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Ep 2790736 B1 (19) TZZ Z¥_T (11) EP 2 790 736 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 15/11 (2006.01) A61K 31/7084 (2006.01) 31.01.2018 Bulletin 2018/05 A61K 48/00 (2006.01) (21) Application number: 12858522.1 (86) International application number: PCT/US2012/069294 (22) Date of filing: 12.12.2012 (87) International publication number: WO 2013/090457 (20.06.2013 Gazette 2013/25) (54) IN VIVO DELIVERY OF OLIGONUCLEOTIDES IN-VIVO-VERABREICHUNG VON OLIGONUCLEOTIDEN ADMINISTRATION IN VIVO D’OLIGONUCLÉOTIDES (84) Designated Contracting States: • M. B. BAKER ET AL: "In vitro quantification of AL AT BE BG CH CY CZ DE DK EE ES FI FR GB specific microRNA using molecular beacons", GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO NUCLEIC ACIDS RESEARCH, vol. 40, no. 2, 21 PL PT RO RS SE SI SK SM TR November 2011 (2011-11-21), pages e13-e13, XP055207619, ISSN: 0305-1048, DOI: (30) Priority: 12.12.2011 US 201161630446 P 10.1093/nar/gkr1016 • Veena Vijayanathan ET AL: "Direct measurement (43) Date of publication of application: of the association constant of HER2/neu 22.10.2014 Bulletin 2014/43 antisense oligonucleotide to its target RNA sequence using a molecular beacon", Antisense (73) Proprietor: ONCOIMMUNIN, INC. & nucleic acid drug development, 1 August 2002 Gaithersburg, (2002-08-01), pages 225-233, XP055207586, Maryland 20877 (US) United States DOI: 10.1089/108729002320351548 Retrieved from the Internet: (72) Inventors: URL:http://www.ncbi.nlm.nih.gov/pubmed/122 • PACKARD, Beverly 38811 [retrieved on 2015-08-12] Potomac • LERGA ET AL: "Rapid determination of total Maryland 20877 (US) hardness in water using fluorescent molecular • KOMORIYA, Akira aptamer beacon", ANALYTICA CHIMICA ACTA, Potomac ELSEVIER, AMSTERDAM, NL, vol. 610, no. 1, 18 Maryland 20877 (US) January 2008 (2008-01-18), pages 105-111, XP022473228, ISSN: 0003-2670, DOI: (74) Representative: Lee, Nicholas John et al 10.1016/J.ACA.2008.01.031 Kilburn & Strode LLP • BEVERLY Z PACKARD ET AL: "A Method in Lacon London Enzymology for Measuring Hydrolytic Activities 84 Theobalds Road in Live Cell Environments", 1 January 2008 London WC1X 8NL (GB) (2008-01-01), FLUORESCENCE SPECTROSCOPY;[METHODS IN ENZYMOLOGY; (56) References cited: ISSN 0076-6879; VOL. 450], ELSEVIER, ACAD. WO-A2-03/106631 WO-A2-2009/045536 PRESS, NL, PAGE(S) 1 - 19, XP008174215, ISBN: US-A1- 2003 224 377 US-A1- 2005 142 581 978-0-12-374586-6 [retrieved on 2009-01-17] * the US-A1- 2009 325 168 whole document * Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 790 736 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 790 736 B1 • EMMANUEL CHANG ET AL: "Novel siRNA-based • PACKARD ET AL.: ’A Method in Enzymology for molecular beacons for dual imaging and Measuring Hydrolytic Activities in Live Cell therapy", BIOTECHNOLOGY JOURNAL, vol. 2, Environments’ METHODS IN ENZYMOLOGY vol. no. 4, 1 April 2007 (2007-04-01), pages 422-425, 450, 2008, pages 1 - 19, XP008174215 XP055207373, ISSN: 1860-6768, DOI: 10.1002/biot.200600257 • HARBORTH J ET AL: "Sequence, chemical, and structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing", ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT, MARY ANN LIEBERT, INC., NEW YORK, US, vol. 13, no. 2, 1 April 2003 (2003-04-01), pages 83-105, XP002284355, ISSN: 1087-2906, DOI: 10.1089/108729003321629638 2 1 EP 2 790 736 B1 2 Description an infectious disease, cancer, a proliferative disease or disorder, a neurological disease or disorder, an inflam- BACKGROUND OF THE INVENTION matory disease or disorder, a disease or disorder of the immune system, a disease or disorder of the cardiovas- Field of the Invention 5 cular system, a metabolic disease or disorder, a disease or disorder of the skeletal system, and a disease or dis- [0001] This invention pertains to the field of oligonu- order of the skin or eyes. cleotide therapeutics. In particular, this invention pro- [0005] Preferred features are set out in the dependent vides improved in vivo delivery for oligonucleotides in- claims herein. The invention is based in part on the im- cluding modified oligonucleotides and oligonucleotide 10 portant discovery of the inventors that the linkage of one mimics. or a plurality of HES to single, double and multiple strand [0002] Over the past several decades the use of oligo- oligonucleotide sequences results in an increased deliv- nucleotides as therapeutic agents has been the focus of ery of the HES-oligonucleotide sequences across phys- much interest. Both blockage of the transcription of spe- iologic boundaries found in in vivo systems. cific genes and addition of oligonucleotide sequences 15 [0006] One of the toughest obstacles limiting the use coding for particular proteins have been attempted as of RNAi and antisense oligonucleotides, (PNAs) and therapies for a plethora of pathologic conditions including PMOs in gene expression altering therapy has been the cancer, infectious diseases, and neurodegenerative con- low uptake of these compounds by eukaryotic cells, ditions. Moreover, multiple chemical approaches have which with currently available delivery methodologies is been developed to address the synthetic, immunogenic, 20 compounded by the sequestration and/or degradation of and biophysical properties of potential oligonucleotide- the compounds that actually do enter the cell; the latter based drugs and drug formulations. However, despite is predominantly via endocytosis. As will be immediately some success in solution and ex vivo systems, delivery apparent to a person of skill in the art, the surprisingly of oligonucleotides across biologic barriers such as cell high efficiency with which the non-toxic HES-oligonucle- membranes and extracellular matrices present in live or- 25 otide complexes useful in the invention are delivered into ganisms as well as structural components of infectious cells through sequence independent passive diffusion agents such as cell walls has been suboptimal. Thus, and the discovery by the inventors that these oligonucle- accessibility to molecular targets inside cells and tissues otides do not co-localize with lysozomes within cells, in- in vivo has been limiting development of the oligonucle- dicate that the HES-oligonucleotide delivery vehicles otide therapeutics field. 30 have the ability to enter all intracellular spaces/compart- [0003] In recent efforts to overcome some of the limi- ments. Thus, there are essentially limitless applications tations of the delivery of DNA and RNA sequences, de- in for example, research, diagnostics and therapeutics livery vehicles composed of lipids, sugars, and proteins arenas. Disclosed herein is the in vivo delivery of HES- conjugated to or encapsulating oligonucleotide sequenc- oligonucleotide complexes containing HES and at least es of interest, e.g., liposomes and lipid nanoparticles, 35 one therapeutic oligonucleotide for the treatment or pre- cholesterol conjugates, and antibody conjugates, have vention of a disease, disorder or condition. been developed. However, none of these formulations [0007] Moreover, with the currently available delivery has enabled delivery of oligonucleotide cargoes for the methodologies the induction of innate antiviral defenses field of oligonucleotide therapeutics to reach its anticipat- inmammalian cellsto exogenousnucleic acid sequences ed role in disease treatment. Accordingly, there is a need 40 have likewise significantly limited the development and for improved in vivo delivery systems of oligonucleotide- use of therapeutic oligonucleotides. The inventors have based therapeutics. discovered that HES-oligonucleotides have low toxicity (at concentrations greater than 10 fold the determined BRIEF SUMMARY OF THE INVENTION oligonucleotide in vivo cell loading level) and in fact, have 45 surprisingly found that the chemical linkage of HES. oli- [0004] In a first aspect, the present invention provides gonucleotides does not induce the interferon response a composition for delivering a therapeutic oligonucleotide in a host subject ( i.e., mouse) compared to that observed to a subject, said composition comprising a therapeuti- with other delivery vehicles. Accordingly, disclosed here- cally effective amount of an H-type excitonic structure in is a method of limiting the interferon response to an (HES)- oligonucleotide containing a therapeutic oligonu- 50 administered exogenous nucleic acid (e.g., oligonucle- cleotide that specifically hybridizes in vivo, to a nucleic otide) in a host, comprising linking 1, 2, 3 or more oligo- acid sequence and modulates the level of a protein en- nucleotides with an HES to form an HES-oligonucleotide coded or regulated by the nucleic acid, the therapeutic complex and administering the HES-oligonucleotide oligonucleotide having at least 85% sequence comple- complex to a subject. mentarity to the nucleic acid sequence or being comple- 55 [0008] An HES-oligonucleotide complex delivery vehi- mentary to the nucleic acid sequence and including 1, 2 cle can be used as a diagnostic to identify and/or quan- or 3 base substitutions, wherein the composition is for titate the presence of
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