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Ep 1013661 B2 (19) TZZ_Z_¥_ T (11) EP 1 013 661 B2 (12) NEW EUROPEAN PATENT SPECIFICATION After opposition procedure (45) Date of publication and mention (51) Int Cl.: of the opposition decision: C07H 19/06 (2006.01) C07H 19/16 (2006.01) 24.10.2018 Bulletin 2018/43 C07H 21/00 (2006.01) C07D 493/08 (2006.01) A61K 31/7064 (2006.01) (45) Mention of the grant of the patent: 18.01.2012 Bulletin 2012/03 (86) International application number: PCT/JP1998/000945 (21) Application number: 98905804.5 (87) International publication number: (22) Date of filing: 09.03.1998 WO 1998/039352 (11.09.1998 Gazette 1998/36) (54) 2’-O,4’-C-methylene bicyclonucleosides 2’-O,4’-C-Methylen Bicyclonukleoside 2’-O,4’-C-methylène bicyclonucleosides (84) Designated Contracting States: • S K SINGH ET AL: "LNA (Locked Nucleic Acids): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC Synthesis and High-Affinity Nucleic Acid NL PT SE Recognition" CHEMICAL COMMUNICATIONS,GB,ROYAL SOCIETY OF (30) Priority: 07.03.1997 JP 5340997 CHEMISTRY, no. 4, 21 February 1998 (1998-02-21), pages 455-456, XP002094303 ISSN: (43) Date of publication of application: 1359-7345 28.06.2000 Bulletin 2000/26 • OBIKA S. et al., "Synthesis of 2’-omicron,4’-C-Methyleneuridine an D-Cytidine. (60) Divisional application: NovelBicyclic Nucleosides Having a Fixed C3,-en 10011863.7 / 2 361 921 do SugarPuckering", TETRAHEDRON LETTERS, 10172971.3 / 2 295 441 Vol. 38, No. 50, (15 December 1997), p. 8735-8738, XP002916464 (73) Proprietors: • ALTMANN K.H. et al., "6’-Carbon-Substituted • Exiqon A/S CarbocyclicAnalogs of 2’-Deoxyribonucleosides 2950 Vedbaek (DK) Synthesis and Effect on DNA/RNA Duplex • Roche Innovation Center Copenhagen A/S Stability",TETRAHEDRON, Vol. 52, No. 39, (1996), 2970 Hørsholm (DK) p. 12699-12722, XP002916465 • OBIKA S. et al., "Properties of Novel (72) Inventors: Oligonucleotide Analogues Containing an • IMANISHI, Takeshi Acyclic Nucleoside and a Carbamate Linkage", Nara-shi BIOORGANIC & MEDICINAL CHEMISTRY Nara 631-0045 (JP) LETTERS, Vol. 6, No. 12, (1996), p. 1357-1360, • OBIKA, Satoshi XP002916466 Takatsuki-shi • KENNETH D. NIELSEN: ’Synthesis and Osaka 569-1022 (JP) Incorporation of 4’-C(hydroxymethyl) Uridine in Oligonucleotides"’, January 1995, CHEMICAL (74) Representative: Weickmann & Weickmann INSTITUTE ODENSE UNIVERSITY PartmbB • D1 translated into English Postfach 860 820 • Corrected Partial English Translation (pp. 67-71) 81635 München (DE) of the thesis by Kenneth Due Nielsen • Declaration of Mr. Christensen , Internal Process (56) References cited: Chief in the library department of Odense WO-A2-99/14226 JP-A- H0 953 409 University, filed during the Re-examination of US US-B1- 6 268 490 6,770,748 • Dr Seth Punit’s declaration dated 25th March 2009 EP 1 013 661 B2 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 013 661 B2 • Dr Emmanuel Theodorakis’ declaratiom dated • Curriculum Vitae of Dr Herdewijn 26th March 2009 • FREIER S.M. ET AL: ’The ups and downs of • Dr Seth Punit’s Curriculum Vitae nucleic acid duplex stability: structure-stability • Dr Emmanuel Theodorakis’ Curriculum Vitae studies on chemically-modified DNA:RNA • BEAUCAGE S. ET AL: ’Advances in the synthesis duplexes’ NUCLEIC ACIDS RESEARCH vol. 25, of oligonucleotides by the phosphoramitide no. 22, 1997, pages 4429 - 4443 approach’ TETRAHEDRON vol. 48, no. 12, 1992, • Declaration by Dr Ravn dated 17 December 2009 pages 2223 - 2311 • Reexamination Certificate for US Patent • Translation of JP 5340997 6,268,490 • Takeshi Imanishi, presentation given during the • Dr Seth Punit’s 2nd declaration dated 19th 16th International Congress of Heterocyclic January 2010 Chemistry during August 1997 • Dr Emmanuel Theodorakis’ 2nd declaration • GRIFFEY R.H. ET AL: ’New Twists on Nucleic dated 20th January 2010 Acids’,vol. CHP. 14, 1994, AMERICAN CHEMICAL • HENDRICKSON J.B. ET AL: ’Organic Chemistry’, SOCIETY pages 212 - 224 vol. 3TH ED., 1970, MCGRAW-HILL BOOK • HERDEWIJN P.: ’Targeting RNA with COMPANY pages 379,384, - 414,418, conformationally restricted oligonucleotides’ • KÖLL P. ET AL: ’Mono-und Dioxetane von LIEBIGS ANN 1996, pages 1337 - 1348 2,5-Anhydroalditolen, Synthesen und • ALTMANNK-H. ET AL: ’4’,6’-Methano carbocyclic Reaktionen’ LIEBIGS ANN. 1987, pages 205 - 214 thymidine: A conformationally constrained • Synthesis, 1989, 191-194 building block for oligonucleotides’ • CODINGTON J.F. ET AL: ’Nucleosides. XXIV. TETRAHEDRON LETTERS vol. 35, no. 15, 1994, 1-(2’,5’- and 3’,5’- pages 2331 - 2334 Epoxy-beta-D-Iyxofuranosyl)uracils’ J. ORG. • Talk given by Dr Wengel at the national seminar CHEM. vol. 30, 1965, pages 476 - 481 on perspectives in interfacial areas of chemistry • KIKUGAWA K. ET AL: ’Studies on the and biolog 20-22nd January 1998 Vilsmeier-Haack reaction. IV. Convenient • Danish Patent Application No. 1054/97 synthesis of • Lab book notes by De Seth Punit whilst 2,2’-Anhydro-I-beta-D-arabinofuranosycytosi ne conducting the experiments disclosed D4 (2,2’-cyclocytidine) and its derivatives’ J. ORG. • Lab book notes by Emmanuel Theodorakis whilst CHEM. vol. 37, no. 2, 1972, pages 284 - 287 conducting the experiments disclosed D5 • DOERR I.L. ET AL: ’Nucleosides. XXIII. 2’,3’- and • Declaration by Kenneth Due Nielsen dated 11 3’,5’-epoxides of pentofuranosyluracils’ September 1997 J.ORG.CHEM. vol. 30, February 1965, pages 467 • Declaration by Dr Wengel dated 20 December - 475 2009 • List of PubMed hits for LC-MS from before 1995 • Curriculum Vitae of Dr Wengel • NIESSEN W.NM.A. ET AL: ’Liquid • OBIKA S. ET SL: ’Synthesis and conformation of chromatography-mass spectrometry general 3’-O,4’-C-methyleneribonucleosides, novel principles and instrumentation’ JOURNAL OF bicyclic nucleoside analougues for 2’,5’-linked CHROMATOGRAPHY A vol. 703, 1995, pages 37 oligonucleotide modification’ CHEM. COMM. - 57 1997, pages 1643 - 1644 • PECSOK R.L. ET AL: ’Modern Methods of • KOSHKIN A.A. ET AL: ’LNA (Locked Nucleic Chemical Analysis’, vol. CHP. 6, JOHN WILEY & Acids): Synthesis of the adenine, cytosine, SONS, INC, NEW YORK pages 89-91 - 117-118 guanine, 5-methylcytosine, thymine and uracil • Declaration by Mr. Nielsen dated 22th September bicyclonucleoside monomers, oligomerisation, 2010 and unprecedented nucleic acid recognition’ TETRAHEDRON vol. 54, 1998, pages 3607 - 3630 • Declaration by Dr Ørum dated 20 December 2009 • Declaration by Dr Herdewijn dated 18 December 2009 2 EP 1 013 661 B2 Description [0001] This invention relates to novel nucleoside analogues and their use in, novel nucleotide analogues and more particularly, to nucleotide analogues suitable as antisense molecules. 5 BACKGROUND ART [0002] In 1978, it was reported for the first time that an antisense molecule inhibited influenza virus infection. Since then, reports have been issued that antisense molecules inhibited the expression of oncogenes and AIDS infection. In 10 recent years, antisense oligonucleotides have become one of the most promising pharmaceuticals, because they spe- cifically control the expression of undesirable genes. [0003] The antisense method is based on the idea of controlling a unidirectional flow called the central dogma, i.e., DNA → RNA → protein, by use of an antisense oligonucleotide. [0004] When a naturally occurring oligonucleotide was applied to this method as an antisense molecule, however, it 15 was decomposed with various nucleases in vivo, or its permeation through the cell membrane was not high. To solve these problems, numerous nucleic acid derivatives and analogues have been synthesized, and their studies have been conducted. Examples of the synthesized products include a phosphorothioate having a sulfur atom substituting for an oxygen atom on the phosphorus atom, and a methylphosphonate having a substituting methyl group. Recently, products have been synthesized in which the phosphorus atom has also been substituted by a carbon atom, or the structure of 20 the sugar portion has been changed, or the nucleic acid base has been modified. Any resulting derivatives or-analogues, however, have not been fully satisfactory in terms of in vivo stability, ease of synthesis, and sequence specificity (the property of selectively controlling the expression of a particular gene alone). [0005] Obika et al. ("Properties of Novel Oligonucleotide Analogues Containing an Acyclic Nucleoside and a Carbamate Linkage", Bioorganic & Medicinal Chemistry Letters, 6(12) (1996) p.1357-1360) describes heterodimers containing an 25 acyclic nucleoside and a carbamate linkage at the 3’ position incorporated into oligonucleotides. The melting temperatures of DNA-DNA and DNA-RNA duplexes as well as the nuclease resistance of the modified oligonucleotides were studied. [0006] Under these circumstances, there has been a demand for the creation of an antisense molecule which is minimally decomposed with a nuclease in vivo, binds to target messenger RNA with high affinity, has high specificity, and can thus efficiently control the expression of a particular gene. 30 DISCLOSURE OF THE INVENTION [0007] The inventors of the present invention designed a nucleic acid analogue with immobilized conformation of the sugar portion in a nucleic acid, which would be useful in the antisense method. They synthesized a nucleoside analogue 35 which will be a unit structure therefor, and confirmed that an oligonucleotide analogue prepared using it was very useful as an antisense molecule. BRIEF DESCRIPTION OF THE DRAWINGS 40 [0008] Fig. 1 is a chart showing the time course of the ultraviolet absorption (260 nm) of a naturally occurring oligonucleotide decomposed
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