CN120349985A - 通过肝导向基因替代疗法治疗严重pku的改良的人pah的产生 - Google Patents

通过肝导向基因替代疗法治疗严重pku的改良的人pah的产生

Info

Publication number
CN120349985A
CN120349985A CN202510330069.9A CN202510330069A CN120349985A CN 120349985 A CN120349985 A CN 120349985A CN 202510330069 A CN202510330069 A CN 202510330069A CN 120349985 A CN120349985 A CN 120349985A
Authority
CN
China
Prior art keywords
pah
nucleic acid
variant
amino acid
pah polypeptide
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
CN202510330069.9A
Other languages
English (en)
Chinese (zh)
Inventor
S·库斯迪奥-穆尔
P·马纳瓦兰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genzyme Corp
Original Assignee
Genzyme Corp
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 Genzyme Corp filed Critical Genzyme Corp
Publication of CN120349985A publication Critical patent/CN120349985A/zh
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/52—Genes encoding for enzymes or proenzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • C12N15/864—Parvoviral vectors, e.g. parvovirus, densovirus
    • C12N15/8645—Adeno-associated virus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y114/00—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14)
    • C12Y114/16—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14) with reduced pteridine as one donor, and incorporation of one atom of oxygen (1.14.16)
    • C12Y114/16001—Phenylalanine 4-monooxygenase (1.14.16.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Biotechnology (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Plant Pathology (AREA)
  • Virology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
CN202510330069.9A 2018-10-12 2019-10-11 通过肝导向基因替代疗法治疗严重pku的改良的人pah的产生 Pending CN120349985A (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201862744944P 2018-10-12 2018-10-12
US62/744,944 2018-10-12
CN201980082127.3A CN113194982B (zh) 2018-10-12 2019-10-11 通过肝导向基因替代疗法治疗严重pku的改良的人pah的产生
PCT/US2019/055917 WO2020077250A1 (en) 2018-10-12 2019-10-11 Generation of improved human pah for treatment of severe pku by liver-directed gene replacement therapy

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201980082127.3A Division CN113194982B (zh) 2018-10-12 2019-10-11 通过肝导向基因替代疗法治疗严重pku的改良的人pah的产生

Publications (1)

Publication Number Publication Date
CN120349985A true CN120349985A (zh) 2025-07-22

Family

ID=68426839

Family Applications (2)

Application Number Title Priority Date Filing Date
CN202510330069.9A Pending CN120349985A (zh) 2018-10-12 2019-10-11 通过肝导向基因替代疗法治疗严重pku的改良的人pah的产生
CN201980082127.3A Active CN113194982B (zh) 2018-10-12 2019-10-11 通过肝导向基因替代疗法治疗严重pku的改良的人pah的产生

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201980082127.3A Active CN113194982B (zh) 2018-10-12 2019-10-11 通过肝导向基因替代疗法治疗严重pku的改良的人pah的产生

Country Status (16)

Country Link
US (1) US20210348135A1 (https=)
EP (2) EP3863662A1 (https=)
JP (2) JP2022504740A (https=)
KR (1) KR20210076051A (https=)
CN (2) CN120349985A (https=)
AR (1) AR116700A1 (https=)
AU (2) AU2019357039B2 (https=)
BR (1) BR112021006796A2 (https=)
CA (1) CA3116283A1 (https=)
CO (1) CO2021006060A2 (https=)
IL (1) IL282140A (https=)
MX (2) MX2021004213A (https=)
PH (1) PH12021550794A1 (https=)
SG (1) SG11202103614RA (https=)
TW (1) TW202035439A (https=)
WO (1) WO2020077250A1 (https=)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ762100A (en) 2017-08-09 2025-12-19 Bioverativ Therapeutics Inc Nucleic acid molecules and uses thereof
US11939601B2 (en) 2017-11-22 2024-03-26 Modernatx, Inc. Polynucleotides encoding phenylalanine hydroxylase for the treatment of phenylketonuria
EP3833766A1 (en) 2018-08-09 2021-06-16 Bioverativ Therapeutics Inc. Nucleic acid molecules and uses thereof for non-viral gene therapy
TW202140791A (zh) * 2020-01-13 2021-11-01 美商霍蒙拉奇醫藥公司 治療苯酮尿症之方法
AU2021261359A1 (en) * 2020-04-21 2022-12-08 Allen Institute Artificial expression constructs for selectively modulating gene expression in neocortical layer 5 glutamatergic neurons
JP2023524577A (ja) * 2020-05-05 2023-06-12 ザ・ユニヴァーシティ・オヴ・ノース・キャロライナ・アト・チャペル・ヒル 改変アデノ随伴ウイルス５カプシドおよびその使用
TW202208632A (zh) 2020-05-27 2022-03-01 美商同源醫藥公司 用於恢復ｐａｈ基因功能的腺相關病毒組成物及其使用方法
EP4158005A1 (en) * 2020-06-01 2023-04-05 ModernaTX, Inc. Phenylalanine hydroxylase variants and uses thereof
MX2023003805A (es) 2020-10-01 2023-04-12 Genzyme Corp Casete de expresion de pah humana para el tratamiento de la pku mediante terapia de reemplazo genico dirigida al higado.
AU2022332276A1 (en) * 2021-08-23 2024-04-04 Bioverativ Therapeutics Inc. Optimized factor viii genes
CN115572730A (zh) * 2022-04-24 2023-01-06 复旦大学附属中山医院 一种gtf2h4高表达的内皮细胞系
CN115772503B (zh) * 2022-08-16 2023-10-17 广东省南山医药创新研究院 一种表达pah的基因修饰细胞药物及其制备方法与应用
CN115948408A (zh) * 2022-09-23 2023-04-11 上海信致医药科技有限公司 改进的人凝血因子viii基因表达盒及其应用
CN117899238A (zh) * 2023-12-07 2024-04-19 哈尔滨工业大学 Pglyrp2基因的用途及其相关药物

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6989264B2 (en) 1997-09-05 2006-01-24 Targeted Genetics Corporation Methods for generating high titer helper-free preparations of released recombinant AAV vectors
US6566118B1 (en) 1997-09-05 2003-05-20 Targeted Genetics Corporation Methods for generating high titer helper-free preparations of released recombinant AAV vectors
DE69918090T2 (de) * 1998-04-24 2005-06-16 University Of Florida, Gainesville Rekombinanter adeno-assoziierter viraler vektor, der alpha-1 antitrypsin kodiert, zur gentherapie
CA2379166C (en) 1999-08-09 2013-03-26 Targeted Genetics Corporation Enhancement of expression of a single-stranded, heterologous nucleotide sequence from recombinant viral vectors by designing the sequence such that it forms instrastrand base pairs
ATE318923T1 (de) 2000-06-01 2006-03-15 Univ North Carolina Doppelsträngige parvovirus-vektoren
ATE437221T1 (de) * 2001-05-14 2009-08-15 Gbp Ip Llc Lentivirale vektoren kodierend für gerinnungsfaktoren für die gentherapie
US6723551B2 (en) 2001-11-09 2004-04-20 The United States Of America As Represented By The Department Of Health And Human Services Production of adeno-associated virus in insect cells
MX359371B (es) 2001-11-13 2018-09-25 Univ Pennsylvania Un metodo para detectar y/o identificar secuencias del virus adeno-asociado y aislamiento de secuencias novedosas identificadas de ese modo.
US7510872B2 (en) 2003-02-26 2009-03-31 Nationwide Children's Hospital Recombinant adeno-associated virus production
US7261544B2 (en) 2003-05-21 2007-08-28 Genzyme Corporation Methods for producing preparations of recombinant AAV virions substantially free of empty capsids
US7765583B2 (en) 2005-02-28 2010-07-27 France Telecom System and method for managing virtual user domains
WO2006119432A2 (en) 2005-04-29 2006-11-09 The Government Of The U.S.A., As Rep. By The Sec., Dept. Of Health & Human Services Isolation, cloning and characterization of new adeno-associated virus (aav) serotypes
US7588772B2 (en) 2006-03-30 2009-09-15 Board Of Trustees Of The Leland Stamford Junior University AAV capsid library and AAV capsid proteins
US8440182B2 (en) * 2007-05-24 2013-05-14 The Board Of Regents Of The University Of Texas System Methods and compositions for treating phenylketonuria
WO2010124180A1 (en) * 2009-04-23 2010-10-28 Phasebio Pharmaceuticals, Inc. Phenylalanine hydroxylase fusion protein and methods for treating phenylketonuria
KR20180000341A (ko) 2009-06-16 2018-01-02 젠자임 코포레이션 재조합 ａａｖ 벡터에 대한 개선된 정제 방법
US8663624B2 (en) 2010-10-06 2014-03-04 The Regents Of The University Of California Adeno-associated virus virions with variant capsid and methods of use thereof
TR201908020T4 (tr) 2011-02-17 2019-06-21 Univ Pennsylvania Doku özgüllüğünü değiştirmek ve aav9-aracılı gen transferini geliştirmek için bileşimler ve yöntemler.
CA2836921C (en) * 2011-06-07 2020-08-18 Wisconsin Alumni Research Foundation Hepatocyte based insulin gene therapy for diabetes
FR2978457A1 (fr) * 2011-07-27 2013-02-01 Univ Paris Diderot Paris 7 Composes contenant un vecteur viral a specificite hepatique et presentant une activite anti-inflammatoire
EP3044231B1 (en) * 2013-09-12 2020-08-05 BioMarin Pharmaceutical Inc. Aav vectors comprising a gene encoding factor viii
LT3137497T (lt) * 2014-05-02 2021-07-26 Genzyme Corporation Aav vektoriai, skirti tinklainės ir cns genų terapijai
WO2016037931A1 (en) * 2014-09-11 2016-03-17 Fundación Para La Investigación Médica Aplicada Nucleic acid constructs and expression vectors for gene therapy of acute porphyrias and other diseases
CR20170406A (es) * 2015-02-10 2017-11-14 Genzyme Corp Arni variante
TWI707951B (zh) * 2015-04-08 2020-10-21 美商健臻公司 過大腺相關載體之製造
EP3283126B1 (en) * 2015-04-16 2019-11-06 Emory University Recombinant promoters and vectors for protein expression in liver and use thereof
MX2018012537A (es) * 2016-04-15 2019-02-25 Univ Pennsylvania Terapia de genes para tratar hemofilia a.
EP3293260A1 (en) * 2016-09-12 2018-03-14 Genethon Acid-alpha glucosidase variants and uses thereof
MX2019006803A (es) * 2016-12-13 2019-11-18 Am Sciences Inc Composicion farmaceutica para prevenir o tratar la hepatitis b.
KR102738752B1 (ko) * 2016-12-30 2024-12-06 더 트러스티스 오브 더 유니버시티 오브 펜실베니아 페닐케톤뇨증을 치료하기 위한 유전자 치료
WO2019028273A1 (en) * 2017-08-02 2019-02-07 Dna2.0, Inc. Dba Atum DNA VECTORS AND ELEMENTS FOR SUSTAINED GENE EXPRESSION IN EUKARYOTIC CELLS
MX2023003805A (es) * 2020-10-01 2023-04-12 Genzyme Corp Casete de expresion de pah humana para el tratamiento de la pku mediante terapia de reemplazo genico dirigida al higado.

Also Published As

Publication number Publication date
BR112021006796A2 (pt) 2021-07-20
AU2019357039A1 (en) 2021-06-03
CN113194982B (zh) 2025-04-01
MX2025013445A (es) 2025-12-01
KR20210076051A (ko) 2021-06-23
AU2025237999A1 (en) 2025-10-23
EP4461814A2 (en) 2024-11-13
TW202035439A (zh) 2020-10-01
JP2022504740A (ja) 2022-01-13
SG11202103614RA (en) 2021-05-28
PH12021550794A1 (en) 2021-12-13
MX2021004213A (es) 2021-07-16
CA3116283A1 (en) 2020-04-16
CN113194982A (zh) 2021-07-30
EP3863662A1 (en) 2021-08-18
EP4461814A3 (en) 2025-02-26
AU2019357039B2 (en) 2025-10-09
JP2024123125A (ja) 2024-09-10
IL282140A (en) 2021-05-31
AR116700A1 (es) 2021-06-02
WO2020077250A1 (en) 2020-04-16
CO2021006060A2 (es) 2021-05-20
US20210348135A1 (en) 2021-11-11

Similar Documents

Publication Publication Date Title
CN113194982B (zh) 通过肝导向基因替代疗法治疗严重pku的改良的人pah的产生
US20250179522A1 (en) Human pah expression cassette for treatment of pku by liver-directed gene replacement therapy
KR20250131772A (ko) 전두측두엽 치매에 대한 유전자 요법
JP2023509443A (ja) 改善されたａａｖ－ａｂｃｄ１コンストラクトならびに副腎白質ジストロフィー（ａｌｄ）および／または副腎脊髄ニューロパチー（ａｍｎ）の処置または予防のための使用
AU2020229772A1 (en) Compositions useful in treatment of krabbe disease
RU2839587C2 (ru) Получение улучшенной человеческой pah для лечения тяжелой pku с помощью генной заместительной терапии, направленной на печень
JP2025521111A (ja) 異染性白質ジストロフィーを治療する方法
HK40116806A (en) Generation of improved human pah for treatment of severe pku by liver-directed gene replacement therapy
EP4465998A1 (en) Gene therapy for gaucher disease
RU2848343C1 (ru) Кассета экспрессии pah человека для лечения pku с помощью направленной на печень генной заместительной терапии
CN116648503A (zh) 通过肝导向基因替代疗法治疗pku的人pah表达盒
US20250297286A1 (en) METHODS AND COMPOSITIONS FOR THE PRODUCTION OF RECOMBINANT ADENO-ASSOCIATED VIRUS (rAAV) VECTORS
WO2024236032A1 (en) Gene therapies for phenylketonuria

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination