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Patent No .: US 10703789 B2 US010703789B2 ( 12 ) United States Patent ( 10 ) Patent No.: US 10,703,789 B2 De Fougerolles et al. (45 ) Date of Patent: * Jul. 7 , 2020 (54 ) MODIFIED POLYNUCLEOTIDES FOR THE (2013.01 ) ; A61K 38/36 ( 2013.01 ) ; A61K PRODUCTION OF SECRETED PROTEINS 38/363 ( 2013.01 ) ; A61K 38/44 ( 2013.01) ; A61K 38/4833 (2013.01 ) ; A61K 38/4846 ( 71 ) Applicant : Moderna TX , Inc., Cambridge, MA (2013.01 ) ; A61K 39/3955 ( 2013.01) ; A61K (US ) 47/10 (2013.01 ) ; A61K 47/54 (2017.08 ) ; A61K 47/542 (2017.08 ) ; A61K 48/0033 ( 2013.01 ) ; ( 72 ) Inventors: Antonin De Fougerolles, Waterloo A61K 48/0066 (2013.01 ) ; A61K 48/0075 ( BE ) ; Justin Guild , Framingham , MA (2013.01 ) ; CO7K 14/47 ( 2013.01 ) ; CO7K (US ) 14/475 ( 2013.01) ; CO7K 14/505 (2013.01 ) ; ( 73 ) Assignee : Moderna TX , Inc., Cambridge , MA CO7K 14/525 (2013.01 ) ; C07K 14/56 (US ) (2013.01 ) ; CO7K 14/565 ( 2013.01 ) ; CO7K 14/745 (2013.01 ) ; C07K 14/75 ( 2013.01) ; ( * ) Notice: Subject to any disclaimer , the term of this CO7K 16/2887 ( 2013.01 ) ; CO7K 16/32 patent is extended or adjusted under 35 ( 2013.01) ; CO7K 19/00 ( 2013.01) ; C12N U.S.C. 154 (b ) by 0 days . 9/0069 ( 2013.01) ; C12N 9/644 ( 2013.01 ) ; C12N 15/85 (2013.01 ) ; C12N 15/88 This patent is subject to a terminal dis ( 2013.01 ) ; C12Y 113/12007 (2013.01 ) ; C12Y claimer . 304/21005 (2013.01 ) ; C12Y 304/21022 (2013.01 ) ; A61K 9/0019 (2013.01 ) ; A61K (21 ) Appl. No.: 16 /438,978 48/00 (2013.01 ) ; C12N 2840/00 (2013.01 ) ( 22 ) Filed : Jun . 12 , 2019 (58 ) Field of Classification Search CPC CO7H 21/02 , C12N 15/67; C12N 15/11 (65 ) Prior Publication Data See application file for complete search history . US 2020/0017565 A1 Jan. 16 , 2020 (56 ) References Cited Related U.S. Application Data U.S. PATENT DOCUMENTS (63 ) Continuation of application No. 14 /987,328 , filed on Jan. 4 , 2016 , now Pat . No. 10,385,106 , which is a 5,489,677 A 2/1996 Sanghvi et al . (Continued ) 5,591,722 A 1/1997 Montgomery et al. (Continued ) ( 51 ) Int. Cl. A61K 48/00 ( 2006.01 ) FOREIGN PATENT DOCUMENTS A61K 38/17 ( 2006.01) CA 2028849 A1 9/1991 A61K 47/54 ( 2017.01 ) CA 2473135 A1 6/2003 A61K 9/127 (2006.01 ) COZK 14/535 ( 2006.01 ) ( Continued ) C12N 15/88 (2006.01 ) A61K 9/50 ( 2006.01 ) OTHER PUBLICATIONS COZK 14/47 ( 2006.01 ) Anderson et al ., “ Incorporation of pseudouridine into mRNA enhances A61K 31/7088 ( 2006.01) translation by diminishing PKR activation , ” Nucleic Acids Res . CO7K 19/00 (2006.01 ) 38( 17 ) : 5884-92 ( 2010 ) . CI2N 15/85 ( 2006.01 ) A61K 38/18 ( 2006.01 ) ( Continued ) A61K 38/19 (2006.01 ) A61K 38/48 (2006.01 ) Primary Examiner — Antonio Galisteo Gonzalez A61K 9/14 ( 2006.01 ) A61K 47/10 ( 2017.01 ) (74 ) Attorney, Agent, or Firm -Clark & Elbing LLP A61K 38/21 (2006.01 ) A61K 38/36 ( 2006.01 ) (57 ) ABSTRACT A61K 38/44 ( 2006.01 ) A61K 39/395 ( 2006.01 ) A pharmaceutical composition which has a plurality of lipid (Continued ) nanoparticles that has a mean particle size ofbetween 80 nm (52 ) U.S. CI. and 160 nm and contains a modified mRNA encoding a CPC CO7K 14/535 (2013.01 ) ; A61K 9/1271 polypeptide. The lipid nanoparticles include a cationic lipid , (2013.01 ) ; AKIK 9/1272 ( 2013.01) ; A6IK a neutral lipid , a cholesterol, and a PEG lipid . The mRNA 9/1277 ( 2013.01) ; A61K 9/14 ( 2013.01) ; A61K contains a 5 '- cap , 5 '- UTR , N1- methyl - pseudouridine , a 9/5031 ( 2013.01) ; A61K 31/7088 (2013.01 ) ; 3 '- UTR , and a poly - A region with at least 100 nucleotides . A61K 38/1767 ( 2013.01) ; A61K 38/1816 ( 2013.01 ) ; A61K 38/1866 ( 2013.01) ; A61K 38/191 (2013.01 ) ; A61K 38/193 ( 2013.01) ; 14 Claims, 14 Drawing Sheets A61K 38/212 ( 2013.01 ) ; A61K 38/215 Specification includes a Sequence Listing . US 10,703,789 B2 Page 2 Related U.S. Application Data CO7K 14/56 (2006.01 ) continuation of application No. 14 / 750,004 , filed on C07K 14/565 ( 2006.01) Jun . 25 , 2015 , now Pat . No. 9,828,416 , which is a CO7K 14/745 (2006.01 ) continuation of application No. 13 / 791,921 , filed on COZK 14/75 ( 2006.01) Mar. 9 , 2013 , now Pat. No. 9,192,651 . CO7K 16/28 ( 2006.01) CO7K 16/32 ( 2006.01 ) (60 ) Provisional application No.61 / 737,174 , filed on Dec. C12N 9/02 (2006.01 ) 14 , 2012 , provisional application No. 61/ 737,168 , CI2N 9/64 (2006.01 ) filed on Dec. 14 , 2012 , provisional application No. A61K 31/7115 (2006.01 ) 61/ 737,160 , filed on Dec. 14 , 2012 , provisional COZK 14/005 ( 2006.01 ) application No. 61/ 737,155 , filed on Dec. 14 , 2012 , CI2N 15/11 ( 2006.01 ) provisional application No. 61/ 737,152 , filed on Dec. CI2N 9/00 (2006.01 ) 14 , 2012 , provisional application No. 61 / 737,147, A61K 9/00 (2006.01 ) filed on Dec. 14 , 2012 , provisional application No. References Cited 61/ 737,139 , filed on Dec. 14 , 2012, provisional ( 56 ) application No. 61/ 737,135 , filed on Dec. 14, 2012, U.S. PATENT DOCUMENTS provisional application No. 61/ 737,134 , filed on Dec. 5,637,459 A 6/1997 Burke et al. 14 , 2012 , provisional application No. 61 / 737,130 , 5,639,873 A 6/1997 Barascut et al. filed on Dec. 14 , 2012 , provisional application No. 5,789,578 A 8/1998 Burton et al. 61/ 737,184 , filed on Dec. 14 , 2012 , provisional 6,248,268 B1 6/2001 Cook application No. 61/ 737,191 , filed on Dec. 14 , 12 , 6,423,492 B1 7/2002 Ha provisional application No. 61/ 737,203 , filed on Dec. 6,511,832 B1 1/2003 Guarino et al . 7,691,569 B2 4/2010 Wohlgemuth et al. 14 , 2012 , provisional application No. 61/ 681,658 , 7,745,391 B2 6/2010 Mintz et al . filed on Aug. 10 , 2012 , provisional application No. 8,093,367 B2 1/2012 Kore et al . 61/ 681,742 , filed on Aug. 10 , 2012 , provisional 8,664,194 B2 3/2014 de Fougerolles et al . application No. 61/ 681,704 , filed on Aug. 10 , 2012 , 8,680,069 B2 3/2014 de Fougerolles et al . 8,710,200 B2 4/2014 Schrum et al. provisional application No. 61 /681,696 , filed on Aug. 8,822,663 B2 9/2014 Schrum et al . 10 , 2012 , provisional application No. 61 /681,687 , 8,898,864 B1 12/2014 Porter filed on Aug. 10 , 2012 , provisional application No. 8,980,864 B2 3/2015 Hoge et al . 61/ 681,675 , filed on Aug. 10 , 2012, provisional 8,999,380 B2 4/2015 Bancel et al. application No. 61/ 681,667 , filed on Aug. 10 , 2012 , 9,050,297 B2 6/2015 Chakraborty et al . 9,061,059 B2 6/2015 Chakraborty et al. provisional application No. 61 /681,661 , filed on Aug. 9,089,604 B2 7/2015 Chakraborty et al. 10 , 2012 , provisional application No. 61/ 681,654 , 9,095,552 B2 8/2015 Chakraborty et al . filed on Aug. 10 , 2012 , provisional application No. 9,107,886 B2 8/2015 Chakraborty et al . 61/ 681,650 , filed on Aug. 10 , 2012, provisional 9,114,113 B2 8/2015 Chakraborty et al. 9,149,506 B2 10/2015 Chakraborty et al. application No. 61/ 681,649 , filed on Aug. 10 , 2012 , 9,428,535 B2 8/2016 de Fougerolles et al. provisional application No. 61/ 681,648 , filed on Aug. 9,533,047 B2 1/2017 de Fougerolles et al . 10, 2012 , provisional application No. 61/ 681,647 , 9,675,668 B2 6/2017 Bancel et al. filed on Aug. 10 , 2012 , provisional application No. 10,385,106 B2 * 8/2019 De Fougerolles A61K 9/5031 61/ 681,645 , filed on Aug. 10 , 2012, provisional 10,463,751 B2 * 11/2019 De Fougerolles application No. 61/ 668,157 , filed on Jul. 5 , 2012 , CO7K 14/43595 10,493,167 B2 * 12/2019 de Fougerolles A61K 9/145 provisional application No. 61/ 648,286 , filed on May 10,501,512 B2 * 12/2019 De Fougerolles C12N 15/85 17 , 2012 , provisional application No. 61/618,868 , 10,501,513 B2 * 12/2019 De Fougerolles A61K 9/1272 filed on Apr. 2 , 2012 , provisional application No. 2002/0058256 A1 5/2002 Rothberg et al. 61/ 618,870 , filed on Apr. 2 , 2012 , provisional 2002/0114784 A1 8/2002 Li et al . 2003/0180779 Al 9/2003 Lofton - Day et al. application No. 61/ 618,873 , filed on Apr. 2 , 2012 , 2004/0076978 A1 4/2004 Verfaillie provisional application No. 61/618,878 , filed on Apr. 2004/0142433 A1 7/2004 Padgett et al . 2 , 2012 , provisional application No.61 / 618,885 , filed 2004/0220127 Al 11/2004 Sternberg et al. on Apr. 2 , 2012 , provisional application No. 2004/0259097 Al 12/2004 De Backer et al. 61/ 618,896 , filed on Apr. 2 , 2012 , provisional 2005/0003496 A1 1/2005 McGall et al . 2005/0019815 Al 1/2005 Gladyshev et al. application No. 61 /618,911 , filed on Apr. 2 , 2012 , 2005/0053942 A1 3/2005 Kauppinen et al . provisional application No. 61/ 618,922 , filed on Apr. 2005/0143336 A1 6/2005 Ramesh et al. 2 , 2012 , provisional application No.61 / 618,935 , filed 2006/0257902 Al 11/2006 Mendoza et al . on Apr. 2 , 2012 , provisional application No. 2007/0037148 Al 2/2007 Fong et al.
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