAW CURT W ,  SAKAMURI SUKUMAR ,  ELTEPU LAXMAN ,  LAM SON ,  LIU DINGGUO ,  MEADE BRYAN ,  IACONO GIUSEPPE DELLO ,  STOCK JOSEPH ,  LIU BIN

Inventor： BRADSHAW CURT W ,  SAKAMURI SUKUMAR ,  ELTEPU LAXMAN ,  LAM SON ,  LIU DINGGUO ,  MEADE BRYAN ,  IACONO GIUSEPPE DELLO ,  STOCK JOSEPH ,  LIU BIN

IPC: C12N15/85 ,  C07H21/04

CPC classification number: C12N15/113 ,  C07H19/10 ,  C07H19/20 ,  C07H21/02 ,  C07H21/04 ,  C12N15/85 ,  C12N2310/14 ,  C12N2310/31 ,  C12N2310/32 ,  C12N2310/346 ,  C12N2310/3513 ,  C12N2310/3515 ,  C12N2330/30

Abstract: The invention features a hybridized polynucleotide construct containing a passenger strand, a guide strand loadable into a RISC complex, and (i) a 3'-terminal or an internucleotide non-bioreversible group in the guide strand; or (ii) a 5'-terminal, a 3'-terminal, or an internucleotide non-bioreversible group in the passenger strand, and a 5'-terminal, a 3'-terminal, or an internucleotide disulfide bioreversible group in the guide strand or the passenger strand. The invention also features methods of delivering a polynucleotide to a cell using the hybridized polynucleotide construct. The invention further features methods of reducing the expression of a polypeptide in a cell using the hybridized polynucleotide construct.

Abstract translation: 本发明的特征在于含有载体链，可加载到RISC复合物中的引导链和（i）引导链中的3'端或核苷酸非生物可逆组的杂交多核苷酸构建体; 或（ii）乘客链中的5'端，3'端或核苷酸非生物逆转基团，以及引物中的5'末端，3'末端或核苷酸间二硫键生物逆转组 绞线或乘客绳。 本发明还涉及使用杂交的多核苷酸构建体将多核苷酸递送至细胞的方法。 本发明还涉及使用杂交的多核苷酸构建体减少细胞中多肽表达的方法。

公开(公告)号：WO2015188197A3

公开(公告)日：2015-12-10

申请号：PCT/US2015/034749

申请日：2015-06-08

Applicant: SOLSTICE BIOLOGICS, LTD. ,  BRADSHAW, Curt, W. ,  SAKAMURI, Sukumar ,  ELTEPU, Laxman ,  LAM, Son ,  LIU, Dingguo ,  MEADE, Bryan ,  IACONO, Giuseppe, Dello ,  STOCK, Joseph ,  LIU, Bin

Inventor： BRADSHAW, Curt, W. ,  SAKAMURI, Sukumar ,  ELTEPU, Laxman ,  LAM, Son ,  LIU, Dingguo ,  MEADE, Bryan ,  IACONO, Giuseppe, Dello ,  STOCK, Joseph ,  LIU, Bin

IPC: C12N15/11 ,  C07H21/00 ,  C12P19/34

Abstract: The invention features a hybridized polynucleotide construct containing a passenger strand, a guide strand loadable into a RISC complex, and (i) a 3'-terminal or an internucleotide non-bioreversible group in the guide strand; or (ii) a 5'-terminal, a 3'-terminal, or an internucleotide non-bioreversible group in the passenger strand, and a 5'-terminal, a 3'-terminal, or an internucleotide disulfide bioreversible group in the guide strand or the passenger strand. The invention also features methods of delivering a polynucleotide to a cell using the hybridized polynucleotide construct. The invention further features methods of reducing the expression of a polypeptide in a cell using the hybridized polynucleotide construct.

公开(公告)号：WO2018035380A1

公开(公告)日：2018-02-22

申请号：PCT/US2017/047447

申请日：2017-08-17

Applicant: SOLSTICE BIOLOGICS, LTD. ,  SAKAMURI, Sukumar ,  BRADSHAW, Curt, W. ,  ELTEPU, Laxman ,  MEADE, Bryan, R. ,  LAM, Son

Inventor： SAKAMURI, Sukumar ,  BRADSHAW, Curt, W. ,  ELTEPU, Laxman ,  MEADE, Bryan, R. ,  LAM, Son

IPC: C07F9/11 ,  A61K31/7088 ,  C07F9/17 ,  C07H21/00

Abstract: Disclosed are polynucleotide constructs having a strand linked to a moiety carrying one or more auxiliary moieties. Also disclosed are polynucleotide constructs interrupted with a sugar analogue, and polynucleotide constructs with stereochemical^ enriched phosphorothioates. The polynucleotide constructs may be provided as hybridized polynucleotide constructs. Also featured are methods of delivery a polynucleotide construct to a cell and methods of reducing the expression of a protein in a cell by contacting the cell with the disclosed polynucleotide construct or hybridized polynucleotide construct.

Abstract translation: 公开了具有与携带一个或多个辅助部分的部分连接的链的多核苷酸构建体。 还公开了用糖类似物中断的多核苷酸构建体，以及具有立体化学丰富的硫代磷酸酯的多核苷酸构建体。 多核苷酸构建体可以作为杂交的多核苷酸构建体提供。 还具有将多核苷酸构建体递送至细胞的方法以及通过使细胞与公开的多核苷酸构建体或杂交的多核苷酸构建体接触来减少细胞中蛋白质表达的方法。

公开(公告)号：WO2015069932A1

公开(公告)日：2015-05-14

申请号：PCT/US2014/064401

申请日：2014-11-06

Applicant: SOLSTICE BIOLOGICS, LTD. ,  BRADSHAW, Curt, W. ,  ELTEPU, Laxman ,  KABAKIBI, Ayman ,  LAM, Son ,  LIU, Bin ,  LIU, Dingguo ,  MEADE, Bryan, R. ,  SAKAMURI, Sukumar

Inventor： BRADSHAW, Curt, W. ,  ELTEPU, Laxman ,  KABAKIBI, Ayman ,  LAM, Son ,  LIU, Bin ,  LIU, Dingguo ,  MEADE, Bryan, R. ,  SAKAMURI, Sukumar

IPC: C07F9/02 ,  C12P19/34

CPC classification number: C12N15/1137 ,  C07F9/65586 ,  C07F9/65616 ,  C07H21/00 ,  C12N2310/14 ,  C12N2310/311 ,  C12N2310/321 ,  C12N2310/351

Abstract: The invention features polynucleotide constructs containing one or more components (i) containing a disulfide linkage, where each of the one or more components is attached to an internudeotide bridging group or a terminal group of the polynucleotide construct, and each of the one or more components (i) contains one or more bulky groups proximal to the disulfide group. The invention also features polynucleotide constructs containing one or more components (i) containing a disulfide linkage, where each of the one or more components (i) is attached to an internudeotide bridging group or a terminal group of the polynucleotide construct, and each of the one or more components (i) contains at least 4 atoms in a chain between the disulfide linkage and the phosphorus atom of the internudeotide bridging group or the terminal group; and where the chain does not contain a phosphate, an amide, an ester, or an alkenylene. The invention also features methods of delivering a polynucleotide to a cell using the polynucleotide constructs of the invention.

Abstract translation: 本发明的特征在于含有一种或多种组分（i）的多核苷酸构建体，所述组分（i）含有二硫键，其中所述一种或多种组分中的每一种均连接到所述多核苷酸构建体的杂种核苷酸桥连基团或末端基团，并且所述一种或多种组分 （i）含有一个或多个邻近二硫基的体积大的基团。 本发明还具有含有一种或多种含有二硫键的组分（i）的多核苷酸构建体，其中所述一种或多种组分（i）中的每一个与多核苷酸构建体的杂种核苷酸桥连基团或末端基团连接， 一个或多个组分（i）在二核苷酸桥联基团或末端基团的二硫键和磷原子之间的链中含有至少4个原子; 并且其中链不含有磷酸酯，酰胺，酯或亚烯基。 本发明还涉及使用本发明的多核苷酸构建体将多核苷酸递送至细胞的方法。

公开(公告)号：WO2019006455A1

公开(公告)日：2019-01-03

申请号：PCT/US2018/040592

申请日：2018-07-02

Applicant: SOLSTICE BIOLOGICS, LTD. ,  SAKAMURI, Sukumar ,  BRADSHAW, Curt, W. ,  LIU, Dingguo ,  ELTEPU, Laxman

Inventor： SAKAMURI, Sukumar ,  BRADSHAW, Curt, W. ,  LIU, Dingguo ,  ELTEPU, Laxman

IPC: C07H19/10 ,  C07H19/20

Abstract: Disclosed are P-stereogenic groups that may be used in the synthesis of compounds including stereochemically enriched P-stereogenic phosphorothioates. P-stereogenic groups may be provided in nucleoside phosphoramidites including a sugar bonded to a nucleobase and to a stereochemically enriched phosphoramidite as well as methods of their use and methods of making them.

公开(公告)号：WO2011094580A3

公开(公告)日：2012-06-28

申请号：PCT/US2011022977

申请日：2011-01-28

Applicant: ALNYLAM PHARMACEUTICALS INC ,  MANOHARAN MUTHIAH ,  ELTEPU LAXMAN ,  RAJEEV KALLANTHOTTAHIL G ,  JAYARAMAN MUTHUSAMY

Inventor： MANOHARAN MUTHIAH ,  ELTEPU LAXMAN ,  RAJEEV KALLANTHOTTAHIL G ,  JAYARAMAN MUTHUSAMY

IPC: B01J31/18 ,  B01J31/16 ,  B01J31/22 ,  C07D213/22 ,  C07D249/04 ,  C12Q1/68

CPC classification number: B01J31/1658 ,  B01J31/1683 ,  B01J31/1805 ,  B01J31/1815 ,  B01J2231/327 ,  B01J2531/0244 ,  B01J2531/0258 ,  B01J2531/16 ,  C07D249/04 ,  C07H21/00

Abstract: In one embodiment, the invention features a process for preparing ligand conjugated oligonucleotides comprising a step of contacting a nucleoside or oligonucleotide containing an alkyne moiety with ligand containing an azide moiety in the presence of a solid supported copper catalyst of formula A, B, C or D.

Abstract translation: 在一个实施方案中，本发明的特征在于制备配体缀合的寡核苷酸的方法，其包括在式A，B，C的固体负载的铜催化剂存在下使含有炔部分的核苷或寡核苷酸与含有叠氮化物部分的配体接触的步骤，或 D.

公开(公告)号：WO2011094580A2

公开(公告)日：2011-08-04

申请号：PCT/US2011/022977

申请日：2011-01-28

Applicant: ALNYLAM PHARMACEUTICALS, INC. ,  MANOHARAN, Muthiah ,  ELTEPU, Laxman ,  RAJEEV, Kallanthottahil, G. ,  JAYARAMAN, Muthusamy

Inventor： MANOHARAN, Muthiah ,  ELTEPU, Laxman ,  RAJEEV, Kallanthottahil, G. ,  JAYARAMAN, Muthusamy

IPC: B01J31/18

CPC classification number: B01J31/1658 ,  B01J31/1683 ,  B01J31/1805 ,  B01J31/1815 ,  B01J2231/327 ,  B01J2531/0244 ,  B01J2531/0258 ,  B01J2531/16 ,  C07D249/04 ,  C07H21/00

Abstract: In one embodiment, the invention features a process for preparing ligand conjugated oligonucleotides comprising a step of contacting a nucleoside or oligonucleotide containing an alkyne moiety with ligand containing an azide moiety in the presence of a solid supported copper catalyst of formula A, B, C or D.

Abstract translation: 在一个实施方案中，本发明的特征在于制备配体缀合的寡核苷酸的方法，其包括在含有式A，B，C的固体负载型铜催化剂存在下，使含有炔部分的核苷或寡核苷酸与含有叠氮基部分的配体接触的步骤， D.

公开(公告)号：WO2017100461A1

公开(公告)日：2017-06-15

申请号：PCT/US2016/065639

申请日：2016-12-08

Applicant: SOLSTICE BIOLOGICS, LTD. ,  BRADSHAW, Curt, W. ,  SAKAMURI, Sukumar ,  MEADE, Bryan, R. ,  ELTEPU, Laxman ,  IACONO, Giuseppe, Dello ,  LAM, Son ,  STOCK, Joseph ,  LIU, Dingguo ,  LIU, Bin

Inventor： BRADSHAW, Curt, W. ,  SAKAMURI, Sukumar ,  MEADE, Bryan, R. ,  ELTEPU, Laxman ,  IACONO, Giuseppe, Dello ,  LAM, Son ,  STOCK, Joseph ,  LIU, Dingguo ,  LIU, Bin

IPC: A61K31/7088 ,  C07F9/02 ,  C12N15/85 ,  C12P19/34

CPC classification number: A61K31/7088 ,  C07F9/65515 ,  C07F9/65586 ,  C07F9/65616 ,  C12N15/85

Abstract: The invention features a hybridized polynucleotide construct including a passenger strand, a guide strand loadable into a RISC complex, and one or more auxiliary moieties. At least one of the auxiliary moieties is non-bioreversibly linked to an internucleoside phosphate or phosphorothioate in the passenger strand. The invention further features methods of delivery a polynucleotide construct to a cell and methods of reducing the expression of a protein in a cell. The methods typically involve contacting the cell with the hybridized polynucleotide construct.

Abstract translation: 本发明的特征在于包含过客链，可加载到RISC复合物中的引导链和一个或多个辅助部分的杂交多核苷酸构建体。 至少一个辅助部分与过客链中的磷酸核苷间磷酸酯或硫代磷酸酯不可逆地连接。 本发明进一步描述了将多核苷酸构建体递送至细胞的方法和减少细胞中蛋白质表达的方法。 该方法通常涉及使细胞与杂交的多核苷酸构建体接触。

公开(公告)号：WO2010054406A1

公开(公告)日：2010-05-14

申请号：PCT/US2009/063933

申请日：2009-11-10

Applicant: ALNYLAM PHARMACEUTICALS, INC. ,  MANOHARAN, Muthiah ,  RAJEEV, Kallanthottathil, G. ,  BUTLER, David ,  NARAYANANNAIR, Jayaprakash, K. ,  JAYARAMAN, Muthusamy ,  ELTEPU, Laxman

Inventor： MANOHARAN, Muthiah ,  RAJEEV, Kallanthottathil, G. ,  BUTLER, David ,  NARAYANANNAIR, Jayaprakash, K. ,  JAYARAMAN, Muthusamy ,  ELTEPU, Laxman

IPC: A01N43/04

CPC classification number: 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

Abstract: 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 structures: (Formula (I) or (XXXV))

Abstract translation: 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的脂质：（式（I）或（XXXV））

公开(公告)号：WO2010054405A1

公开(公告)日：2010-05-14

申请号：PCT/US2009/063931

申请日：2009-11-10

Applicant: ALNYLAM PHARMACEUTICALS, INC. ,  MANOHARAN, Muthiah ,  RAJEEV, Kallanthottathil, G. ,  JAYARAMAN, Muthusamy ,  BUTLER, David ,  NARAYANANNAIR, Jayaprakash, K. ,  MAIER, Martin ,  ELTEPU, Laxman

Inventor： MANOHARAN, Muthiah ,  RAJEEV, Kallanthottathil, G. ,  JAYARAMAN, Muthusamy ,  BUTLER, David ,  NARAYANANNAIR, Jayaprakash, K. ,  MAIER, Martin ,  ELTEPU, Laxman

IPC: A61K47/00 ,  A61K31/01

CPC classification number: 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

Abstract: 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 R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 30 alkyl, optionally substituted C 10 -C 30 alkenyl, optionally substituted C 10 -C 30 alkynyl, optionally substituted C 10 -C 30 acyl, or -linker-ligand; R 3 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ω-aminoalkyls, ω -(substituted)aminoalkyls, ω-phosphoalkyls, ω -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(O)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, ω-aminoalkyl, ω-(substituted)aminoalky, ω-phosphoalkyl or ω-thiophosphoalkyl.

Abstract translation: 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链烯基，任选取代的C 2 -C 10炔基，烷基化合物，烷基磷酸酯，烷基硫代磷酸酯，烷基二硫代磷酸酯，烷基膦酸酯，烷基胺，羟基烷基， - （取代的）氨基烷基，α-磷酸烷基， - 硫代磷酸烷基，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，杂环或连接体 - 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。