KR20240154682A - RNAi 활성을 갖는 화학 수식 올리고뉴클레오티드 - Google Patents

RNAi 활성을 갖는 화학 수식 올리고뉴클레오티드 Download PDF

Info

Publication number
KR20240154682A
KR20240154682A KR1020247034185A KR20247034185A KR20240154682A KR 20240154682 A KR20240154682 A KR 20240154682A KR 1020247034185 A KR1020247034185 A KR 1020247034185A KR 20247034185 A KR20247034185 A KR 20247034185A KR 20240154682 A KR20240154682 A KR 20240154682A
Authority
KR
South Korea
Prior art keywords
rna
oligonucleotide
nucleoside
ome
pharmaceutically acceptable
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.)
Pending
Application number
KR1020247034185A
Other languages
English (en)
Korean (ko)
Inventor
마코토 고이즈미
다카오 쇼지
다이치 후쿠나가
Original Assignee
다이이찌 산쿄 가부시키가이샤
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 다이이찌 산쿄 가부시키가이샤 filed Critical 다이이찌 산쿄 가부시키가이샤
Publication of KR20240154682A publication Critical patent/KR20240154682A/ko
Pending legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088Compounds having three or more nucleosides or nucleotides
    • A61K31/712Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088Compounds having three or more nucleosides or nucleotides
    • A61K31/7125Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088Compounds having three or more nucleosides or nucleotides
    • A61K31/713Double-stranded nucleic acids or oligonucleotides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549Sugars, nucleosides, nucleotides or nucleic acids
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/10Type of nucleic acid
    • C12N2310/14Type of nucleic acid interfering nucleic acids [NA]
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/30Chemical structure
    • C12N2310/31Chemical structure of the backbone
    • C12N2310/315Phosphorothioates
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/30Chemical structure
    • C12N2310/32Chemical structure of the sugar
    • C12N2310/3212'-O-R Modification
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/30Chemical structure
    • C12N2310/32Chemical structure of the sugar
    • C12N2310/3222'-R Modification
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/30Chemical structure
    • C12N2310/32Chemical structure of the sugar
    • C12N2310/323Chemical structure of the sugar modified ring structure
    • C12N2310/3231Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/30Chemical structure
    • C12N2310/35Nature of the modification
    • C12N2310/351Conjugate

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
KR1020247034185A 2022-03-16 2023-03-15 RNAi 활성을 갖는 화학 수식 올리고뉴클레오티드 Pending KR20240154682A (ko)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JPJP-P-2022-041865 2022-03-16
JP2022041865 2022-03-16
PCT/JP2023/009974 WO2023176863A1 (ja) 2022-03-16 2023-03-15 RNAi活性を有する化学修飾オリゴヌクレオチド

Publications (1)

Publication Number Publication Date
KR20240154682A true KR20240154682A (ko) 2024-10-25

Family

ID=88023882

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020247034185A Pending KR20240154682A (ko) 2022-03-16 2023-03-15 RNAi 활성을 갖는 화학 수식 올리고뉴클레오티드

Country Status (7)

Country Link
US (1) US20250188477A1 (https=)
EP (1) EP4495241A1 (https=)
JP (1) JPWO2023176863A1 (https=)
KR (1) KR20240154682A (https=)
CN (1) CN118871585A (https=)
TW (1) TW202400786A (https=)
WO (1) WO2023176863A1 (https=)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12454693B1 (en) * 2024-09-27 2025-10-28 Dexcel Pharma Technologies Ltd. Nucleic acids for inhibiting expression of transferrin receptor 2

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012058210A1 (en) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACIDS (siNA)
WO2013074974A2 (en) 2011-11-18 2013-05-23 Alnylam Pharmaceuticals, Inc. Modified rnai agents
WO2016028649A1 (en) 2014-08-20 2016-02-25 Alnylam Pharmaceuticals, Inc. Modified double-stranded rna agents

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7119184B2 (en) 1991-08-12 2006-10-10 Isis Pharmaceuticals, Inc. Oligonucleotides having A-DNA form and B-DNA form conformational geometry
JPH0787982A (ja) 1993-01-29 1995-04-04 Sankyo Co Ltd 修飾オリゴデオキシリボヌクレオチド
US6096881A (en) 1997-05-30 2000-08-01 Hybridon, Inc. Sulfur transfer reagents for oligonucleotide synthesis
JP4236812B2 (ja) 1997-09-12 2009-03-11 エクシコン エ/エス オリゴヌクレオチド類似体
ES2234563T5 (es) 1999-02-12 2018-01-17 Daiichi Sankyo Company, Limited Nuevos análogos de nucleósidos y oligonucleótidos
US6261840B1 (en) 2000-01-18 2001-07-17 Isis Pharmaceuticals, Inc. Antisense modulation of PTP1B expression
WO2009073809A2 (en) 2007-12-04 2009-06-11 Alnylam Pharmaceuticals, Inc. Carbohydrate conjugates as delivery agents for oligonucleotides
US20110196141A1 (en) 2009-09-07 2011-08-11 Council Of Scientific & Industrial Research Locked and unlocked 2'-o phosphoramidite nucleosides, process of preparation thereof and oligomers comprising the nucleosides
WO2011072082A2 (en) 2009-12-09 2011-06-16 Nitto Denko Corporation Modulation of hsp47 expression
WO2012074038A1 (ja) 2010-12-02 2012-06-07 第一三共株式会社 修飾1本鎖ポリヌクレオチド
EP2723861A4 (en) 2011-06-21 2014-12-10 Alnylam Pharmaceuticals Inc COMPOSITIONS AND METHODS FOR INHIBITING HEPCIDINE ANTIMICROBIAL PEPTIDE (HAMP) OR THE ASSOCIATED GENE EXPRESSION
EP3730618A1 (en) 2011-11-18 2020-10-28 Alnylam Pharmaceuticals, Inc. Rnai agents, compositions and methods of use thereof for treating transthyretin (ttr) associated diseases
CN104837996A (zh) 2012-11-15 2015-08-12 罗氏创新中心哥本哈根有限公司 抗apob反义缀合物化合物
WO2014109384A1 (ja) 2013-01-10 2014-07-17 塩野義製薬株式会社 架橋型核酸誘導体の製造方法
DK2992098T3 (da) 2013-05-01 2019-06-17 Ionis Pharmaceuticals Inc Sammensætninger og fremgangsmåder til modulering af hbv- og ttr-ekspression
WO2015006740A2 (en) 2013-07-11 2015-01-15 Alnylam Pharmaceuticals, Inc. Oligonucleotide-ligand conjugates and process for their preparation
JP6482475B2 (ja) 2014-01-07 2019-03-13 レナセラピューティクス株式会社 アンチセンスオリゴヌクレオチド及び糖誘導体を含む二本鎖オリゴヌクレオチド
US20170034685A1 (en) 2015-07-27 2017-02-02 Qualcomm Incorporated Lte-d2d discovery in the unlicensed band
KR102222186B1 (ko) 2015-08-13 2021-03-03 머크 샤프 앤드 돔 코포레이션 Sting 효능제로서 시클릭 디-뉴클레오티드 화합물
BR112018003910B1 (pt) 2015-11-16 2022-03-22 F. Hoffmann-La Roche Ag Derivado de fosforamidita galnac, processo para a preparação de um derivado de fosforamidita galnac de fórmula i e uso dos derivados de fosforamidita galnac de fórmula i
AU2017213404A1 (en) 2016-01-29 2018-09-20 Kyowa Kirin Co., Ltd. Nucleic acid conjugate
UY37695A (es) 2017-04-28 2018-11-30 Novartis Ag Compuesto dinucleótido cíclico bis 2’-5’-rr-(3’f-a)(3’f-a) y usos del mismo
KR102398295B1 (ko) 2018-03-09 2022-05-17 다이이찌 산쿄 가부시키가이샤 당원병 Ia형 치료약
JP2021520355A (ja) * 2018-04-13 2021-08-19 ディセルナ ファーマシューティカルズ インコーポレイテッド Tm上昇ヌクレオチドで修飾された二本鎖核酸阻害剤分子
KR20220062517A (ko) * 2019-08-15 2022-05-17 아이오니스 파마수티컬즈, 인코포레이티드 결합 변형된 올리고머 화합물 및 이의 용도
IL291251B1 (en) 2019-09-10 2026-02-01 Daiichi Sankyo Co Ltd Oligonucleotide-galnac conjugate for targeted delivery to the liver and method for its production
KR20220148241A (ko) * 2020-02-28 2022-11-04 알리고스 테라퓨틱스 인코포레이티드 Pd-l1을 표적화하기 위한 방법 및 조성물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012058210A1 (en) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACIDS (siNA)
WO2013074974A2 (en) 2011-11-18 2013-05-23 Alnylam Pharmaceuticals, Inc. Modified rnai agents
WO2016028649A1 (en) 2014-08-20 2016-02-25 Alnylam Pharmaceuticals, Inc. Modified double-stranded rna agents

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
Antisense and Nucleic Acid Drug Development, 2002년, 제12권, p. 301-309
Antisense Nucleic Acid Drug Development, 2000년, 제10권, p. 117-121
Biochemistry, 2003년, 제42권, p. 7967-7975
EMBO Journal, 2001년, 제20권, p. 6877-6888
Journal of Medical Chemistry, 1993년, 제36권, p. 831-841
Journal of Medical Chemistry, 2005년, 제48권, p. 4247-4253
Journal of Medicinal Chemistry., 2005년, 제48권, p. 901-904
Nature, 2001년, 제411권, p. 494-498
Nucleic Acids Research, 1987년, 제15권, p. 6131-6148
Nucleic Acids Research, 2003년, 제31권, p. 2705-2716
RNA, 제9권, 2003년, p. 1034-1048

Also Published As

Publication number Publication date
US20250188477A1 (en) 2025-06-12
JPWO2023176863A1 (https=) 2023-09-21
EP4495241A1 (en) 2025-01-22
CN118871585A (zh) 2024-10-29
WO2023176863A1 (ja) 2023-09-21
TW202400786A (zh) 2024-01-01

Similar Documents

Publication Publication Date Title
JP5637849B2 (ja) 2本鎖ポリヌクレオチド
EP3569711B1 (en) Ligand-modified double-stranded nucleic acids
JP5816556B2 (ja) 治療剤のためのunaオリゴマー構造
CN103555722B (zh) 利用不对称双链rna特异性抑制kras的方法和组合物
JP2022078069A (ja) 二本鎖RNAによるα-1アンチトリプシンの特異的阻害のための方法及び組成物
EP2647713B1 (en) Modified single-strand polynucleotide
WO2010093788A2 (en) Multiplex dicer substrate rna interference molecules having joining sequences
KR20220069103A (ko) 최소 플루오린 함량을 갖는 작은 간섭 rna의 화학적 변형
CN117120612A (zh) 用于抑制己酮糖激酶(khk)的组合物及方法
EP4495240A1 (en) Sirna for suppressing expression of transferrin receptor-2
CN117120613A (zh) 用于调节pnpla3表达的组合物和方法
KR20240002200A (ko) 막관통 세린 프로테아제 6(tmprss6) 발현을 억제하기 위한 조성물 및 방법
KR20240154682A (ko) RNAi 활성을 갖는 화학 수식 올리고뉴클레오티드
HK40114768A (en) Chemically-modified oligonucleotide having rnai activity
CA3255765A1 (en) Sirna for suppressing expression of transferrin receptor-2
HK40119182A (en) Sirna for suppressing expression of transferrin receptor-2
EP2495323A1 (en) Modified double-stranded polynucleotide
HK1155478A (en) Double-stranded polynucleotide
HK1189911A (en) Modified single-strand polynucleotide

Legal Events

Date Code Title Description
PA0105 International application

St.27 status event code: A-0-1-A10-A15-nap-PA0105

P11-X000 Amendment of application requested

St.27 status event code: A-2-2-P10-P11-nap-X000

P13-X000 Application amended

St.27 status event code: A-2-2-P10-P13-nap-X000

PG1501 Laying open of application

St.27 status event code: A-1-1-Q10-Q12-nap-PG1501

E13 Pre-grant limitation requested

Free format text: ST27 STATUS EVENT CODE: A-2-3-E10-E13-LIM-X000 (AS PROVIDED BY THE NATIONAL OFFICE)

E13-X000 Pre-grant limitation requested

St.27 status event code: A-2-3-E10-E13-lim-X000

P11 Amendment of application requested

Free format text: ST27 STATUS EVENT CODE: A-2-2-P10-P11-NAP-X000 (AS PROVIDED BY THE NATIONAL OFFICE)

P11-X000 Amendment of application requested

St.27 status event code: A-2-2-P10-P11-nap-X000

P13 Application amended

Free format text: ST27 STATUS EVENT CODE: A-2-2-P10-P13-NAP-X000 (AS PROVIDED BY THE NATIONAL OFFICE)

P13-X000 Application amended

St.27 status event code: A-2-2-P10-P13-nap-X000

P11 Amendment of application requested

Free format text: ST27 STATUS EVENT CODE: A-2-2-P10-P11-NAP-X000 (AS PROVIDED BY THE NATIONAL OFFICE)

P11-X000 Amendment of application requested

St.27 status event code: A-2-2-P10-P11-nap-X000

P13 Application amended

Free format text: ST27 STATUS EVENT CODE: A-2-2-P10-P13-NAP-X000 (AS PROVIDED BY THE NATIONAL OFFICE)

P13-X000 Application amended

St.27 status event code: A-2-2-P10-P13-nap-X000