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(12) United States Patent (10) Patent No.: US 9,725,721 B2 Moeller (45) Date of Patent: Aug

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(12) United States Patent (10) Patent No.: US 9,725,721 B2 Moeller (45) Date of Patent: Aug USO09725721B2 (12) United States Patent (10) Patent No.: US 9,725,721 B2 MOeller (45) Date of Patent: Aug. 8, 2017 (54) OLIGOMERS WITH IMPROVED (56) References Cited OFF-TARGET PROFILE FOREIGN PATENT DOCUMENTS (71) Applicant: MIRRX THERAPEUTICS, Vejle (DK) WO WO 2005/061710 A1 7/2005 WO WO 2007/031081 A2 3, 2007 (72) Inventor: Thorleif Moeller, Odense SOE (DK) WO WO 2008/061537 A2 5, 2008 WO WO 2008/074328 6, 2008 WO WO 2008,151639 A2 12/2008 (73) Assignee: MIRRX THERAPEUTICS, Vejle WO WO 2009/068033 6, 2009 (DK) WO WO 2009,090.182 A1 T 2009 WO WO 2010, 122538 A1 10, 2010 (*) Notice: Subject to any disclaimer, the term of this WO WO 2011/115818 9, 2011 patent is extended or adjusted under 35 WO WO 2011 115818 A1 9, 2011 U.S.C. 154(b) by 0 days. WO WO 2011, 117353 A1 9, 2011 (21) Appl. No.: 14/431,212 OTHER PUBLICATIONS (22) PCT Filed: Sep. 26, 2013 International Search Report dated Dec. 18, 2013 for corresponding International Patent Application No. PCT/DK2013/050308, filed (86). PCT No.: PCT/DK2O13AOSO3O8 Sep. 26, 2013, 4 pages. International Preliminary Report on Patentability dated Dec. 11, S 371 (c)(1), 2014 for corresponding International Patent Application No. PCT/ (2) Date: Mar. 25, 2015 DK2013/050308, filed Sep. 26, 2013, 6 pages. Takagi-Sato, M. et al., “Fine-Tuning of ENAR. Gapmers as Anti (87) PCT Pub. No.: WO2014/048441 sense Oligonucleotides for Sequence-Specific Inhibition'. Oligo PCT Pub. Date: Apr. 3, 2014 nucleotides, 2007, vol. 17. No. 3, pp. 291-301. Lennox et al., “Chemical modification and design of anti-miRNA (65) Prior Publication Data oligonucleotides.” Gener Therapy (2011)pp. 1111-1120. Stanley T. Crooke: “Principles, Strategies and Applications'. Anti US 2016/O145620 A1 May 26, 2016 sense Drug Technology, 2" Edition, 2007, p. 93. Third Party Observation filed in related European Patent Applica Related U.S. Application Data tion No. 13842025.2, dated Apr. 12, 2017, 15 pages. (60) Provisional application No. 61/705,668, filed on Sep. Jens Kurrecket al.: “Design of antisense oligonucleotides stabilized 26, 2012. by locked nucleic acids.” Nucleic Acids Research, 2002, vol. 30, No. 9, pp. 1911-1918. (30) Foreign Application Priority Data Primary Examiner — Amy Bowman Sep. 26, 2012 (DK) ................................. 2012 OO587 (74) Attorney, Agent, or Firm — Merchant & Gould (51) Int. Cl. (57) ABSTRACT C7H 2L/04 (2006.01) The present invention provides oligomers that binds RNA C7H 2L/02 (2006.01) that consists of a lower affinity region and a higher affinity CI2N IS/IT3 (2010.01) region, wherein the monomers in the higher affinity region CI2N IS/II (2006.01) increases the melting temperature (i.e. affinity) of the oli (52) U.S. Cl. gomer base paired to RNA more than the monomers used in CPC ........ CI2N 15/II31 (2013.01); C12N 15/III the lower affinity region, wherein said increase in melting (2013.01); C12N 15/113 (2013.01); C12N temperature is relatively to the alternative use of DNA 23 10/11 (2013.01); C12N 23 10/113 (2013.01); monomers of the same (base) sequence. The oligomers of CI2N 23.10/315 (2013.01); C12N 23.10/321 the invention are useful for binding to target RNA such as (2013.01); C12N 23.10/3231 (2013.01); C12N mRNA and non-coding RNA and have the advantage that 23.10/341 (2013.01); C12N 2320/53 (2013.01) they will be less prone to off-target binding via the lower (58) Field of Classification Search affinity region than via the higher affinity region. CPC .......................... C12N 15/113; C12N 2310/11 See application file for complete search history. 7 Claims, 3 Drawing Sheets U.S. Patent Aug. 8, 2017 Sheet 1 of 3 US 9,725,721 B2 On-target binding with various oligomer designs A Oligomer A. On-target Oligomer B On-targeted r Mn- ESSEE, C Oligomer Cre On-target Fig. 1 U.S. Patent Aug. 8, 2017 Sheet 2 of 3 US 9,725,721 B2 Off-target binding to competing consensus sequence A. Oligomer A Off-target Oligomer B a 1. Off-target Consensus COinSensus Fig. 2 U.S. Patent Aug. 8, 2017 Sheet 3 of 3 US 9,725,721 B2 Off-target binding to non-consensus target O Cer B sesssssssssssssssssssssssssssssss : 1. Off-target Off-target-re8:ox:xx H SS Fig. 3 US 9,725,721 B2 1. 2 OLGOMERS WITH IMPROVED in melting temperature is relatively to the alternative OFF-TARGET PROFILE use of DNA monomers of the same (base) sequence. The oligomers of the invention are useful for binding to This application is a National Stage Application of PCT/ target RNA such as mRNA and non-coding RNA and have DK2013/050308, filed 26 Sep. 2013, which claims benefit of 5 the advantage that they will be less prone to off-target Serial No. PA 2012 00587, filed 26 Sep. 2012 in Denmark, binding via the lower affinity region than via the higher and also claims benefit of Ser. No. 61/705,668, filed 26 Sep. affinity region. 2012 in the United States and which applications are incor porated herein by reference. To the extent appropriate, a BRIEF DESCRIPTION OF THE FIGURES claim of priority is made to each of the above disclosed 10 applications. FIG. 1A show a typical steric block oligomer bound to its intended target (the on-target). The consensus sequence is a BACKGROUND OF THE INVENTION sequence that is shared with other RNAs and is preferably part of a binding site for at cellular molecule, e.g. a micro The present invention relate to oligomers and oligonucle 15 RNA. The sequence adjacent to the consensus sequence is otides that can bind to complementary RNA. Oligonucle denoted unique 1 and is sequence that differs (also herein otides are useful as reagents in Science, research and devel termed 'specificity sequence') among RNAS sharing the opment e.g. for detection and analysis of cellular RNA or for consensus sequence. Base pairs are indicated by lines modulation of the activity of cellular RNA. between the oligomer and the target. The oligomer is uni Oligonucleotides are also being developed as therapeu formly modified with monomer analogues that enhance tics, where they are typically also intended to bind to and affinity toward complementary RNA and the position of modulate the activity of cellular RNA. Oligonucleotides that these modifications is shown by a bold (base pair) line to the bind cellular RNA are herein also termed antisense oligo target. The oligomer may e.g. be a BNA/2"O-methyl RNA nucleotides. oligomer and the affinity enhancing analogues is then BNA Some antisense oligonucleotides act by inducing desta 25 (bicyclic nucleic acids). The illustrated design could just as bilization of their target RNA e.g. by activating RNase H well have been affinity enhancing analogues in every third degradation of the target RNA or by activating the RISC position or even in all positions or any other repeating pathway. Such oligonucleotides are typically described as pattern, which gives a relatively uniform affinity over the gapmers and siRNAS respectively. Another class of oligo length of the oligomer. It is clear that G:C base pairs are nucleotides act as steric blocker and hence prevents the 30 stronger than A: U base pairs. However, for the sake of target RNA from interacting with another macromolecule. simplicity Such sequence specific affinity variations are not One example is splice switching oligonucleotides that considered in the present example. modulate splicing of pre-mRNA. Another example is micro FIG. 1B shows a steric block oligonucleotide of same RNA inhibitors that bind to microRNA and prevent the sequence as oligomer A of FIG. 1A, but with a non-uniform microRNA from binding to its mRNA targets. A thorough 35 distribution of affinity increasing modifications bound to its description of the design, preparation and use of antisense intended target. The affinity of this oligomer toward comple oligonucleotides can be found in “Antisense Drug Technol mentary RNA will not differ dramatically from the oligomer ogy, Principles, Strategies and Applications, 2nd Edition, of 1A. Depending on the monomers chosen, the overall Edited by Stanley Crooke'. affinity may be higher or lower. It is easy to design an antisense oligonucleotide that is 40 FIG. 1C shows a yet another steric block oligonucleotide complementary to a given target RNA and hence is capable of same sequence as oligomer A of FIG. 1A, but with a of binding to the target RNA. However, when attempting to non-uniform distribution of affinity increasing modifications develop antisense oligonucleotides as therapeutics, comple bound to its intended target. The affinity of this oligomer mentarity to the target is not enough. The antisense oligo toward complementary RNA will not differ dramatically nucleotide need to be modified to give it more drug-like 45 from the oligomer of 1A or 1B. Depending on the monomers properties, e.g. better potency, bioavailability and biostabil chosen, the overall affinity may be higher or lower. ity. Moreover, it has turned out that a problem of many In theory, all 3 oligomers have a similar affinity toward antisense oligonucleotides is off-target binding, i.e. binding complementary RNA and would therefore be expected to to non-intended RNAs, which may lead to undesirable have a similar potency, e.g. when used in cells or organisms. effects. To minimize off-target binding, it is typically 50 However, they have a different off-target profile (binds to a attempted to target unique sequences in the RNA transcrip different set of off-targets). tome. Even So, off-target binding of antisense oligonucle FIG.
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