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TOAN HARIA a LA TAULERWEILUUUTTTUS009868692B2 (12 ) United States Patent (10 ) Patent No

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TOAN HARIA a LA TAULERWEILUUUTTTUS009868692B2 (12 ) United States Patent (10 ) Patent No TOAN HARIA A LA TAULERWEILUUUTTTUS009868692B2 (12 ) United States Patent (10 ) Patent No. : US 9 ,868 , 692 B2 Benenato ( 45) Date of Patent: Jan . 16 , 2018 ( 54 ) COMPOUNDS AND COMPOSITIONS FOR C07F 9 / 09 (2006 .01 ) INTRACELLULAR DELIVERY OF A61K 9 / 16 (2006 .01 ) THERAPEUTIC AGENTS A61K 38 / 18 ( 2006 . 01 ) COZK 14 / 505 ( 2006 . 01 ) (71 ) Applicant: MODERNATX , Inc. , Cambridge , MA A61K 9 / 00 ( 2006 .01 ) (US ) A61K 47 /54 ( 2017 . 01 ) A61K 47/ 69 ( 2017 .01 ) (72 ) Inventor: Kerry E . Benenato , Cambridge , MA (52 ) U . S . CI. (US ) CPC .. .. C07C 229 / 12 (2013 . 01) ; A61K 9 /0019 (73 ) Assignee : ModernaTX , Inc. , Cambridge , MA (2013 .01 ) ; A61K 9 / 127 ( 2013 .01 ) ; A61K (US ) 9 / 1617 ( 2013 . 01 ) ; A61K 38 / 1816 ( 2013 .01 ) ; A61K 47 /543 ( 2017 . 08 ) ; A61K 47 /6911 ( * ) Notice : Subject to any disclaimer , the term of this (2017 .08 ) ; A61K 48 / 005 ( 2013 .01 ) ; C07C patent is extended or adjusted under 35 229 / 16 (2013 .01 ) ; C07C 233 /36 ( 2013 . 01 ) ; U . S . C . 154 (b ) by 0 days . C07C 235 / 10 ( 2013 . 01 ) ; C07C 255 /24 ( 2013 .01 ) ; C07C 271 /20 ( 2013 .01 ) ; C07C ( 21 ) Appl. No. : 15 /476 , 263 275 / 14 (2013 .01 ) ; C07C 279 / 12 ( 2013 . 01 ) ; C07C 279 / 24 ( 2013 .01 ) ; C07C 279 / 28 ( 22 ) Filed : Mar. 31 , 2017 (2013 . 01 ) ; C07C 279 /32 ( 2013 .01 ) ; C07C 311/ 05 (2013 .01 ) ; C07C 335 / 08 ( 2013 . 01 ) ; (65 ) Prior Publication Data C070 207 /27 ( 2013 . 01 ) ; C07D 233 / 72 US 2017 /0210698 A1 Jul . 27 , 2017 (2013 . 01 ) ; C07D 249 /04 ( 2013 . 01 ) ; C07D 263 / 20 ( 2013 .01 ) ; C07D 265 /33 (2013 .01 ) ; C07D 271/ 06 ( 2013 .01 ) ; C07D 271/ 10 Related U . S . Application Data ( 2013 .01 ) ; CO7D 277 /38 ( 2013 . 01 ) ; CO7F (63 ) Continuation of application No . 9 /091 ( 2013 .01 ) ; C07K 14 /505 ( 2013 .01 ) ; PCT/ US2016 /052352 , filed on Sep . 16 , 2016 . C07C 2601 /02 ( 2017 .05 ) ; C07C 2601 / 04 ( 60 ) Provisional application No . 62/ 220 , 085, filed on Sep . ( 2017. 05 ) ; C07C 2601 / 14 ( 2017 . 05 ) ; C07C 17 , 2015 , provisional application No . 62 / 220 , 091, 2601 / 18 ( 2017 .05 ) filed on Sep . 17 , 2015 , provisional application No . (58 ) Field of Classification Search 62/ 252 , 316 , filed on Nov. 6 , 2015 , provisional USPC .. .. 435 / 6 . 1 , 6 . 11 , 6 , 9 . 1 , 91. 1 , 9 , 1 .31 , 455 , application No . 62 /253 ,433 , filed on Nov . 10 , 2015 , 435 / 456 , 458 ; 514 / 44 ; 536 / 23 . 1 , 23 . 2 , provisional application No. 62/ 266 ,460 , filed on Dec . 536 /23 . 5 , 24. 5 11 , 2015 , provisional application No. 62 / 333 , 557 , See application file for complete search history . filed on May 9 , 2016 , provisional application No . (56 ) References Cited (Continued ) U . S . PATENT DOCUMENTS (51 ) Int . Ci. A61K 9 / 51 ( 2006 . 01 ) 3 , 872 , 171 A 3 / 1975 Henry et al . A61K 48 /00 ( 2006 .01 ) 5 ,807 , 861 A 9 / 1998 Klein et al . C07C 229 / 12 ( 2006 .01 ) (Continued ) A61K 9 / 127 ( 2006 .01 ) C07C 271/ 20 ( 2006 .01 ) FOREIGN PATENT DOCUMENTS C07C 279 / 12 ( 2006 . 01 ) WO WO 2009 /086558 AL 7 /2009 C07C 279 /28 ( 2006 .01 ) WO WO 2009 / 129385 Al 10 /2009 C07C 279 / 32 ( 2006 .01 ) (Continued ) CO7D 233/ 72 ( 2006 .01 ) CO7D 249 / 04 ( 2006 . 01) Primary Examiner — Jane Zara C07D 263 / 20 ( 2006 . 01 ) (74 ) Attorney, Agent, or Firm — Cooley LLP ; Heidi A . CO7D 265 /33 ( 2006 .01 ) Erlacher ; Christine C . Pemberton CO7D 271 /06 ( 2006 .01 ) C07D 271 / 10 ( 2006 . 01 ) (57 ) ABSTRACT C070 207 /27 ( 2006 . 01 ) The disclosure features novel lipids and compositions C07D 27738 ( 2006 . 01 ) involving the same. Nanoparticle compositions include a C07C 275 / 14 (2006 .01 ) novel lipid as well as additional lipids such as phospholipids , C07C 279 / 24 ( 2006 . 01) structural lipids, and PEG lipids. Nanoparticle compositions C07C 311 /05 ( 2006 .01 ) further including therapeutic and / or prophylactics such as C07C 229 / 16 (2006 .01 ) RNA are useful in the delivery of therapeutic and / or pro C07C 335 /08 ( 2006 . 01 ) phylactics to mammalian cells or organs to , for example , C07C 233 /36 ( 2006 .01 ) regulate polypeptide , protein , or gene expression . C07C 235 / 10 ( 2006 .01 ) C07C 255 /24 ( 2006 .01 ) 30 Claims, 11 Drawing Sheets US 9 , 868 ,692 B2 Page 2 Related U . S . Application Data 2015 /0284317 A1 10 / 2015 Colletti et al . 2015 / 0343062 A1 12 / 2015 Kuboyama et al . 62/ 382 , 740 , filed on Sep . 1 , 2016 , provisional appli 2015 /0376115 A1 12 / 2015 Ansell et al. cation No. 62/ 393 , 940 , filed on Sep . 13 , 2016 . 2016 /0002178 A1 1 / 2016 Fenton et al . 2016 /0009657 AL 1 /2016 Anderson et al. ( 56 ) References Cited 2016 / 0151284 Al 6 / 2016 Heyes et al . U . S . PATENT DOCUMENTS FOREIGN PATENT DOCUMENTS 8 , 158 , 601 B2 4 / 2012 Chen et al . WO WO 2009 / 129395 AL 10 / 2009 8 ,802 , 644 B2 8 / 2014 Chen et al. WO WO 2010 / 030739 A1 3 / 2010 9 , 006, 487 B2 4 / 2015 Anderson et al. WO WO 2011 / 136368 A1 11 / 2011 9 , 029 , 590 B2 5 / 2015 Colletti et al. WO WO 2012 /054365 A2 4 /2012 9 , 394 ,234 B2 7 / 2016 Chen et al. WO WO 2013 /016058 AL 1 / 2013 2011 / 0009641 Al 1 /2011 Anderson et al . WO WO 2013 /086373 A1 6 / 2013 2012 / 0136073 Al 5 / 2012 Yang et al. WO WO 2014 /007398 A1 1 / 2014 2013/ 0108685 Al 5 / 2013 Kuboyama et al . WO WO 2014 / 172045 A1 10 / 2014 2013 / 0274504 Al 10 / 2013 Colletti et al. wo WO 2015 / 011633 A11 / 2015 2014 /0308304 Al 10 /2014 Manoharan et al . WO WO 2015 / 199952 A1 12 /2015 2015 / 0174260 A16 / 2015 Yang et al. Wo WO 2016 / 004202 AL 1 / 2016 2015 /0174261 A1 6 / 2015 Kuboyama et al. WO WO 2016 / 176330 A1 11/ 2016 U . S . Patent Jan . 16 , 2018 Sheet 1 of 11 US 9 ,868 ,692 B2 Yi ISOG SILOZI hi ISOQ SUZZ post 48hrs ???????? Seneste sod sjuyz Day22 KXXXXXXXXXXXXXXXXXXXXXXXXXXXXX isod suz ) XXXXXXXXXXXXXXXXXX in sod sj4g ??? X Y sp? ?? ? asopeld Y isod s 402 uyu postes 72hrs aheromRNAinMC3/Dexamethasone post 48hrs XXXXZXZYSZXXZXS XXX postingan 24hrs Day15 XXXXX : 3X3, XXSXSXX2 ZXXXXXXXXXXX SOO SIUZI VWXXXXXXXXX post Ghrs ??? SZ nnnnnn asopald 1500 Silozi hEPO(pg/mL) er sod sluzi nnnnnnnnnnnnnnnnnn rental a post 48hrs 022ZXXX post 24his pay??? XXXXXXXXXXXXXXX sod sj?ZI YAMAHWA } S00 & 09 post 2hrs Predose ???? } ? ????? OMC3BhopomRNAinMC3dhePOMethotrexate ???????nnnnnnnnnn sod sj?ZL SASALAN mer 1900 sugy SX 2XZ :23 SX SOO sut Day1 WO XXSXX2 2XXXX isod Suck Fig.1 SYSZYWY sad s }{ { isod Juz ???????? } 400000 350000 300000 250000 200000 150000 100000 5 U . S . Patent Jan . 16 , 2018 Sheet 2 of 11 US 9 ,868 ,692 B2 odbioouoouoouchwoowoonwoowoowooooooons 2hrspost6hrs12hrs24hrs48hrs72hrs96hrs HEPO Group.Compound26 aGroup2.Compound18OGroup3-Compound25 mGroup5-Compound48 601 oGroup1-MC3 Predose 140.00 120.00 0.00 -20.00 (wo ) wonejj083100 0034 Fig.2 U . S . Patent Jan . 16 , 2018 Sheet 3 of 11 US 9 ,868 ,692 B2 40 Compound260.005mpkCompound 260.01mpk Compound260.025mpk Compound260.05mpk Compound260.1mpk Compound260.25mpk Compound260.5mpk1mpk26 Compound Compound262mpk Time(Hours) * . MC32mpken 20 . 722222222222 * * * .: : 1722 * N ! I0x1072. 8.0x1071 0x107.6 0x107.4 entration Fig.3 atent Jan . 16 , 2018 Sheet 4 of 11 US 9 , 868 ,692 B2 40 005mpk0.18Compound 01mpk0.Compound18 Compound180.025mpk Compound180.05mpk Compound180.1mpk Compound180.25mpk Compound180.5mpk ydwr8Lpunoduod Time(Hours) w owowwwwwwwwwwwww 20 ow * innenge by * . 2009 : 09 : 09 : : 09 : 09 :00 2009 : 09 : 09 : 09 marathon0 20x107 1.5x107 20LXO1 5.0x1067 )ml / pg ( Concentration HEPO Fig.4 U . S . Patent Jan . 16 , 2018 Sheet 5 of 11 US 9 ,868 ,692 B2 05mpkCompound250. Compound250.1mpk Compound250.25mpk Compound250.5mpk walityCompound250.005mpk +Compound250.01mpk moderneCompound250.025mpk inCompound251mpk Time(Hours) w 20 w wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww.ww 8x1067 4x1060 B.2x106 000000000 )ml / pg( Concentration HEPO Fig.5 U . S . Patent Jan . 16 , 2018 Sheet 6 of 11 US 9 ,868 ,692 B2 40 MC30.25mpk *MC30.005mpk MC30.01mpk MC30.025mpk MC30.05mpk 1mpkMC30.- MC30.5mpk MC31mpk MC32mpk ? ? ? Time(Hours) ?? ? ? 20 ??? ? ? ? ?? ? ? ? ? wwwwwwwwwwwwwwwwwwwwoooowwwwwwwwwwwwwww * * * to 5x1067 4x106 2x106 Fig.6 )ml / pg ( Concentration HEPO U . S . Patent Jan . 16 , 2018 Sheet 7 of 11 US 9 ,868 ,692 B2 wirinin www ??????????????????????????????????????? www 1 mang. millhallo Dose(mg/kg) 0.01025051255 8, gzpunodwood 97punodwood wwwwwwwww MMC-3 2017 wwwwwwwwwwwwwwwwwwwwwww 0.005 600000000 500000000 400000000 00000000€ 200000000 100000000 ( 7w /odwy ) Ony U . S . Patent Jan . 16 , 2018 Sheet 8 of 11 US 9 ,868 ,692 B2 3hrtimepoint 6hrtimepoint 24hrtimepoint N O 3456712 0.1X019 5.3x 3.% 16.0x 1234567 ONNIN Fig.8 8x10087 6x1008 4x1008 2x1008 ) s/ p ( Flux Total atent Jan . 16 , 2018 Sheetsterben 9 of 11 US 9 ,868 ,692 B2 3hrtimepoint 6htimepoint 24htimepoint W D il.Moldo1 1234567891011, femme KW funny formann TT NI mo / / / / / 2 / 44 Fig.9 5x1004LI ANUNCILLLLLL 2x1005 1x1005 5x1004 OSAN ( quód ) Concentration huEpo U . S . Patent Jan . 16 , 2018 Sheet 10 of 11 US 9 ,868 ,692 B2 0 010 0 0 91011121314151617181920 * ** 678 mi en per altres * 45 123 3x1011, 2x1011 1x1011 -1x1011bun 1 Total wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww Fig.10 atent Jan . 16 , 2018 Sheet 11 of 11 US 9 ,868 ,692 B2 -Compound180.3mpk -wo menghinaMC30.3mpk 400 Anti-HAAntibodyExpression,0.3mpk II time(h) Fig.11B enwe 200200 A om h 641 mething a {{ { { { { -Compound180.1mpk * * I withMC30.1mpk w 400 w * Anti-HAAntibodyExpression,0.1mpk ** Fig.11A 200 time(h) Omos* Ž FA 2.0, @ 5774111.0 Twion US 9 , 868, 692 B2 COMPOUNDS AND COMPOSITIONS FOR A first aspect of the disclosure relates to compounds of INTRACELLULAR DELIVERY OF Formula ( I ) : THERAPEUTIC AGENTS RELATED APPLICATIONS R4 R1 N R This application is a continuation application of Interna RI RZ RAS tional Application PCT/ US2016 /052352 , having an interna REN tional filing date of Sep .
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