CN116254246B - 工程化cas12b效应蛋白及其使用方法 - Google Patents

工程化cas12b效应蛋白及其使用方法

Info

Publication number
CN116254246B
CN116254246B CN202211581644.5A CN202211581644A CN116254246B CN 116254246 B CN116254246 B CN 116254246B CN 202211581644 A CN202211581644 A CN 202211581644A CN 116254246 B CN116254246 B CN 116254246B
Authority
CN
China
Prior art keywords
cas12b
engineered
amino acid
nuclease
nucleic acid
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.)
Active
Application number
CN202211581644.5A
Other languages
English (en)
Chinese (zh)
Other versions
CN116254246A (zh
Inventor
李伟
周琪
陈阳灿
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.)
Beijing Institute Of Stem Cell And Regenerative Medicine
Institute of Zoology of CAS
Original Assignee
Beijing Institute Of Stem Cell And Regenerative Medicine
Institute of Zoology of CAS
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 Beijing Institute Of Stem Cell And Regenerative Medicine, Institute of Zoology of CAS filed Critical Beijing Institute Of Stem Cell And Regenerative Medicine
Publication of CN116254246A publication Critical patent/CN116254246A/zh
Application granted granted Critical
Publication of CN116254246B publication Critical patent/CN116254246B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • 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
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/90—Stable introduction of foreign DNA into chromosome
    • C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
    • C12N15/907—Stable introduction of foreign DNA into chromosome using homologous recombination in mammalian cells
    • 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
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • 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
    • 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
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
    • 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
    • C12N15/113—Non-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
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6816—Hybridisation assays characterised by the detection means
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6816—Hybridisation assays characterised by the detection means
    • C12Q1/6823—Release of bound markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • 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
    • C12N15/113—Non-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
    • C12N15/1138—Non-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
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/20—Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPR]
    • 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
    • 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
    • C12N2800/00—Nucleic acids vectors
    • C12N2800/10—Plasmid DNA
    • C12N2800/106—Plasmid DNA for vertebrates
    • C12N2800/107—Plasmid DNA for vertebrates for mammalian
    • 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
    • C12N2800/00—Nucleic acids vectors
    • C12N2800/22—Vectors comprising a coding region that has been codon optimised for expression in a respective host

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Plant Pathology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Analytical Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Virology (AREA)
  • Cell Biology (AREA)
  • Mycology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
CN202211581644.5A 2021-12-09 2022-12-09 工程化cas12b效应蛋白及其使用方法 Active CN116254246B (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNPCT/CN2021/136761 2021-12-09
CN2021136761 2021-12-09

Publications (2)

Publication Number Publication Date
CN116254246A CN116254246A (zh) 2023-06-13
CN116254246B true CN116254246B (zh) 2025-09-23

Family

ID=86686936

Family Applications (2)

Application Number Title Priority Date Filing Date
CN202211581644.5A Active CN116254246B (zh) 2021-12-09 2022-12-09 工程化cas12b效应蛋白及其使用方法
CN202280079229.1A Pending CN118339285A (zh) 2021-12-09 2022-12-09 工程化Cas12b效应子蛋白及其使用方法

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN202280079229.1A Pending CN118339285A (zh) 2021-12-09 2022-12-09 工程化Cas12b效应子蛋白及其使用方法

Country Status (5)

Country Link
US (1) US20250051742A1 (https=)
EP (1) EP4444875A4 (https=)
JP (1) JP2025501473A (https=)
CN (2) CN116254246B (https=)
WO (1) WO2023104185A1 (https=)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025067403A1 (zh) * 2023-09-28 2025-04-03 上海天泽云泰生物医药有限公司 用于治疗血红蛋白疾病的组合物和方法
WO2025076291A1 (en) * 2023-10-06 2025-04-10 Bluerock Therapeutics Lp Engineered type v rna programmable endonucleases and their uses
WO2025096367A1 (en) * 2023-11-03 2025-05-08 University Of Florida Research Foundation, Inc. Thermostable and/or charge-engineered cas12a variants for nucleic acid detection
CN120330162A (zh) * 2023-12-06 2025-07-18 尧唐(上海)生物科技有限公司 一种Cas蛋白、包含其的CRISPR-Cas系统及其应用
CN120796267A (zh) * 2024-07-05 2025-10-17 上海天泽云泰生物医药有限公司 用于使用CRISPR/Cas系统进行基因编辑的经修饰的gRNA
WO2026060637A1 (en) * 2024-09-20 2026-03-26 Shanghai Vitalgen Biopharma Co., Ltd. Engineered mrna for gene editing using crispr/cas12b

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113308451A (zh) * 2020-12-07 2021-08-27 中国科学院动物研究所 工程化的Cas效应蛋白及其使用方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019127087A1 (zh) * 2017-12-27 2019-07-04 中国科学院动物研究所 基因组编辑系统和方法
WO2019178427A1 (en) * 2018-03-14 2019-09-19 Arbor Biotechnologies, Inc. Novel crispr dna targeting enzymes and systems
US20210292747A1 (en) * 2018-07-27 2021-09-23 The Regents Of The University Of Colorado, A Body Corporate Engineered chimeric nucleic acid guided nucleases compositions, methods for making, and systems for gene editing
JP2021532815A (ja) * 2018-08-07 2021-12-02 ザ・ブロード・インスティテュート・インコーポレイテッド 新規Ｃａｓ１２ｂ酵素およびシステム
WO2020081267A2 (en) * 2018-10-04 2020-04-23 The Regents Of The University Of Colorado, A Body Corporate Engineered chimeric nucleic acid guided nuclease constructs and uses thereof
MX2022004549A (es) * 2019-10-17 2022-07-21 Pairwise Plants Services Inc Variantes de nucleasas cas12a, metodos de fabricacion y uso de las mismas.
WO2021178934A1 (en) * 2020-03-06 2021-09-10 Metagenomi Ip Technologies, Llc Class ii, type v crispr systems
CN115851665B (zh) * 2021-05-27 2025-01-24 中国科学院动物研究所 工程化的Cas12i核酸酶及其效应蛋白以及用途
EP4349979A4 (en) * 2021-05-27 2024-08-21 Institute Of Zoology, Chinese Academy Of Sciences MANIPULATED CAS12I NUCLEASE, EFFECTOR PROTEIN AND USE THEREOF

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113308451A (zh) * 2020-12-07 2021-08-27 中国科学院动物研究所 工程化的Cas效应蛋白及其使用方法

Also Published As

Publication number Publication date
CN118339285A (zh) 2024-07-12
WO2023104185A1 (en) 2023-06-15
US20250051742A1 (en) 2025-02-13
EP4444875A4 (en) 2025-07-02
EP4444875A1 (en) 2024-10-16
JP2025501473A (ja) 2025-01-22
CN116254246A (zh) 2023-06-13

Similar Documents

Publication Publication Date Title
CN113308451B (zh) 工程化的Cas效应蛋白及其使用方法
CN115851665B (zh) 工程化的Cas12i核酸酶及其效应蛋白以及用途
CN116254246B (zh) 工程化cas12b效应蛋白及其使用方法
KR102935609B1 (ko) 유전자 편집을 위한 cpf1-관련 방법 및 조성물
US20240425830A1 (en) Engineered cas12i nuclease, effector protein and use thereof
WO2022040909A1 (en) Split cas12 systems and methods of use thereof
US20210277366A1 (en) ENHANCED hAT FAMILY TRANSPOSON-MEDIATED GENE TRANSFER AND ASSOCIATED COMPOSITIONS, SYSTEMS, AND METHODS
US11492614B2 (en) Stem loop RNA mediated transport of mitochondria genome editing molecules (endonucleases) into the mitochondria
WO2022120520A1 (en) Engineered cas effector proteins and methods of use thereof
JP7770447B2 (ja) タウの播種または凝集の遺伝的修飾因子を同定するためのｃｒｉｓｐｒ／ｃａｓスクリーニングプラットフォーム
CN119013395A (zh) 工程化的CasX核酸酶、效应蛋白及其用途
CN118632622A (zh) 突变型肌纤蛋白疾病模型及其用途
HK40094999B (zh) 工程化cas12b效应蛋白及其使用方法
HK40094999A (zh) 工程化cas12b效应蛋白及其使用方法
HK40109303A (en) Engineered cas12i nuclease, effector protein and use thereof
HK40054104B (en) Engineered cas12i nuclease as well as effector protein and use thereof
HK40054104A (en) Engineered cas12i nuclease as well as effector protein and use thereof
JP2025521154A (ja) Ｃ９ｏｒｆ７２反復伸長疾患のためのｃｒｉｓｐｒ干渉療法
CN119487200A (zh) 用于基因治疗方法的组织特异性基因外安全港的鉴定
HK40099049A (zh) 工程化的cas效应蛋白及其使用方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40094999

Country of ref document: HK

SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant