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WO 2015/034925 Al 12 March 2015 (12.03.2015) P O P C T

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WO 2015/034925 Al 12 March 2015 (12.03.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/034925 Al 12 March 2015 (12.03.2015) P O P C T (51) International Patent Classification: (74) Agents: WARD, Donna T. et al; 142A Main Street, Gro- C12N 15/63 (2006.01) C12N 15/67 (2006.01) ton, Massachusetts 01450 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US2014/053904 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 3 September 2014 (03.09.2014) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (26) Publication Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (30) Priority Data: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 61/873,010 3 September 2013 (03.09.2013) US SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 61/877,527 13 September 2013 (13.09.2013) US TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: MODERNA THERAPEUTICS, INC. [US/US]; 200 Technology Square, Cambridge, Massachu (84) Designated States (unless otherwise indicated, for every setts 02139 (US). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (72) Inventors: HOGE, Stephen G.; 250 East 63rd Street TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, # ID, New York, New York 10065 (US). DE FOUGER- TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, OLLES, Antonin; Avenue Neptune 15, B-1410 Waterloo DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (BE). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, [Continued on nextpage] (54) Title: CIRCULAR POLYNUCLEOTIDES FIGURE 1 0 - ! 3 o (57) Abstract: The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of circular o polynucleotides. SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, , , . ,. , , « τ before the expirationt of the timet limit for amending the W , J - , ML, 1V1 , i , N, . claims ana to be republished n the event oj receipt oj Published: amendments (Rule 48.2(h)) CIRCULAR POLYNUCLEOTIDES REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority U.S. Provisional Patent Application No US 61/873,010, filed September 3, 2013, entitled Circular Polynucleotides and U.S. Provisional Patent Application No US 61/877,527, filed September 13, 2013, entitled Circular Polynucleotides, the contents of each of which are herein incorporated by reference in its entirety. REFERENCE TO THE SEQUENCE LISTING [0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled M51PCTSEQLST.txt, created on September 3, 2014 which is 53,152 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0003] The invention relates to compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of single stranded circular polynucleotides (circP). BACKGROUND OF THE INVENTION [0004] Circular RNA was first discovered in 1979 by electron microscope (Hsu et al, Nature (1979) 280:339-340; herein incorporated by reference in its entirety). With its 5' and 3' ends joined together, circRNA has no free ends and has extradinary long half-life (Harland & Misher, Development (1988) 102:837-852; herein incorporated by reference in its entirety). Recent studies have confirmed that circRNA is resistant to digestion with RNase R exonuclease and turns over more slowly than its counterpart linear RNA in vivo (Memczak et al. Nature (2013) 495:333-338; herein incorporated by reference in its entirety). An analysis of circRNA and their associated linear mRNAs revealed that the circRNA isoforms were highly stable, with transcript half-lives exceeding 48 hours, while the associated linear transcripts exhibited half-lives of less than 20 hours (Jeck et al., RNA (2013) 19:141-157; herein incorporated by reference in its entirety). [0005] Since their initial discovery circRNAs have been developed for various uses. In US Patent No. US5766903 to Sarnow et al., herein incorporated by reference in its entirety, circRNAs comprise an internal ribosome entry site (IRES) element that engages a eukaryotic ribosome and an RNA sequence element encoding a polypeptide operatively linked to the IRES. The circRNA described by Sarnow can then be inserted into cells in order to produce a polypeptide of interest. US Patent No. US5580859 to Feigner et al, herein incorporated by reference in its entirety, describes polynucleotide sequences, which may be circularized, which may be administered directly to tissues in order to produce proteins. CircRNAs for vascular disease are described in International Publication No. WO20 12050975, herein incorporated by reference in its entirety, where Sharpless et al. described circRNAs comprising one or more ANRIL exons which play an active role in atherosclerotic vascular disease. US Patent No. US5426180 to Kool et al., herein incorporated by reference in its entirety, discloses single-stranded circular oligonucleotides that bind to both single-stranded and double-stranded target nucleic acids. [0006] The production of circRNAs has been attempted by various methods such as the method described in US Patent No. US621093 1 to Feldstein et al., herein incorporated by reference in its entirety, which teaches a method of synthesizing circRNAs by inserting DNA fragments into a plasmid containing sequences having the capability of spontaneous cleavage and self-circularization. Another method is described in US Patent No. US5773244 to Ares Jr. et al. which teaches producing circRNAs by making a DNA construct encoding an RNA cyclase ribozyme, expressing the DNA construct as an RNA, and then allowing the RNA to self-splice, which produces a circRNA free from intron in vitro. International Publication No. WO1992001813 to Ruth et al., herein incorporated by reference in its entirety, teaches a process of making single strand circular nucleic acids by synthesizing a linear polynucleotide, combining the linear nucleotide with a complementary linking oligonucleotide under hybridization conditions, and ligating the linear polynucleotide. [0007] However, the synthetic circRNA molecules are still suceptible to the pitfalls of their linear counterparts including, but not limited to, reduced structural and functional integrity and/or triggering bio-responses such as the immune response and/or degradation pathways. [0008] It has been previously shown that certain linear modified mRNA sequences have the potential as therapeutics. Such studies are detailed in International Publication No. WO2012019168, filed August 5, 201 1, International Publication No. WO2012045075, filed October 3, 201 1, International Publication No. WO2012135805, filed April 2, 2012, International Publication No. WO2012045082, filed October 3, 201 1, International Publication No. WO2013052523, filed October 3, 2012, and International Publication No. WO2013090648, filed December 14, 2012, the contents of each of which are herein incorporated by reference in its entirety. [0009] The present invention provides single stranded circular polynucleotides (circP) which may comprise structural and/or chemical features such as, but not limited to, features which are useful for optimizing formulation and delivery of nucleic acid- based therapeutics while retaining structural and functional integrity, overcoming the threshold of expression, improving expression rates, half life and/or protein concentrations, optimizing protein localization, and avoiding deleterious bio-responses such as the immune response and/or degradation pathways. The circular polynucleotides which may comprise the structural and/or chemical features described herein may have potential in the fields of therapeutics, diagnostics, reagents and for biological assays. SUMMARY OF THE INVENTION [00010] Described herein are compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of circular polynucleotides. [00011] In one aspect, a circular polynucleotide (circP) comprises a first region of linked nucleosides, a first flanking region located 5' relative to said first region of linked nucleosides and a second flanking region located 3' relative to said first region of linked nucleosides. The first and/or second flanking region may comprise a first region of polarity. [00012] The circPs of the present invention may comprise at least one modification described herein such as, but not limited to, a structural and/or chemical modification. As a non-limiting example, the chemical modification may be a nucleotide and/or nucleoside modification including a nucleobase modification and/or a sugar modification. Nucleobases include, but are not limited to, cytosine, guanine, adenine, thymine and uracil. As another non-limiting example, the circPs of the present invention comprise at least two modifications. The modifications may be located on one or more nucleosides and/or backbone linkage between the nucleosides. In one aspect, at least one backbone linkage may be replaced with a phophorothioate linkage. [00013] The first region of linked nucleosides of a circP described herein may encode a polypeptide of interest. The polypeptide of interest may be one known in the art and/or described herein. The circPs described herein may also comprise a second region of linked nucleosides which can encode a polypeptide of interest. The second region of linked nucleosides may comprise a third flanking region located 5' relative to the second region of linked nucleosides and a fourth flanking region located 3' relative to the second region of linked nucleosides.
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