Claims for Patent: 9,707,250

Summary for Patent: 9,707,250

Title:	Hydrophobically modified antisense oligonucleotides comprising a triple alkyl chain
Abstract:	The present invention concerns an oligonucleotide modified by substitution at the 3\' or the 5\' end by a moiety comprising at least three saturated or unsaturated, linear or branched hydrocarbon chains comprising from 2 to 30 carbon atoms, and the use therefore as a medicament, in particular for use for treating cancer.
Inventor(s):	Barthelemy; Philippe (Bordeaux, FR), Oumzil; Khalid (Bordeaux, FR), Gissot; Arnaud (Bordeaux, FR), Rocchi; Palma (Marseilles, FR), Acunzo; Julie (Marseilles, FR)
Assignee:	INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM) (Paris, FR) UNIVERSITE DE BORDEAUX (Paris, FR) Universite d\' Aix-Marseille (Marseilles, FR) Institut Jean Paoli & Irene Calmettes (Marseilles, FR) Centre Regional de Lutte Contre le Cancer (Marseilles, FR) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (C.N.R.S) (Paris, FR)
Application Number:	14/895,344
Patent Claims:	1. An oligonucleotide modified by substitution at the 3' or the 5' end by a moiety comprising at least three saturated or unsaturated, linear or branched hydrocarbon chains comprising from 2 to 30 carbon atoms. 2. The modified oligonucleotide according to claim 1, of the general formula (I): ##STR00008## wherein: Oligo represents an oligonucleotide sequence which may be oriented 3'-5' or 5'-3', simple and/or double stranded, Deoxyribonucleic Acid (DNA), Ribonucleic acide (RNA), and/or comprise modified nucleotides selected from the group consisting of locked nucleic acid (LNA), 2'-OMe analogs, 2'-phosphorothioate analogs, 2'-fluoro analogs, 2'-Cl analogs, 2'-Br analogs, 2'-CN analogs, 2'-CF.sub.3 analogs, 2'-OCF.sub.3 analogs, 2'-OCN analogs, 2'-O-alkyl analogs, 2'-S-alkyl analogs, 2'-N-alkyl analogs, 2'-O-alkenyl analogs, 2'-S-alkenyl analogs, 2'-N-alkenyl analogs, 2'-SOCH.sub.3 analogs, 2'-SO.sub.2,CH.sub.3 analogs, 2'-ONO.sub.2 analogs, 2'-NO.sub.2 analogs, 2'-N.sub.3 analogs, 2'-NH.sub.2, analogs and combinations thereof; X represents a divalent linker moiety selected from ether --O--, thio --S--, amino --NH--, and methylene --CH.sub.2--; R.sub.1 and R.sub.2 may be identical or different and represent: (i) a hydrogen atom, (ii) a halogen, (iii) a hydroxyl group, (iv) an alkyl group comprising from 1 to 12 carbon atoms; M.sub.1, M.sub.2 and M.sub.3 may be identical or different and represent: a saturated or unsaturated, linear or branched hydrocarbon chain comprising from 2 to 30 carbon atoms, which may be substituted by one or more halogen atoms, and/or be interrupted by one or more groups selected from ether --O--, thio --S--, amino --NH--, oxycarbonyl --O--C(O)--, thiocarbamate --O--C(S)--NH--, carbonate --O--C(O)--O--, carbamate --O--C(O)--NH--, phosphate --O--P(O)(O)--O-- and phosphonate --P--O(O)(O)-- groups; and/or be substituted at the terminal carbon atom by an aliphatic or aromatic; an acyl radical with 2 to 30 carbon atoms, or an acylglycerol, sphingosine or ceramide group. 3. The modified oligonucleotide according to claim 2, wherein the modified nucleotides are selected from the group consisting of LNA, 2'-OMe analogs, 2'-phosphorothioate analogs and 2'-fluoro analogs. 4. The modified oligonucleotide according to claim 1, wherein the oligonucleotide is selected from the group consisting of dT.sub.15, dA.sub.15 and an oligonucleotide consisting of the sequence SEQ ID NO: 6. 5. The modified oligonucleotide according to claim 2, wherein the divalent linker moiety is ether --O--. 6. The modified oligonucleotide according to claim 2, wherein R.sub.1 and R.sub.2 are hydrogen atoms. 7. The modified oligonucleotide according to claim 2, wherein M.sub.1, M.sub.2 and M.sub.3 represent a hydrocarbon chain comprising from 6 to 22 carbon atoms. 8. The modified oligonucleotide according to claim 1, wherein the oligonucleotide comprises a fragment of at least 10 consecutive nucleotides of a sequence selected from the group consisting of SEQ ID NO: 2 (5'-ACCAATGAGCGAGTCATCAA-3'), SEQ ID NO: 3 (5'-AACCCGUCCGCGAUCUCCCGG-3'), SEQ ID NO: 6 (5'-AACTTGTTTCCTGCAGGTGA-3'), SEQ ID NO: 7 (5'-TGGTTCATGACAATATCGAC-3'), SEQ ID NO: 8 (5'-TAATCATGATGGCGACTGAA-3'), SEQ ID NO: 16 (5'-ACCAGTGATTACTGTGCTTT-3'), SEQ ID NO: 17 (5'-CTTGTAGGCTTCTTTTGTGA-3'), SEQ ID NO: 18 (5'-ATGTAATCTTTGATGTACTT-3'), SEQ ID NO: 19 (5'-GTTTCCCTTTGATTGATTTC-3'), SEQ ID NO: 20 (5'-TTCTGGTCTCTGTTCTTCAA-3'), SEQ ID NO: 25 (5'-AGAAAATCATATATGGGGTC-3'), SEQ ID NO: 27 (5'-TTAACATTTCTCCATTTCTA-3'), SEQ ID NO: 29 (5'-GTCATAAAAGGTTTTACTCT-3') and SEQ ID NO: 31 (5'-GAAATTAGCAAGGATGTGCT-3'). 9. The modified oligonucleotide according to claim 1, wherein the oligonucleotide comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 6and SEQ ID NO: 7. 10. A process of manufacture of a modified oligonucleotide according to claim 1, comprising the steps of: (i) synthesizing the oligonucleotide; (ii) modifying the oligonucleotide by reaction with a suitable reactant comprising a moiety having at least three saturated or unsaturated, linear or branched hydrocarbon chains comprising from 2 to 30 carbon atoms; (iii) recovering the modified oligonucleotide. 11. A medicament comprising a modified antisense oligonucleotide as defined in claim 1. 12. A method for treating cancer, comprising the administration to a patient in need thereof of a pharmaceutically acceptable amount of a modified antisense oligonucleotide according to claim 1. 13. The method of claim 12, wherein the cancer is selected from the group consisting of prostate cancer, colon cancer, colorectal cancer, breast cancer, liver cancer, erythroleukemia, gliomas, melanomas, hepatoblastomas and lymphomas. 14. The method of claim 12, wherein the cancer is a prostate cancer. 15. An aqueous composition comprising modified oligonucleotides according to claim 1, wherein the modified oligonucleotides self-assembled into micelles and optionally comprising a hydrophobic active principle hosted in said micelles, said hydrophobic active principle being preferably selected from the group consisting of Paclitaxel, Docetaxel, Vincristine, Vinorelbine, and Abraxane; Tamoxifen, Gonadotrophin-releasing hormone (GnRH) agonists and antagonists, androgen receptor (AR) antagonist, and estrogen receptor (ER) antagonists; Cyclophosphamide, Chlorambucil and Melphalan; Methotrexate, Cytarabine, Fludarabine, 6-Mercaptopurine and 5-Fluorouracil; Doxorubicin, Irinotecan, Platinum derivatives, Cisplatin, Carboplatin, Oxaliplatin; Bicalutamide, Anastrozole, Examestane and Letrozole; Imatinib (Gleevec), Gefitinib and Erlotinib; Rituximab, Trastuzumab (Herceptin) and Gemtuzumab ozogamicin; Interferon-alpha; Tretinoin and Arsenic trioxide; Bevicizumab, Serafinib and Sunitinib. 16. The aqueous composition according to claim 13 as a vehicle. 17. The aqueous composition according to claim 16, as a vehicle of a sparingly hydrosoluble active principle, wherein the active principle is selected from the group consisting of Paclitaxel, Docetaxel, Vincristine, Vinorelbine, and Abraxane; Tamoxifen, Gonadotrophin-releasing hormone (GnRH) agonists and antagonists, androgen receptor (AR) antagonist, and estrogen receptor (ER) antagonists; Cyclophosphamide, Chlorambucil and Melphalan; Methotrexate, Cytarabine, Fludarabine, 6-Mercaptopurine and 5-Fluorouracil; Doxorubicin, Irinotecan, Platinum derivatives, Cisplatin, Carboplatin, Oxaliplatin; Bicalutamide, Anastrozole, Examestane and Letrozole; Imatinib (Gleevec), Gefitinib and Erlotinib; Rituximab, Trastuzumab (Herceptin) and Gemtuzumab ozogamicin; Interferon-alpha; Tretinoin and Arsenic trioxide; Bevicizumab, Serafinib and Sunitinib. 18. A medicament comprising the aqueous composition as defined in claim 15. 19. A method for treating cancer, comprising the administration to a patient in need thereof of a pharmaceutically acceptable amount of the aqueous composition according to claim 15.

Details for Patent 9,707,250

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2033-06-05
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2033-06-05
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2033-06-05
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2033-06-05
Wyeth Pharmaceuticals Llc	MYLOTARG	gemtuzumab ozogamicin	For Injection	761060	09/01/2017		2033-06-05