Claims for Patent: 9,701,962

Summary for Patent: 9,701,962

Title:	Hydrophobically modified antisense oligonucleotides comprising a ketal group
Abstract:	The present invention concerns an oligonucleotide modified by substitution at the 3\' or the 5\' end by a moiety comprising at least one ketal functional group, wherein the ketal carbon of said ketal functional group bears two saturated or unsaturated, linear or branched, hydrocarbon chains comprising from 1 to 22 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), Rocchi; Palma (Marseille, FR), Acunzo; Julie (Marseille, FR)
Assignee:	INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM) (Paris, FR) UNIVERSITE DE BORDEAUX (Bordeaux, FR) UNIVERSITE D \'AIX-MARSEILLE (Marseille, FR) INSTITUT JEAN PAOLI & IRENE CALMETTES (Marseille, FR) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) (Paris, FR)
Application Number:	14/895,277
Patent Claims:	1. A medicament comprising as an active agent, an oligonucleotide modified by substitution at the 3' or the 5' end by a moiety comprising at least one ketal functional group, wherein a ketal carbon of the at least one ketal functional group bears two saturated or unsaturated, linear or branched, hydrocarbon chains comprising from 1 to 22 carbon atoms, wherein said oligonucleotide is an antisense oligonucleotide or an interfering RNA which targets an mRNA of interest and is capable of reducing the amount of protein encoded by said mRNA. 2. The medicament according to claim 1, wherein the modified oligonucleotide is of the general formula (I): ##STR00009## wherein: Oligo represents an oligonucleotide sequence which may be oriented 3'-5' or 5'-3', simple and/or double stranded, deoxyribonucleic acid (DNA), ribonucleic acid (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.2CH.sub.3 analogs, 2'-ONO.sub.2 analogs, 2'-NO, analogs, 2'-N.sub.3 analogs, 2'-NH, 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 atom, (iii) a hydroxyl group, (iv) an alkyl group comprising from 1 to 12 carbon atoms; L.sub.1 and L.sub.2 may be identical or different and represent a saturated or unsaturated, linear or branched hydrocarbon chain comprising from 1 to 22 carbon atoms, B is an optionally substituted nucleobase, selected from the group consisting of purine nucleobases, pyrimidine nucleobases, and non-natural monocyclic or bicyclic heterocyclic nucleobases wherein each cycle comprises from 4 to 7 atoms. 3. The medicament 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 medicament 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 medicament according to claim 2, wherein the divalent linker moiety is ether --O--. 6. The medicament according to claim 2, wherein R.sub.1 and R.sub.2 are hydrogen atoms. 7. The medicament according to claim 2, wherein L.sub.1 and L.sub.2 represent a hydrocarbon chain comprising from 6 to 22 carbon atoms. 8. The medicament according to claim 2, wherein B is a non substituted nucleobase selected from the group consisting of uracil, thymine, adenine, cytosine, 6-methoxypurine and hypoxanthine. 9. The medicament according to claim 2, wherein the oligonucleotide comprises a fragment of at least 10 consecutive nucleotides of a sequence selected from the group consisting of TABLE-US-00003 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'). 10. The medicament 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: 6 and SEQ ID NO: 7. 11. A method for treating cancer, comprising the administration to a patient in need thereof of a pharmaceutically acceptable amount of a medicament according to claim 1. 12. The method of claim 11 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. 13. The method of claim 11 wherein the cancer is a prostate cancer. 14. An aqueous composition comprising oligonucleotides modified by substitution at the 3' or the 5' end by a moiety comprising at least one ketal functional group, wherein a ketal carbon of the at least one ketal functional group bears two saturated or unsaturated, linear or branched, hydrocarbon chains comprising from 1 to 22 carbon atoms, wherein the modified oligonucleotides self-assembled into micelles, and optionally comprising a hydrophobic active principle hosted in said micelles. 15. The aqueous composition according to claim 14 as a vehicle. 16. The aqueous composition of claim 15, as a vehicle of a sparingly hydrosoluble active principle. 17. A medicament comprising the aqueous composition as defined in claim 14. 18. A method for treating cancer, comprising the administration to a patient in need thereof of a pharmaceutically acceptable amount of the aqueous compositions according to claim 14. 19. The aqueous composition according to claim 14, wherein said hydrophobic 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. 20. The aqueous composition according to claim 16, wherein said sparingly hydrosoluble 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.

Details for Patent 9,701,962

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