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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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    Ref. Ares(2019)6843167 - 05/11/2019 31 October 2019 EMA/CVMP/158366/2019 Committee for Medicinal Products for Veterinary Use Advice on implementing measures under Article 37(4) of Regulation (EU) 2019/6 on veterinary medicinal products – Criteria for the designation of antimicrobials to be reserved for treatment of certain infections in humans Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Introduction On 6 February 2019, the European Commission sent a request to the European Medicines Agency (EMA) for a report on the criteria for the designation of antimicrobials to be reserved for the treatment of certain infections in humans in order to preserve the efficacy of those antimicrobials. The Agency was requested to provide a report by 31 October 2019 containing recommendations to the Commission as to which criteria should be used to determine those antimicrobials to be reserved for treatment of certain infections in humans (this is also referred to as ‘criteria for designating antimicrobials for human use’, ‘restricting antimicrobials to human use’, or ‘reserved for human use only’). The Committee for Medicinal Products for Veterinary Use (CVMP) formed an expert group to prepare the scientific report. The group was composed of seven experts selected from the European network of experts, on the basis of recommendations from the national competent authorities, one expert nominated from European Food Safety Authority (EFSA), one expert nominated by European Centre for Disease Prevention and Control (ECDC), one expert with expertise on human infectious diseases, and two Agency staff members with expertise on development of antimicrobial resistance .
  • Beta Lactam Antibiotics Penicillins Pharmaceutical

    Beta Lactam Antibiotics Penicillins Pharmaceutical

    BETA LACTAM ANTIBIOTICS PENICILLINS PHARMACEUTICAL CHEMISTRY II PHA386 PENICILLINS Penicillin was discovered in 1928 by Scottish scientist Alexander Fleming, who noticed that one of his experimental cultures of staphylococcus was contaminated with mold (fortuitous accident), which caused the bacteria to lyse. Since mold belonged to the family Penicillium (Penicillium notatum), he named the antibacterial substance Penicillin. Penicillin core structure CHEMICAL STRUCTURE PENAM RING PENICILLIN G 6-APA • 6-APA is the chemical compound (+)-6-aminopenicillanic acid. • It is the core of penicillin. PENAM RING 5 1 • 7-oxo-1- thia-4-azabicylo [3,2,0] heptane 6 2 7 3 4 PENICILLANIC ACID • 2,2–dimethyl penam –3– carboxylic acid • 2,2-dimethyl-7-oxo-1- thia-4-azabicylo [3,2,0]heptane -3-carboxylic acid 6-AMINO PENICILLANIC ACID (6-APA) • 6-amino-2,2–dimethyl penam –3– carboxylic acid • 6-amino-2,2-dimethyl-7-oxo-1- thia-4-azabicylo [3,2,0] heptane-3-carboxylic acid PENISILLIN G (BENZYL PENICILLIN) O S CH3 CH2 C NH CH3 N O COO-K+ 6-(2-Phenylacetamino) penicillanic acid potassium salt PENICILLIN G PROCAINE O C 2 H 5 ‐ H N C H 2 C H 2 O C N H 2 C 2 H 5 PENICILLIN G BENZATHINE ‐ ‐ C H 2 C H 2 H N C H 2 C H 2 N H H H PENICILLIN V (PHENOXYMETHYL PENICILLIN) PHENETHICILLIN PROPACILLIN METHICILLIN SODIUM OCH3 S CH3 CONH CH3 N - + OCH3 O COO Na 6-[(2,6-dimethoxybenzoyl)amino] penicillanic acid sodium salt NAFCILLIN SODIUM 6-(2-ethoxy-1-naphtylcarbonylamino) penicillanic acid sodium salt OXACILLIN SODIUM 6-[(5-methyl-3-phenylizoxazole-4-yl)-carbonylamino] sodium
  • 2-Substituted Methyl Penam Derivatives 2-Substituierte Methyl-Penam-Derivate Dérivés 2-Substitués Du Méthyl Pénam

    2-Substituted Methyl Penam Derivatives 2-Substituierte Methyl-Penam-Derivate Dérivés 2-Substitués Du Méthyl Pénam

    (19) TZZ ZZ _T (11) EP 2 046 802 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: C07D 499/87 (2006.01) C07D 499/21 (2006.01) of the grant of the patent: C07D 499/28 (2006.01) C07D 499/32 (2006.01) 21.08.2013 Bulletin 2013/34 A61K 31/431 (2006.01) A61P 31/00 (2006.01) (21) Application number: 07804590.3 (86) International application number: PCT/IB2007/001941 (22) Date of filing: 11.07.2007 (87) International publication number: WO 2008/010048 (24.01.2008 Gazette 2008/04) (54) 2-SUBSTITUTED METHYL PENAM DERIVATIVES 2-SUBSTITUIERTE METHYL-PENAM-DERIVATE DÉRIVÉS 2-SUBSTITUÉS DU MÉTHYL PÉNAM (84) Designated Contracting States: • SRIRAM, Rajagopal AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Chennai, Tamil Nadu 600 119 (IN) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • PAUL-SATYASEELA, Maneesh SI SK TR Chennai, Tamil Nadu 600 119 (IN) • SOLANKI, Shakti, Singh (30) Priority: 12.07.2006 IN CH12172006 Chennai, Tamil Nadu 600 119 (IN) • DEVARAJAN, Sathishkumar (43) Date of publication of application: Chennai, Tamil Nadu 600 119 (IN) 15.04.2009 Bulletin 2009/16 (74) Representative: Murphy, Colm Damien et al (73) Proprietor: Allecra Therapeutics GmbH Ipulse 79539 Lörrach (DE) Carrington House 126-130 Regent Street (72) Inventors: London W1B 5SE (GB) • UDAYAMPALAYAM, Palanisamy, Senthilkumar Chennai, Tamil Nadu 600 119 (IN) (56) References cited: • GNANAPRAKASAM, Andrew EP-A1- 0 097 446 EP-A1- 0 367 124 Chennai, Tamil Nadu 600 119 (IN) JP-A- 60 215 688 US-A1- 2005 070 705 • GANAPATHY, Panchapakesan US-A1- 2005