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WO 2018/231709 Al 20 December 2018 (20.12.2018) W !P O PCT

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WO 2018/231709 Al 20 December 2018 (20.12.2018) W !P O PCT (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 2018/231709 Al 20 December 2018 (20.12.2018) W !P O PCT (51) International Patent Classification: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, C08G 79/00 (2006.01) C08G 79/04 (2006.01) TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (21) International Application Number: MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, PCT/US20 18/036920 TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (22) International Filing Date: KM, ML, MR, NE, SN, TD, TG). 11 June 2018 ( 11.06.2018) Published: (25) Filing Language: English — with international search report (Art. 21(3)) (26) Publication Langi English — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (30) Priority Data: amendments (Rule 48.2(h)) 62/5 18,3 13 12 June 2017 (12.06.2017) US with sequence listing part of description (Rule 5.2(a)) (71) Applicant: TRANSLATE BIO, INC. [US/US]; 29 Hartwell Avenue, Lexington, MA 02421 (US). (72) Inventors: DEROSA, Frank; c/o Translate Bio, Inc., 29 Hartwell Avenue, Lexington, MA 02421 (US). HEARTLEIN, Michael; c/o Translate Bio, Inc., 29 Hartwell Avenue, Lexington, MA 02421 (US). KARVE, Shrirang; c/o Translate Bio, Inc., 29 Hartwell Avenue, Lex ington, MA 02421 (US). ZHANG, Yi; c/o Translate Bio, Inc., 29 Hartwell Avenue, Lexington, MA 02421 (US). (74) Agent: ESPINO, Christine, G. et al; Proskauer Rose LLP, One International Place, Boston, MA 021 10 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (54) Title: POLY(PHOSPHOESTERS) FOR DELIVERY OF NUCLEIC ACIDS (57) Abstract: Disclosed are polymers comprising the moiety A„ which is a moiety of formula I: and pharmaceutically acceptable salts thereof, wherein R, R1, R2, , nl and n2 are as defined herein. These polymers are useful for delivering nucleic acids to subject. These polymers and pharmaceutically acceptable compositions comprising such polymers and nucleic acids can be useful for treating various diseases, disorders and conditions. © ∞ (I) o o POLY(PHOSPHOESTERS) FOR DELIVERY O F NUCLEIC ACIDS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims benefit of U.S. Provisional Application No. 62/518,313, filed June 12, 2017, which is hereby incorporated by reference in its entirety. SEQUENCE LISTING [0002] The present specification makes reference t o a Sequence Listing provided in electronic form as an ASCI I.txt file named " M RT-1248WO_ST25.txt" that was generated on June 11, 2018, and is 3,013 bytes in size. BACKGROUND [0003] Nucleic acids have been explored as a potential therapeutic option for certain disease states. In particular, ribonucleic acid (RNA) interference (RNAi) using, for example, small interfering RNA (siRNA), short hairpin RNA (sh RNA), and antisense RNA (a RNA) approaches have been the subject of significant research and clinical development, for example, for binding t o messenger RNA (mRNA), long non-coding RNA (IncRNA), micro-RNA (miRNA) and other endogenous targets. More recently, administration of m RNA, multimeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA) and CRISPR RNA (crRNA) have been investigated as possible treatments of various diseases. However, the delivery of nucleic acids as therapeutics remains a challenge. SUMMARY [0004] The present invention provides, among other things, polymers useful in delivering nucleic acids as a therapeutic. The invention is based, in part, on the surprising discovery that the polymers described herein provide safe and efficient delivery of nucleic acids, such as m RNA. In particular, the polymers of the present invention may provide one or more advantages over other polymers. For example, as described in more detail herein, the polymers of the present invention may provide enhanced endosomal release of the nucleic acid being delivered by the polymer. Additionally, the biodegradable nature of the polymer may provide greater patient tolerability than other polymeric delivery vehicles. Thus, the polymers of the present invention may provide more potent and/or safer nucleic acid delivery for the treatment of a variety of diseases. [0005] In some aspects, the present invention provides a polymer comprising the moiety A : , which is a moiet of formula ( I): or a pharmaceutically acceptable salt thereof, wherein : each instance of R1 independently is - H or a C1-C20 aliphatic group; each instance of R2 independently is - H or a C1-C20 aliphatic group; each instance of R3 independently is - H or a C1-C20 aliphatic group; X is independently S or O; nl is an integer from 1 to 6; n2 is an integer from 1 to 6; R is N or CH; and L is Ci-6 alkyl or a protonatable group provided that when R is CH then L is a protonatable group, wherein the protonatable group comprises at least one 1° amino, 2° amino, 3° amino or imidazolyl group. [0006] In some aspects, the present invention provides methods of preparing the polymers of the present invention. [0007] In some aspects, the present invention provides a pharmaceutical composition (a "provided composition") comprising a polymer of the present invention and one or more nucleic acids or polynucleotides. [0008] In some aspects, the present invention provides methods of treating a disease in a subject comprising administering t o the subject a provided composition. Definitions [0009] In order for the present invention t o be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference materials referenced herein t o describe the background of the invention and t o provide additional detail regarding its practice are hereby incorporated by reference for all purposes. [0010] As used in this Specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. [0011] Unless specifically stated or obvious from context, as used herein, the term "or" is understood t o be inclusive and covers both "or" and "and". [0012] The terms "e.g.," and "i.e." as used herein, are used merely by way of example, without limitation intended, and should not be construed as referring only those items explicitly enumerated in the specification. [0013] The terms "or more", "at least", "more than", and the like, e.g., "at least one" are understood to include but not be limited t o at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000 or more than the stated value. Also included is any greater number or fraction in between. [0014] The terms "plurality", "at least two", "two or more", "at least second", and the like, are understood to include but not limited t o at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000 or more.
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