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( 12 ) United States Patent US010391098B2 (12 ) United States Patent (10 ) Patent No. : US 10 , 391, 098 B2 Geller et al. (45 ) Date of Patent: * Aug . 27 , 2019 ( 54 ) ANTISENSE ANTIBACTERIAL COMPOUNDS 5 ,698 ,685 A 12 / 1997 Summerton et al . 6 , 245 , 747 B1 6 / 2001 Porter et al. AND METHODS 6 , 965, 025 B2 11/ 2005 Gaarde et al. 6 , 969 ,400 B2 11 /2005 Rhee et al. (71 ) Applicants :Oregon State University , Corvallis , 7 ,625 ,873 B2 * 12 /2009 Geller . .. C07F 9 /65583 OR (US ) ; Board of Regents , The 435 /471 University of Texas System , Austin , 7 ,790 ,694 B2 9 /2010 Geller et al. 8 , 067 , 571 B2 11 / 2011 Weller et al. TX (US ) 8 , 076 ,476 B2 12 / 2011 Reeves et al. 8 , 299 , 206 B2 10 / 2012 Fox et al. (72 ) Inventors : Bruce L . Geller, Corvallis , OR (US ) ; 8 , 314 ,072 B2 11 / 2012 Geller et al. David Greenberg , Coppell , TX (US ) 8 , 536 , 147 B2 * 9 /2013 Weller .. A61K 48 / 00 514 /44 A ( 73 ) Assignees: Board of Regents , The University of 9 , 249 , 243 B2 * 2 / 2016 Weller . A61K 48 / 00 Texas System , Austin , TX (US ) ; 9 ,790 ,495 B2 10 /2017 Geller et al . Oregon State University , Corvallis , 2004 / 0029129 AL 2 / 2004 Wang et al. 2005 / 0288246 AL 12 / 2005 Iversen et al. OR (US ) 2006 / 0241075 Al 10 / 2006 McSwiggen 2006 /0270621 AL 11 /2006 Christiano ( * ) Notice : Subject to any disclaimer , the term of this 2007 /0049542 A1 3 / 2007 Geller et al . patent is extended or adjusted under 35 2008 / 0194463 Al 8 / 2008 Weller et al . 2010 / 0016215 A1 1 / 2010 Moulton et al . U . S . C . 154 (b ) by 0 days. 2010 / 0234281 Al 9 / 2010 Weller et al. This patent is subject to a terminal dis 2010 / 0261777 Al 10 / 2010 Shaw et al . 2012 / 0040460 A1 2 / 2012 Rigoutsos et al . claimer . 2012 /0122769 A1 5 / 2012 Iversen 2012 /0213663 A1 8 / 2012 Atieh et al. ( 21 ) Appl . No . : 14 /714 , 104 2012 /0289457 AL 11 /2012 Hanson 2012 / 0296087 Al 11 / 2012 Sinha et al . ( 22 ) Filed : May 15 , 2015 2013 /0197220 Al 8 /2013 Veda 2013 /0288369 Al 10 /2013 Iverson 2015 /0141321 A1 5 / 2015 Kole et al . (65 ) Prior Publication Data 2015 /0361425 Al 12 /2015 Geller et al. US 2016 /0106857 A1 Apr . 21 , 2016 FOREIGN PATENT DOCUMENTS Related U . S . Application Data KR 2013 /0005208 A 1 / 2013 ( 60 ) Provisional application No . 62/ 129 ,746 , filed on Mar . WO WO 1993 /001286 A2 1 / 1993 WO WO 2004 / 097017 A2 11 / 2004 6 , 2015 , provisional application No . 62 /000 ,431 , filed Wo WO 2006 / 085973 A2 8 / 2006 on May 19 , 2014 . wo WO 2007/ 009094 A2 1 / 2007 WO WO 2008 / 008113 A1 1 / 2008 (51 ) Int . Cl. WO WO 2009 /005793 A2 1 /2009 A61K 45 / 06 ( 2006 .01 ) WO WO 2009 /064471 A1 5 /2009 C12N 15 / 113 ( 2010 .01 ) ( Continued ) A61K 31 /5377 ( 2006 .01 ) A61K 31 / 712 ( 2006 . 01 ) OTHER PUBLICATIONS A61K 31/ 7036 ( 2006 . 01 ) A61K 47 /64 ( 2017 .01 ) GenBank 01251363 [ KR 1020130005208 - A /39 : Method and kit for ( 52 ) U . S . CI. detecting carbapenem resistant enterobacteriaceae using real - time CPC . .. .. A61K 31 /5377 ( 2013 .01 ) ; A61K 31 / 7036 PCR ] ( retrieved on Oct . 13 , 2015 from http : // www . ncbi. nlm .nih . ( 2013 .01 ) ; A61K 31/ 712 (2013 .01 ) ; A61K gov / nucleotide/ 662699238 ? report = genbank & log $ = nuclalign & blast _ 45 / 06 ( 2013 .01 ) ; A61K 47/ 645 ( 2017 .08 ) ; rank = 1 & RID = 1V403DGD016 ] Jul . 8 , 2014 ( Jul. 8 , 2014 ) whole C12N 15 / 113 ( 2013 .01 ) ; C12N 2310 / 3233 ( 2013. 01 ) ; C12N 2310 / 3513 ( 2013 .01 ) ; YO2A doc . 50 /473 ( 2018 .01 ) ( Continued ) ( 58 ) Field of Classification Search Primary Examiner — Brian Whiteman CPC .. .. .. .. A61K 31/ 712 ; C12N 15 / 113 ; C12N 2310 /3233 ( 74 ) Attorney, Agent, or Firm — Parker Highlander PLLC See application file for complete search history . (57 ) ABSTRACT (56 ) References Cited Provided are antisense oligomers targeted against or genes associated with a biochemical pathway and / or cellular pro U . S . PATENT DOCUMENTS cess , and related compositions and methods of using the 5 ,034 ,506 A 7 / 1991 Summerton et al. oligomers and compositions to treat an infected mammalian 5 , 142 , 047 A 8 / 1992 Summerton et al. subject, for example , as primary antimicrobials or as adjunc 5 , 166 , 315 A 11 / 1992 Summerton et al. tive therapies with classic antimicrobials . 5 , 185 , 444 A 2 / 1993 Summerton et al. 5 ,217 , 866 A 6 / 1993 Summerton et al. 16 Claims, 26 Drawing Sheets 5 , 506 , 337 A 4 / 1996 Summerton et al. 5 , 521 , 063 A 5 / 1996 Summerton et al . Specification includes a Sequence Listing . US 10 ,391 ,098 B2 Page 2 References Cited Summerton et al . 1997 , “ Morpholino antisense oligomers : design , ( 56 ) preparation , and properties .” Antisense and Nucleic Acid Drug Development ( 1997 ) ; 7 . 3 : 187 - 195 . FOREIGN PATENT DOCUMENTS EP 15795398 . 5 , Partial Supplementary European Search Report dated Nov. 29 , 2017 , 7 pages. WO WO 2012 /043730 AL 4 / 2012 Greenberg , et al. , “ Antisense Phosphorodiamidate Morpholino Oligom WO WO 2012 / 064991 A1 5 / 2012 WO WO 2012 / 150960 AL 11 /2012 ers Targeted to an Essential Gene Inhibit Burkholderia cepacia WO WO 2013 /011072 A1 1 / 2013 Complex . " The Journal of Infectious Diseases ( 2010 ) ; 12 : 1822 WO WO 2015 / 175977 A2 11 / 2015 1830 . wo WO 2015 / 179249 AL 11 / 2015 EP 15792493 . 7 , Partial Supplementary European Search Report WO WO 2016 / 108930 A2 7 / 2016 dated Nov . 29 , 2017 , 10 pages. WO WO 2017 / 112885 A16 / 2017 Youngblood , Derek S . , et al. “ Stability of cell -penetrating peptide morpholino oligomer conjugates in human serum and in cells. ” WO WO 2017 / 112888 AL 6 /2017 Bioconjugate Chemistry (2007 ) ; 18 . 1 : 50 -60 . PCT/ US2015 /031150 , International Preliminary Report on Patent OTHER PUBLICATIONS ability dated Nov. 22 , 2016 , 11 pages . PCT/ US2015 /031213 , International Preliminary Report on Patent PCT/ US2015 /031150 , International Search Report and Written Opin ability dated Nov . 22 , 2016 , 7 pages. ion dated Jan . 14 , 2016 . Nikaido et al. , “ Broad - specificity efflux pumps and their role in PCT/ US2015 /031213 , International Search Report and Written Opin multidrug resistance of Gram -negative bacteria , ” FEMS Microbial ion dated Sep . 2 , 2015 . Rev ., 36 :340 - 363 , 2012 . PCT/ US2015 /000280 , International Search Report and Written Opin ion dated May 2 , 2016 . * cited by examiner U . S . Patent Aug . 27, 2019 Sheet 1 of 26 US 10 , 391, 098 B2 Fig.1E Fig.10 Fig.1D Fig.1B * + + $. .t Fig.1A U . S . Patent Aug . 27, 2019 Sheet 2 of 26 US 10 , 391, 098 B2 Fig.16 EXR*RXRRRRXANHA . " - OWdd£1000 ACHÅRFSREFRFERIE XRKXARXRRXRX8.ACHN* U .S . Patentatent Aug . 27 , 2019 Sheet 3 of 26 US 10 , 391, 098 B2 . NO Tobraugimi 2+ 4XB )RXR (uM 1 E.coliAIS070834(MDR;NDM-1) Tobram /ug 2+ Scr UM 1 TA 9 *Topra4XBTobramycin )RXRuglmi ( uMmi 2 1/ +ug 2 # 2 PPMO AcpP UM 1 FIG.2A ControlScr UM 1 *2 #PPMO AcPP uM 1 . 000000000 00000000 h24 Treatment NO cum. Log onTreatment No U . S . Patent Aug. 27, 2019 Sheet 4 of 26 US 10 , 391 , 098 B2 AcPPPPMO#1 ScrPPMO CES h FIG.2B Concentration(UM)PPMO0008 -1)AIS070834(MDR;NDME.coli ST ** *ARE O )ml / ug ( Tobramycin MIC U . S . Patent Aug . 27, 2019 Sheet 5 of 26 US 10 , 391, 098 B2 AcppPPMO#1 ScrPPMO 000 gooox W 20 3 x FIG.2C E.coliAIS070834(MDR;NDM-1) PPMOConcentration(UM) HHHHHHHHH . :VO OOO opport 000$ Romora U . S . Patent Aug . 27, 2019 Sheet 6 of 26 US 10 , 391, 098 B2 +ControlColistin Scrml 24M/ 25ug .0 SOS Q . 1999 +7# PPMOColistin ACPPml / g2uM25 .0 2:32 AcinetobacterbaumaniiAYE Colistin.254cm .0 ControlScr 2uM 7#PPMO ACPP 2um 24hrTreatment No Boddess onrTreatment No CRUM U . S . Patent Aug . 27 , 2019 Sheet 7 of 26 US 10 ,391 , 098 B2 +Control MeropenemScr M ml2 /50ug .0 AcinetobacterbaumaniiAYE +7# MeropenemPPMO ACPP ml2uM/ 50mg .0 MeropenemmL /50ug .0 ControlScr 2UM 7#PPMO ACPP 2uM 24hrTreatment No ,101 100ohr Treatment No ORUML U . S . Patent Aug . 27 , 2019 Sheet 8 of 26 US 10 ,391 , 098 B2 +ControlTobramycin Scr 2umml /Bug Tobramycinml /8?g AcinetobacterbaumaniiAYE Tobramycin+7# PPMO ACPPSugu quelmi2UM 2t ControlScr 2uM .FIG 7#PPMO ACPP 2uM 24hrTreatment No ??????????????????????????88????????? 10111 1070 102 **onr Treatment No CUM U . S . Patent Aug . 27, 2019 Sheet 9 of 26 US 10 , 391, 098 B2 Colistinonly L#OWddddowD Scr 16 106 Hi povou 000000000000000 248 PPMO(UM] A.baumanniiAYE FIG.6 1 0 1.00, )mL pood / Vog ug[ ooooo poodColistin MIC U . S . Patent Aug . 27, 2019 Sheet 10 of 26 US 10 , 391, 098 B2 Meropenemonly L#Owddddoy Scr OD 16 WW 8 podos 4 PPMO(UM) 000 A.baumanniiAYE . ! sosssssssssssssssssssss 2 Bodo OOOOOOOOOOOOOOOOOOOO de 1 0 )10mL 1000 / ug( gooo Meropenem MIC U . S . Patent Aug . 27, 2019 Sheet 11 of 26 US 10 ,391 , 098 B2 TobramycinOnly ScrPPMON7 AoppDy . 9999 000000ccogooooo00000200000oooogoooo000000000000doogoooooooooo PPMO(UM) FIG.8 012A816 000000000.goooooooooo 0000oooooogoooooooooo W ) mL /ug ( Tobramycin MIC TTTTTT U . S . Patent Aug . 27, 2019 Sheet 12 of 26 US 10 , 391, 098 B2 RXR4-'3- SCR 24#PPMO 5#PPMO collW3110 4#PPMO FIG.9A 3#PPMO 2#PPMO minime mimiminiwiminimin 1#PPMO 8.3 U . S . Patent Aug . 27, 2019 Sheet 13 of 26 US 10 , 391, 098 B2 Scramble :: : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : :: Scramble 29#PPMO A :: : :: : : : : : : : : :: : :: : 34#PPMO PPMO mantanpacanamasapananalmasparamaanaserandesanatos33#PPMO FIG.9B : : : : : : : : : : : : : : : : : : : : : : : 14#PPMO : : : : : : : : : : : : : 13#PPMO :: : : : : : : : : :: : :: : 8#PPMO : : : : : : : : : : : :: : :: 7#PPMO Serie >> > (W ) DIW U . S . Patent Aug . 27, 2019 Sheet 14 of 26 US 10 , 391, 098 B2 Scramble Scramble 29#PPMO . 34#PPMO A.baumannii0057 33#PPMO FIG.9C .
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