JP2017522004A5 - - Google Patents
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- Publication number
- JP2017522004A5 JP2017522004A5 JP2016568430A JP2016568430A JP2017522004A5 JP 2017522004 A5 JP2017522004 A5 JP 2017522004A5 JP 2016568430 A JP2016568430 A JP 2016568430A JP 2016568430 A JP2016568430 A JP 2016568430A JP 2017522004 A5 JP2017522004 A5 JP 2017522004A5
- Authority
- JP
- Japan
- Prior art keywords
- seq
- antisense morpholino
- morpholino oligomer
- formula
- cpp
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000692 anti-sense effect Effects 0.000 claims description 65
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 64
- 108090000623 proteins and genes Proteins 0.000 claims description 32
- 102000004169 proteins and genes Human genes 0.000 claims description 32
- 108010051109 Cell-Penetrating Peptides Proteins 0.000 claims description 22
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 claims description 22
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 20
- 230000008685 targeting Effects 0.000 claims description 20
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 230000008238 biochemical pathway Effects 0.000 claims description 18
- 230000033077 cellular process Effects 0.000 claims description 18
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 14
- 230000003115 biocidal effect Effects 0.000 claims description 14
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- -1 4-methoxytrityl Chemical group 0.000 claims description 12
- 230000001580 bacterial effect Effects 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 108020004999 messenger RNA Proteins 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 229940113082 thymine Drugs 0.000 claims description 10
- 229940035893 uracil Drugs 0.000 claims description 10
- 241000894006 Bacteria Species 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000005647 linker group Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002773 nucleotide Substances 0.000 claims description 7
- 125000003729 nucleotide group Chemical group 0.000 claims description 7
- MHCMWGPPLOSCJY-UHFFFAOYSA-N 4-$l^{1}-azanylmorpholine Chemical compound [N]N1CCOCC1 MHCMWGPPLOSCJY-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
- 210000004899 c-terminal region Anatomy 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- 238000000034 method Methods 0.000 description 13
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 6
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 6
- 241000589291 Acinetobacter Species 0.000 description 4
- 239000004599 antimicrobial Substances 0.000 description 4
- 241000588722 Escherichia Species 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 230000014621 translational initiation Effects 0.000 description 3
- 241000588626 Acinetobacter baumannii Species 0.000 description 2
- 101710146995 Acyl carrier protein Proteins 0.000 description 2
- 108010003662 Chorismate synthase Proteins 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- 102000002278 Ribosomal Proteins Human genes 0.000 description 2
- 108010000605 Ribosomal Proteins Proteins 0.000 description 2
- 108091081024 Start codon Proteins 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 101710135912 50S ribosomal protein L28 Proteins 0.000 description 1
- 241000023308 Acca Species 0.000 description 1
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 description 1
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 description 1
- 102100032534 Adenosine kinase Human genes 0.000 description 1
- 108020000543 Adenylate kinase Proteins 0.000 description 1
- 101000634117 Arabidopsis thaliana RNA polymerase sigma factor sigD, chloroplastic Proteins 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102000007132 Carboxyl and Carbamoyl Transferases Human genes 0.000 description 1
- 108010072957 Carboxyl and Carbamoyl Transferases Proteins 0.000 description 1
- 108010078777 Colistin Proteins 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 102000005877 Peptide Initiation Factors Human genes 0.000 description 1
- 108010044843 Peptide Initiation Factors Proteins 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- 108010085193 UDP-N-acetylglucosamine 1-carboxyvinyltransferase Proteins 0.000 description 1
- 101150023061 acpP gene Proteins 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960003346 colistin Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000019439 energy homeostasis Effects 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 1
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 1
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 1
- 229940041153 polymyxins Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462000431P | 2014-05-19 | 2014-05-19 | |
| US62/000,431 | 2014-05-19 | ||
| US201562129746P | 2015-03-06 | 2015-03-06 | |
| US62/129,746 | 2015-03-06 | ||
| PCT/US2015/031213 WO2015179249A1 (en) | 2014-05-19 | 2015-05-15 | Antisense antibacterial compounds and methods |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2017522004A JP2017522004A (ja) | 2017-08-10 |
| JP2017522004A5 true JP2017522004A5 (OSRAM) | 2018-06-21 |
| JP6687542B2 JP6687542B2 (ja) | 2020-04-22 |
Family
ID=54554572
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016568430A Active JP6687542B2 (ja) | 2014-05-19 | 2015-05-15 | アンチセンス抗菌化合物および方法 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US10391098B2 (OSRAM) |
| EP (2) | EP3569252B1 (OSRAM) |
| JP (1) | JP6687542B2 (OSRAM) |
| AU (1) | AU2015264449B2 (OSRAM) |
| CA (1) | CA2948568A1 (OSRAM) |
| WO (1) | WO2015179249A1 (OSRAM) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0992230A3 (en) | 1998-10-08 | 2001-08-22 | KCI Licensing, Inc. | Medical pumping apparatus and related methods |
| WO2015175977A2 (en) | 2014-05-16 | 2015-11-19 | Geller Bruce L | Antisense antibacterial compounds and methods |
| US10391098B2 (en) | 2014-05-19 | 2019-08-27 | Board Of Regents, The University Of Texas System | Antisense antibacterial compounds and methods |
| EP3240794A4 (en) | 2014-12-31 | 2018-10-31 | Oregon State University | Antisense antibacterial compounds and methods |
| US10907158B2 (en) | 2015-12-23 | 2021-02-02 | Board Of Regents, The University Of Texas System | Antisense antibacterial compounds and methods |
| JP7393121B2 (ja) | 2015-12-23 | 2023-12-06 | オレゴン ステイト ユニバーシティー | アンチセンス抗菌化合物および方法 |
| MA45616A (fr) * | 2016-04-29 | 2019-03-06 | Sarepta Therapeutics Inc | Analogues d'oligonucléotide ciblant lmna humain |
| US20200283768A1 (en) * | 2017-10-23 | 2020-09-10 | Board Of Regents, The University Of Texas System | Antisense antibacterial compounds and methods |
| GB2579253A (en) | 2018-11-28 | 2020-06-17 | Pedanius Therapeutics Ltd | Antibacterial antisense agents |
| CN110885364B (zh) * | 2019-12-26 | 2021-02-02 | 江南大学 | 一种促进N-乙酰氨基葡萄糖生产的RamA转录因子突变体及其应用 |
Family Cites Families (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5521063A (en) | 1985-03-15 | 1996-05-28 | Antivirals Inc. | Polynucleotide reagent containing chiral subunits and methods of use |
| EP0215942B1 (en) | 1985-03-15 | 1995-07-12 | Antivirals Inc. | Polynucleotide assay reagent and method |
| US5217866A (en) | 1985-03-15 | 1993-06-08 | Anti-Gene Development Group | Polynucleotide assay reagent and method |
| US5166315A (en) | 1989-12-20 | 1992-11-24 | Anti-Gene Development Group | Sequence-specific binding polymers for duplex nucleic acids |
| US5506337A (en) | 1985-03-15 | 1996-04-09 | Antivirals Inc. | Morpholino-subunit combinatorial library and method |
| US5034506A (en) | 1985-03-15 | 1991-07-23 | Anti-Gene Development Group | Uncharged morpholino-based polymers having achiral intersubunit linkages |
| US5185444A (en) | 1985-03-15 | 1993-02-09 | Anti-Gene Deveopment Group | Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages |
| AU659482B2 (en) | 1991-06-28 | 1995-05-18 | Massachusetts Institute Of Technology | Localized oligonucleotide therapy |
| PT2111876E (pt) | 1995-12-18 | 2011-12-23 | Angiodevice Internat Gmbh | Composições de polímero reticulado e seus métodos de utilização |
| US6245747B1 (en) | 1996-03-12 | 2001-06-12 | The Board Of Regents Of The University Of Nebraska | Targeted site specific antisense oligodeoxynucleotide delivery method |
| US20060241075A1 (en) | 2001-05-18 | 2006-10-26 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of desmoglein gene expression using short interfering nucleic acid (siNA) |
| US20040029129A1 (en) | 2001-10-25 | 2004-02-12 | Liangsu Wang | Identification of essential genes in microorganisms |
| US6965025B2 (en) | 2001-12-10 | 2005-11-15 | Isis Pharmaceuticals, Inc. | Antisense modulation of connective tissue growth factor expression |
| CA2522184A1 (en) | 2003-04-17 | 2004-11-04 | The Trustees Of Columbia University In The City Of New York | Desmoglein 4 is a novel gene involved in hair growth |
| ES2351976T3 (es) | 2003-04-29 | 2011-02-14 | Avi Biopharma, Inc. | Composiciones para mejorar el transporte y la eficacia antisentido de análogos de ácidos nucleicos en células. |
| US20050288246A1 (en) | 2004-05-24 | 2005-12-29 | Iversen Patrick L | Peptide conjugated, inosine-substituted antisense oligomer compound and method |
| CA2875436A1 (en) | 2004-07-02 | 2006-08-17 | Sarepta Therapeutics, Inc. | Antisense antibacterial method and compound |
| US20060263798A1 (en) | 2005-02-11 | 2006-11-23 | International Business Machines Corporation | System and method for identification of MicroRNA precursor sequences and corresponding mature MicroRNA sequences from genomic sequences |
| AU2006267051B2 (en) * | 2005-07-13 | 2013-03-07 | Sarepta Therapeutics, Inc. | Antisense antibacterial method and compound |
| US8067571B2 (en) * | 2005-07-13 | 2011-11-29 | Avi Biopharma, Inc. | Antibacterial antisense oligonucleotide and method |
| US7790694B2 (en) | 2005-07-13 | 2010-09-07 | Avi Biopharma Inc. | Antisense antibacterial method and compound |
| WO2007025016A1 (en) | 2005-08-25 | 2007-03-01 | Texas Tech University System | Inhibition of metallo-beta-lactamase by double-stranded dna |
| CA2691673A1 (en) | 2007-06-29 | 2009-01-08 | Avi Biopharma, Inc. | Tissue specific peptide conjugates and methods |
| US20100016215A1 (en) | 2007-06-29 | 2010-01-21 | Avi Biopharma, Inc. | Compound and method for treating myotonic dystrophy |
| HRP20140646T1 (hr) | 2007-11-15 | 2014-09-26 | Sarepta Therapeutics, Inc. | Postupak sinteze morfolino oligomera |
| US8299206B2 (en) | 2007-11-15 | 2012-10-30 | Avi Biopharma, Inc. | Method of synthesis of morpholino oligomers |
| US8076476B2 (en) | 2007-11-15 | 2011-12-13 | Avi Biopharma, Inc. | Synthesis of morpholino oligomers using doubly protected guanine morpholino subunits |
| US20110269665A1 (en) | 2009-06-26 | 2011-11-03 | Avi Biopharma, Inc. | Compound and method for treating myotonic dystrophy |
| WO2011018798A2 (en) | 2009-08-14 | 2011-02-17 | Indian Association For The Cultivation Of Science | Morpholino-based antisense agent |
| US10017763B2 (en) | 2010-09-03 | 2018-07-10 | Sarepta Therapeutics, Inc. | dsRNA molecules comprising oligonucleotide analogs having modified intersubunit linkages and/or terminal groups |
| JP5831455B2 (ja) | 2010-09-30 | 2015-12-09 | 日本新薬株式会社 | モルホリノ核酸誘導体 |
| CA2817090A1 (en) | 2010-11-12 | 2012-05-18 | Sarepta Therapeutics, Inc. | Antisense antibacterial compounds and methods |
| US20120213663A1 (en) | 2011-02-23 | 2012-08-23 | King Fahd University Of Petroleum And Minerals | Method of removing e. coli bacteria from an aqueous solution |
| KR102229650B1 (ko) | 2011-05-05 | 2021-03-19 | 사렙타 쎄러퓨틱스, 인코퍼레이티드 | 펩타이드 올리고뉴클레오타이드 접합체 |
| US9161948B2 (en) | 2011-05-05 | 2015-10-20 | Sarepta Therapeutics, Inc. | Peptide oligonucleotide conjugates |
| KR101317263B1 (ko) | 2011-07-05 | 2013-10-10 | (주)지노첵 | 리얼타임 ｐｃｒ을 이용한 카바페넴 내성 장내균 검사 방법 및 키트 |
| WO2013011072A1 (en) | 2011-07-20 | 2013-01-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Carbapenemase and antibacterial treatment |
| WO2015175977A2 (en) | 2014-05-16 | 2015-11-19 | Geller Bruce L | Antisense antibacterial compounds and methods |
| US10391098B2 (en) | 2014-05-19 | 2019-08-27 | Board Of Regents, The University Of Texas System | Antisense antibacterial compounds and methods |
| EP3240794A4 (en) | 2014-12-31 | 2018-10-31 | Oregon State University | Antisense antibacterial compounds and methods |
| US10907158B2 (en) | 2015-12-23 | 2021-02-02 | Board Of Regents, The University Of Texas System | Antisense antibacterial compounds and methods |
| JP7393121B2 (ja) | 2015-12-23 | 2023-12-06 | オレゴン ステイト ユニバーシティー | アンチセンス抗菌化合物および方法 |
-
2015
- 2015-05-15 US US14/714,104 patent/US10391098B2/en active Active
- 2015-05-15 WO PCT/US2015/031213 patent/WO2015179249A1/en not_active Ceased
- 2015-05-15 CA CA2948568A patent/CA2948568A1/en active Pending
- 2015-05-15 AU AU2015264449A patent/AU2015264449B2/en active Active
- 2015-05-15 JP JP2016568430A patent/JP6687542B2/ja active Active
- 2015-05-15 EP EP19167404.3A patent/EP3569252B1/en active Active
- 2015-05-15 EP EP15795398.5A patent/EP3146047A4/en not_active Withdrawn
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