CN104781007B - 循环肿瘤细胞的体外捕获和分析 - Google Patents

循环肿瘤细胞的体外捕获和分析 Download PDF

Info

Publication number
CN104781007B
CN104781007B CN201380058487.2A CN201380058487A CN104781007B CN 104781007 B CN104781007 B CN 104781007B CN 201380058487 A CN201380058487 A CN 201380058487A CN 104781007 B CN104781007 B CN 104781007B
Authority
CN
China
Prior art keywords
seprase
epcam
affinity reagent
targeting
ctcs
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
CN201380058487.2A
Other languages
English (en)
Chinese (zh)
Other versions
CN104781007A (zh
Inventor
G.A.马丁
S.索珀
M.韦特克
J.J.叶
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.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
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 F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of CN104781007A publication Critical patent/CN104781007A/zh
Application granted granted Critical
Publication of CN104781007B publication Critical patent/CN104781007B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
    • G01N33/5759—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites involving compounds localised on the membrane of tumour or cancer cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96433—Serine endopeptidases (3.4.21)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96466—Cysteine endopeptidases (3.4.22)

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • General Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Cell Biology (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Food Science & Technology (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Clinical Laboratory Science (AREA)
  • Dispersion Chemistry (AREA)
  • Zoology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Oncology (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
CN201380058487.2A 2012-11-09 2013-11-08 循环肿瘤细胞的体外捕获和分析 Active CN104781007B (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201261724753P 2012-11-09 2012-11-09
US61/724753 2012-11-09
PCT/EP2013/073381 WO2014072465A1 (en) 2012-11-09 2013-11-08 In vitro capture and analysis of circulating tumor cells

Publications (2)

Publication Number Publication Date
CN104781007A CN104781007A (zh) 2015-07-15
CN104781007B true CN104781007B (zh) 2017-11-17

Family

ID=49582733

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201380058487.2A Active CN104781007B (zh) 2012-11-09 2013-11-08 循环肿瘤细胞的体外捕获和分析

Country Status (7)

Country Link
US (2) US9250242B2 (https=)
EP (1) EP2919910B1 (https=)
JP (1) JP6404824B2 (https=)
CN (1) CN104781007B (https=)
CA (1) CA2891028C (https=)
ES (1) ES2660438T3 (https=)
WO (1) WO2014072465A1 (https=)

Families Citing this family (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10155988B2 (en) * 2010-04-07 2018-12-18 Board Of Regents, The University Of Texas System Methods of detecting tumor cells
TWI539158B (zh) * 2010-06-08 2016-06-21 維里德克斯有限責任公司 使用血液中之循環黑色素瘤細胞預測黑色素瘤病患之臨床結果的方法。
WO2012170560A2 (en) 2011-06-06 2012-12-13 Cornell University Microfluidic device for extracting, isolating, and analyzing dna from cells
US10130946B2 (en) 2011-09-30 2018-11-20 The Regents Of The University Of Michigan System for detecting rare cells
WO2013049636A1 (en) 2011-09-30 2013-04-04 The Regents Of The University Of Michigan System for detecting rare cells
US10073024B2 (en) 2012-10-29 2018-09-11 The Regents Of The University Of Michigan Microfluidic device and method for detecting rare cells
WO2014072465A1 (en) 2012-11-09 2014-05-15 Roche Diagnostics Gmbh In vitro capture and analysis of circulating tumor cells
EP2799872B1 (en) * 2013-05-01 2017-10-18 F. Hoffmann-La Roche AG Selective release of sub-group of biological units
US20150160246A1 (en) 2013-12-11 2015-06-11 Analiza, Inc. Devices and methods for determining and/or isolating cells such as circulating cancer or fetal cells
US9709556B2 (en) 2013-12-11 2017-07-18 Analiza, Inc. Devices and methods for determining and/or isolating circulating cancer cells
CA2959072C (en) * 2014-08-25 2025-12-09 Creatv Microtech, Inc. Use of circulating cell biomarkers in the blood for detection and diagnosis of diseases and methods of isolating them
US10829804B2 (en) 2015-03-23 2020-11-10 The University Of North Carolina At Chapel Hill Method for identification and enumeration of nucleic acid sequences, expression, splice variant, translocation, copy, or DNA methylation changes using combined nuclease, ligase, polymerase, terminal transferase, and sequencing reactions
ES2856691T3 (es) 2015-03-23 2021-09-28 Univ North Carolina Chapel Hill Procesador molecular universal para la medicina de precisión
US10317406B2 (en) 2015-04-06 2019-06-11 The Regents Of The University Of Michigan System for detecting rare cells
CN105259096B (zh) * 2015-10-19 2018-01-12 武汉顺可达生物科技有限公司 磷酸锌纳米基底及其制备方法和在循环肿瘤细胞捕获与释放中的应用
CN106868098A (zh) * 2015-12-10 2017-06-20 益善生物技术股份有限公司 循环肿瘤细胞分型鉴定试剂盒
CN108884445A (zh) 2016-03-09 2018-11-23 北京智康博药肿瘤医学研究有限公司 肿瘤细胞悬浮培养物和相关方法
JPWO2017188346A1 (ja) * 2016-04-27 2019-02-28 国立大学法人 東京大学 マイクロファイバーを用いた血中循環細胞の捕捉及び回収用材料及び当該材料を用いる方法
US20190113510A1 (en) * 2016-05-18 2019-04-18 Sony Corporation Biological material analysis device, biological material analysis system, biological material selection method, biological material analysis program, and cell culture vessel
US11602747B2 (en) 2016-05-22 2023-03-14 Cornell University Multifunctional microfluidic device for capturing target cells and analyzing genomic DNA isolated from the target cells while under flow conditions
CN107475354A (zh) * 2016-06-08 2017-12-15 益善生物技术股份有限公司 前列腺癌组织溯源ctc分型鉴定试剂盒
CN107475355A (zh) * 2016-06-08 2017-12-15 益善生物技术股份有限公司 肺癌早期筛查试剂盒
CN106366197B (zh) * 2016-08-31 2021-03-30 上海美吉生物医药科技有限公司 一种HER2、EGFR、EpCAM、MUC1多重抗体免疫磁珠及其制备方法
CN106434904A (zh) * 2016-09-07 2017-02-22 上海交通大学医学院附属仁济医院 一种实时监控肝癌复发或转移的CD133、EpCAM和CK19联合检测试剂盒
CN116474108A (zh) 2016-12-14 2023-07-25 普渡研究基金会 成纤维细胞活化蛋白(fap)-靶向成像和治疗
US20200088731A1 (en) * 2016-12-22 2020-03-19 Hitachi Chemical Company, Ltd. Method for Detecting HER2-Positive Cancer Cells
CN106866820B (zh) * 2017-02-17 2020-04-03 艾比玛特医药科技（上海）有限公司 一种用于捕获肿瘤细胞的抗人角蛋白18的单克隆抗体及其应用
CN110573629B (zh) * 2017-03-30 2024-08-13 伊利诺伊大学理事会 用于诊断早期胰腺癌的方法和试剂盒
EP3735281B1 (en) 2018-01-05 2024-11-27 Path Ex, Inc. Device for the capture and removal of disease material from fluids
CN108344615B (zh) * 2018-01-24 2020-10-23 杭州安弼晟生物科技有限公司 一种循环肿瘤细胞捕获系统及控制方法
CA3103714A1 (en) * 2018-06-13 2019-12-19 23Ikigai Pte Ltd Method for analysing pluripotent stem cell biomarkers, and implementations thereof
EP3870969A4 (en) * 2018-10-24 2022-07-27 Path Ex, Inc. PROCESS FOR RECOVERING AND ISOLATION OF DISEASE MATERIAL FROM FLOWING MATERIAL
US12303899B2 (en) 2018-11-28 2025-05-20 Cornell University Systems and methods for on-chip analysis of nucleic acids and for multiplexed analysis of cells
US12338487B2 (en) 2018-11-28 2025-06-24 Cornell University Multiomic analysis of cell analytes using microfluidic systems
WO2020139211A1 (en) 2018-12-28 2020-07-02 Mikro Biyosistemler Elektronik Sanayi Ve Ticaret A.S. A microfluidic device for selective capture of biological entities
CN110082529B (zh) * 2019-03-11 2022-04-19 南方医科大学深圳医院 一种肿瘤细胞表面标志物及其应用
CN112143732B (zh) * 2019-06-28 2022-03-22 中国科学院苏州纳米技术与纳米仿生研究所 特异性识别N-cadherin的ssDNA适配体、其筛选方法及应用
US12053569B2 (en) 2019-09-04 2024-08-06 The Regents Of The University Of Michigan Indwelling intravascular aphaeretic system for in vivo enrichment of circulating tumor cells
WO2021241283A1 (ja) * 2020-05-25 2021-12-02 東京応化工業株式会社 ターゲット粒子の分離方法およびシステム
US20230242983A1 (en) * 2020-07-06 2023-08-03 Sony Group Corporation Bioparticle analysis method and bioparticle analysis system
CN112569362B (zh) * 2020-12-23 2022-05-17 北京航空航天大学 一种通过打散ctc细胞团抑制肿瘤转移的方法
CN112924363A (zh) * 2021-01-22 2021-06-08 中国科学院苏州纳米技术与纳米仿生研究所 中间型循环肿瘤细胞作为肿瘤诊断和预后标志物及其应用
EP4284911A4 (en) * 2021-01-27 2025-01-08 BioFluidica, Inc. High efficiency capture of fetal cells from maternal samples
CN112730840B (zh) * 2021-01-29 2023-10-17 章毅 鉴别cd44和cd24分子表型的方法
US12576194B2 (en) 2021-06-29 2026-03-17 Regents Of The University Of Michigan Microfluidic flow control using direct-current peristaltic pump
CN114874989B (zh) * 2022-04-11 2024-06-25 中国科学院苏州纳米技术与纳米仿生研究所 一种循环肿瘤细胞捕获方法
EP4564006A1 (en) * 2022-07-29 2025-06-04 Fan-Gang Tseng Cell identification method

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020825A1 (en) * 2000-09-09 2002-03-14 The Research Foundation Of State University Of New York Method and compositions for isolating metastatic cancer cells, and use in measuring metastatic potential of a cancer thereof
WO2005043121A2 (en) * 2003-10-31 2005-05-12 Vitatex, Inc. Blood test prototypes and methods for the detection of circulating tumor and endothelial cells
WO2008131048A2 (en) * 2007-04-16 2008-10-30 Cellpoint Diagnotics, Inc. Devices and methods for diagnosing, prognosing, or theranosing a condition by enriching rare cells
CN102405411A (zh) * 2009-03-18 2012-04-04 加利福尼亚大学董事会 用于捕获循环细胞的装置
CN202279815U (zh) * 2011-07-19 2012-06-20 西门子公司 循环肿瘤细胞捕获装置

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999041613A1 (en) * 1998-02-12 1999-08-19 Immunivest Methods and reagents for the rapid and efficient isolation of circulating cancer cells
EP2201134B1 (en) 2007-09-19 2018-11-21 The Research Foundation of State University of New York Gene expression signatures in enriched tumor cell samples
MX2010004671A (es) 2007-12-10 2010-05-27 Hoffmann La Roche Seprasa como marcador para cancer.
EP2291509B1 (en) 2008-05-16 2023-11-15 Board of Supervisors of Louisiana State University and Agricultural and Mechanical College Microfluidic isolation of tumor cells or other rare cells from whole blood or other liquids
GR1006582B (el) 2008-07-14 2009-11-03 Ελενη Στυλιανου Μωυσιαδου Προϊοντα καθαρισμου και απολυμανσης με φυσικα αβλαβη υλικα που εχουν βαση την ζαχαρη
US20100210989A1 (en) * 2008-12-23 2010-08-19 Janet Lesley Macpherson Processing blood
AU2010229924B2 (en) 2009-03-24 2016-07-21 Plus Therapeutics Inc. Devices and methods of cell capture and analysis
US20120077246A1 (en) 2009-04-24 2012-03-29 The Board Of Trustees Of The University Of Illinoi Methods and Devices for Capturing Circulating Tumor Cells
ES2687144T3 (es) 2011-02-03 2018-10-23 Northeastern University Métodos y composiciones para la captura y liberación altamente específicas de materiales biológicos
WO2014072465A1 (en) 2012-11-09 2014-05-15 Roche Diagnostics Gmbh In vitro capture and analysis of circulating tumor cells

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020825A1 (en) * 2000-09-09 2002-03-14 The Research Foundation Of State University Of New York Method and compositions for isolating metastatic cancer cells, and use in measuring metastatic potential of a cancer thereof
WO2005043121A2 (en) * 2003-10-31 2005-05-12 Vitatex, Inc. Blood test prototypes and methods for the detection of circulating tumor and endothelial cells
WO2008131048A2 (en) * 2007-04-16 2008-10-30 Cellpoint Diagnotics, Inc. Devices and methods for diagnosing, prognosing, or theranosing a condition by enriching rare cells
CN102405411A (zh) * 2009-03-18 2012-04-04 加利福尼亚大学董事会 用于捕获循环细胞的装置
CN202279815U (zh) * 2011-07-19 2012-06-20 西门子公司 循环肿瘤细胞捕获装置

Also Published As

Publication number Publication date
US20160139116A1 (en) 2016-05-19
EP2919910A1 (en) 2015-09-23
EP2919910B1 (en) 2017-12-20
US20140134646A1 (en) 2014-05-15
CA2891028C (en) 2017-02-07
JP2015537210A (ja) 2015-12-24
WO2014072465A1 (en) 2014-05-15
CA2891028A1 (en) 2014-05-15
CN104781007A (zh) 2015-07-15
ES2660438T3 (es) 2018-03-22
US9250242B2 (en) 2016-02-02
JP6404824B2 (ja) 2018-10-17
US9952212B2 (en) 2018-04-24

Similar Documents

Publication Publication Date Title
CN104781007B (zh) 循环肿瘤细胞的体外捕获和分析
Park et al. Enhanced isolation and release of circulating tumor cells using nanoparticle binding and ligand exchange in a microfluidic chip
Tayebi et al. Exosome purification and analysis using a facile microfluidic hydrodynamic trapping device
Trinidad et al. Reducing ovarian cancer mortality through early detection: approaches using circulating biomarkers
Xu et al. Magnetic-based microfluidic device for on-chip isolation and detection of tumor-derived exosomes
Dong et al. Nanostructured substrates for detection and characterization of circulating rare cells: from materials research to clinical applications
Zhou et al. Integrated microfluidic device for accurate extracellular vesicle quantification and protein markers analysis directly from human whole blood
Cheng et al. Three-dimensional scaffold chip with thermosensitive coating for capture and reversible release of individual and cluster of circulating tumor cells
Stoecklein et al. Challenges for CTC-based liquid biopsies: low CTC frequency and diagnostic leukapheresis as a potential solution
Brown et al. Characterization of circulating tumor cells as a reflection of the tumor heterogeneity: myth or reality?
Li et al. Dual-aptamer-targeted immunomagnetic nanoparticles to accurately explore the correlations between circulating tumor cells and gastric cancer
Yin et al. Molecular profiling of pooled circulating tumor cells from prostate cancer patients using a dual-antibody-functionalized microfluidic device
US20160091489A1 (en) Devices and methods for isolating cells
CN105980615A (zh) 寡核苷酸探针及其用途
US11865541B2 (en) Dual-depth thermoplastic microfluidic device and related systems and methods
Zhu et al. Dynamically monitoring the clonal evolution of lung cancer based on the molecular characterization of circulating tumor cells using aptamer cocktail-modified nanosubstrates
Lou et al. Dual-functional lipid coating for the nanopillar-based capture of circulating tumor cells with high purity and efficiency
Wang et al. Digital circulating tumor cells quantification
Li et al. Biofluid-based circulating tumor molecules as diagnostic tools for use in personalized medicine
WO2018107930A1 (zh) 外周血循环肿瘤细胞检测体系及其应用
Tveito et al. Analysis of EpCAM positive cells isolated from sentinel lymph nodes of breast cancer patients identifies subpopulations of cells with distinct transcription profiles
Kamal et al. Circulating tumor cells in breast cancer: a potential liquid biopsy
WO2021198303A1 (en) New method of prostate cancer diagnosis
Si et al. Fusion of Molecular and Mechanical Phenotypes Enables High-Purity and Low-Loss Reacquisition of Viable CTCs for Transcriptome Analysis
Zhang Extracellular Vesicles as Emerging Biomarkers for Precision Diagnostics

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant