CN105452479B - 可逆肝素分子 - Google Patents

可逆肝素分子 Download PDF

Info

Publication number
CN105452479B
CN105452479B CN201480044429.9A CN201480044429A CN105452479B CN 105452479 B CN105452479 B CN 105452479B CN 201480044429 A CN201480044429 A CN 201480044429A CN 105452479 B CN105452479 B CN 105452479B
Authority
CN
China
Prior art keywords
sulfotransferase
heparin
phosphosulfate
substrate
compound
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
CN201480044429.9A
Other languages
English (en)
Chinese (zh)
Other versions
CN105452479A (zh
Inventor
刘健
徐咏梅
罗伯特·J·林哈特
爱德华·哈里斯
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.)
Knob Tyke Wen Tusi Co
University of North Carolina at Chapel Hill
Rensselaer Polytechnic Institute
Original Assignee
University of North Carolina at Chapel Hill
Rensselaer Polytechnic Institute
NuTech Ventures Inc
University of Nebraska System
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 University of North Carolina at Chapel Hill, Rensselaer Polytechnic Institute, NuTech Ventures Inc, University of Nebraska System filed Critical University of North Carolina at Chapel Hill
Publication of CN105452479A publication Critical patent/CN105452479A/zh
Application granted granted Critical
Publication of CN105452479B publication Critical patent/CN105452479B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/10—Heparin; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/04—Polysaccharides, i.e. compounds containing more than five saccharide radicals attached to each other by glycosidic bonds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/18—Preparation of compounds containing saccharide radicals produced by the action of a glycosyl transferase, e.g. alpha-, beta- or gamma-cyclodextrins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Polymers & Plastics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Materials Engineering (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Sustainable Development (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
CN201480044429.9A 2013-06-17 2014-06-17 可逆肝素分子 Active CN105452479B (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201361835875P 2013-06-17 2013-06-17
US61/835,875 2013-06-17
PCT/US2014/042683 WO2014204929A2 (en) 2013-06-17 2014-06-17 Reversible heparin molecules and methods of making and using the same

Publications (2)

Publication Number Publication Date
CN105452479A CN105452479A (zh) 2016-03-30
CN105452479B true CN105452479B (zh) 2021-05-18

Family

ID=52105487

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201480044429.9A Active CN105452479B (zh) 2013-06-17 2014-06-17 可逆肝素分子

Country Status (6)

Country Link
US (1) US9951149B2 (https=)
EP (1) EP3011043B1 (https=)
JP (1) JP6670235B2 (https=)
CN (1) CN105452479B (https=)
ES (1) ES2924830T3 (https=)
WO (1) WO2014204929A2 (https=)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11633424B2 (en) 2018-06-20 2023-04-25 The University Of North Carolina At Chapel Hill Cell protective methods and compositions
US11865137B2 (en) 2017-11-03 2024-01-09 The University Of North Carolina At Chapel Hill Sulfated oligosaccharides having anti-inflammatory activity
US11993627B2 (en) 2017-07-03 2024-05-28 The University Of North Carolina At Chapel Hill Enzymatic synthesis of homogeneous chondroitin sulfate oligosaccharides
US12539311B2 (en) 2017-03-10 2026-02-03 The University Of North Carolina At Chapel Hill Short-acting heparin-based anticoagulant compounds and methods
US12569512B2 (en) 2019-11-13 2026-03-10 The University Of North Carolina At Chapel Hill Heparan sulfate (HS) oligosaccharides effect in liver ischemia reperfusion injury

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11203772B2 (en) 2010-12-23 2021-12-21 The University Of North Carolina At Chapel Hill Chemoenzymatic synthesis of structurally homogeneous ultra-low molecular weight heparins
ES2924830T3 (es) 2013-06-17 2022-10-11 Univ North Carolina Chapel Hill Moléculas de heparina reversibles
EP3273239A1 (en) * 2016-07-19 2018-01-24 Laboratorios Farmacéuticos Rovi, S.A. Procedure of analysis of glycosaminoglycans, heparins and their derivatives by nuclear magnetic resonance
TWI769176B (zh) 2016-09-07 2022-07-01 瑞瑟勒綜合技術協會 生合成肝素
US10864227B2 (en) 2017-03-20 2020-12-15 Rensselaer Polytechnic Institute Enzymatic preparation of increased anticoagulant bovine sourced heparin
US11141428B2 (en) * 2017-12-12 2021-10-12 Academia Sinica Octasaccharides and uses thereof
CN111867603A (zh) * 2018-03-01 2020-10-30 中央研究院 检测癌细胞的装置与方法
CN109321508B (zh) * 2018-10-12 2022-12-27 北京化工大学 产heparosan的基因工程菌及其应用
WO2022015794A1 (en) 2020-07-14 2022-01-20 Optimvia, Llc Methods for synthesizing non-anticoagulant heparan sulfate
CN113646427A (zh) 2019-01-15 2021-11-12 奥普蒂姆维亚有限公司 工程化芳基硫酸酯依赖性酶
CA3144968A1 (en) 2019-07-09 2021-01-14 Optimvia Llc Methods for synthesizing anticoagulant polysaccharides
CN111154819B (zh) * 2020-01-15 2022-08-30 山东大学 一种非动物源低分子量肝素及其制备方法与应用
CN113583151B (zh) * 2021-07-07 2023-06-20 山东大学 含at结合序列和连续2-o-葡糖醛酸残基的肝素分子及其制备方法与应用
CN113564139B (zh) * 2021-08-02 2023-03-10 山东大学 巴氏杆菌肝素骨架合酶BtHS1及其突变体与应用
CN116120484B (zh) * 2022-09-01 2024-11-08 山东大学 一种抗凝血肝素寡糖苯联二聚体及其制备方法与应用
CN116297984A (zh) * 2023-04-12 2023-06-23 重庆望业药物研究有限公司 一种采用lc-ms检测低分子肝素中寡糖含量的方法及应用
WO2026057759A1 (en) * 2024-09-13 2026-03-19 Sanofi Novel bioengineered heparins, low molecular weight heparins derived thereof, and their method of production

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012088416A2 (en) * 2010-12-23 2012-06-28 The University Of North Carolina At Chapel Hill Chemoenzymatic synthesis of structurally homogeneous ultra-low molecular weight heparins
US20120322760A1 (en) * 2009-09-23 2012-12-20 Momenta Pharmaceuticals, Inc. Methods of treatment with a low molecular weight heparin composition

Family Cites Families (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4554101A (en) 1981-01-09 1985-11-19 New York Blood Center, Inc. Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity
US4865870A (en) 1988-07-07 1989-09-12 Becton, Dickinson And Company Method for rendering a substrate surface antithrombogenic
PT93847A (pt) 1989-04-24 1990-11-20 Harvard College Processo para a preparacao de oligossacaridos de baixo peso molecular derivados de heparina ou de sulfato de heparano despolimerizados e de composicoes farmaceuticas que os contem
US5378829A (en) 1990-04-23 1995-01-03 Akzo N.V. Sulfated glycosaminoglycanoid derivatives of the heparin and heparan sulfate type
IT1260137B (it) 1992-04-17 1996-03-28 Alfa Wassermann Spa Glicosaminoglicani semisintetici a struttura eparinica od eparanica modificati nella posizione 2 dell'acido alfa-l-iduronico-2-0-solfato
JP3818676B2 (ja) 1994-07-22 2006-09-06 生化学工業株式会社 ヘパラン硫酸６−ｏ−硫酸基転移酵素
IT1271057B (it) 1994-11-04 1997-05-26 Inalco Spa Polisaccaridi aventi un elevato contenuto di acido iduronico
JP3672359B2 (ja) 1995-07-24 2005-07-20 生化学工業株式会社 ヘパラン硫酸 ２−ｏ−硫酸基転移酵素
US5935824A (en) 1996-01-31 1999-08-10 Technologene, Inc. Protein expression system
US6861254B1 (en) 1997-10-24 2005-03-01 Massachusetts Institute Of Technology Heparan sulfate D-glucosaminyl 3-O-sulfotransferases, and uses therefor
US8088604B2 (en) 1998-04-02 2012-01-03 The Board Of Regents Of The University Of Oklahoma Production of defined monodisperse heparosan polymers and unnatural polymers with polysaccharide synthases
US7307159B2 (en) 2001-05-08 2007-12-11 The Board Of Regents Of The University Of Oklahoma Heparin/heparosan synthase from P. multocida and methods of making and using same
US6624141B1 (en) * 1999-03-17 2003-09-23 The Regents Of The University Of Michigan Protamine fragment compositions and methods of use
US6255088B1 (en) 1999-05-11 2001-07-03 The Scripps Research Institute Enzymatic sulfation of biomolecules
US8067196B2 (en) 2001-03-28 2011-11-29 Massachusetts Institute Of Technology 6-O sulfated polysaccharides and methods of preparation thereof
US7300922B2 (en) 2001-05-25 2007-11-27 Duke University Modulators of pharmacological agents
WO2003018598A2 (en) * 2001-08-30 2003-03-06 University College Dublin Monosaccharide derivatives
WO2004005475A2 (en) 2002-07-05 2004-01-15 University Of North Carolina At Chapel Hill Purified and isolated heparan sulfate 3-o-sulfotransferase isoform 5 nucleic acids and polypeptides and therapeutic and screening methods using same
GB0216861D0 (en) 2002-07-19 2002-08-28 Univ Birmingham Saccharide libraries
AU2003262794A1 (en) * 2002-08-23 2004-03-11 Neose Technologies, Inc. Total synthesis of heparin
WO2005014619A2 (en) * 2003-03-28 2005-02-17 Thomas Jefferson University Heparin-binding peptides and uses thereof
US7655445B2 (en) 2003-11-12 2010-02-02 Massachusetts Institute Of Technology Methods for synthesis of sulfated saccharides
WO2006124801A2 (en) 2005-05-12 2006-11-23 The University Of North Carolina At Chapel Hill Enzymatic synthesis of sulfated polysaccharides
CN101495517B (zh) * 2006-05-25 2012-10-10 莫曼塔医药品有限公司 低分子量肝素及其用途
WO2009014715A2 (en) * 2007-07-23 2009-01-29 The University Of North Carolina At Chapel Hill Enzymatic synthesis of sulfated polysaccharides without iduronic acid residues
EP2364165B1 (en) 2008-11-14 2018-01-03 Portola Pharmaceuticals, Inc. Antidotes for factor xa inhibitors and methods of using the same in combination with blood coagulating agents
US20110054236A1 (en) 2009-08-25 2011-03-03 The Regents Of The University Of Michigan Compositions and methods for targeting tumors
TW201309305A (zh) * 2011-02-22 2013-03-01 Rensselaer Polytech Inst 用於製造生物工程肝素之單一步驟肝素前體之ｎ－去乙醯化作用及解聚合作用
US8519189B2 (en) 2011-06-01 2013-08-27 University Of British Columbia Polymers for reversing heparin-based anticoagulation
ES2924830T3 (es) 2013-06-17 2022-10-11 Univ North Carolina Chapel Hill Moléculas de heparina reversibles

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120322760A1 (en) * 2009-09-23 2012-12-20 Momenta Pharmaceuticals, Inc. Methods of treatment with a low molecular weight heparin composition
WO2012088416A2 (en) * 2010-12-23 2012-06-28 The University Of North Carolina At Chapel Hill Chemoenzymatic synthesis of structurally homogeneous ultra-low molecular weight heparins

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Toward the chemoenzymatic synthesis of heparin sulfate oligoccharides: oxidative cleavage of p-nitrophenyl group with ceric ammonium salts;Chao Cai et al.;《Tetrahedron Letters》;20130618;第54卷;摘要，scheme1，第4472页左栏第2段 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12539311B2 (en) 2017-03-10 2026-02-03 The University Of North Carolina At Chapel Hill Short-acting heparin-based anticoagulant compounds and methods
US11993627B2 (en) 2017-07-03 2024-05-28 The University Of North Carolina At Chapel Hill Enzymatic synthesis of homogeneous chondroitin sulfate oligosaccharides
US11865137B2 (en) 2017-11-03 2024-01-09 The University Of North Carolina At Chapel Hill Sulfated oligosaccharides having anti-inflammatory activity
US12397016B2 (en) 2017-11-03 2025-08-26 The University Of North Carolina At Chapel Hill Sulfated oligosaccharides having anti-inflammatory activity
US11633424B2 (en) 2018-06-20 2023-04-25 The University Of North Carolina At Chapel Hill Cell protective methods and compositions
US12569512B2 (en) 2019-11-13 2026-03-10 The University Of North Carolina At Chapel Hill Heparan sulfate (HS) oligosaccharides effect in liver ischemia reperfusion injury

Also Published As

Publication number Publication date
EP3011043A2 (en) 2016-04-27
WO2014204929A3 (en) 2015-10-29
JP2016523535A (ja) 2016-08-12
US9951149B2 (en) 2018-04-24
CN105452479A (zh) 2016-03-30
US20160122446A1 (en) 2016-05-05
EP3011043A4 (en) 2017-01-18
EP3011043B1 (en) 2022-05-11
JP6670235B2 (ja) 2020-03-18
WO2014204929A2 (en) 2014-12-24
ES2924830T3 (es) 2022-10-11

Similar Documents

Publication Publication Date Title
CN105452479B (zh) 可逆肝素分子
US11203772B2 (en) Chemoenzymatic synthesis of structurally homogeneous ultra-low molecular weight heparins
US8771995B2 (en) Enzymatic synthesis of sulfated polysaccharides
US8088604B2 (en) Production of defined monodisperse heparosan polymers and unnatural polymers with polysaccharide synthases
TWI769176B (zh) 生合成肝素
US11629364B2 (en) Methods for synthesizing anticoagulant polysaccharides
WO2001080810A2 (en) Chondroitin synthase gene and methods of making and using same
AU2001253805A1 (en) Chondroitin synthase gene and methods of making and using same
Zhang et al. Uncovering the detailed mode of cleavage of heparinase I toward structurally defined heparin oligosaccharides
Hu et al. Probing cleavage promiscuity of heparinase III towards chemoenzymatically synthetic heparan sulfate oligosaccharides
US20080108110A1 (en) Targeted glycosaminoglycan polymers by polymer grafting and methods of making and using same
Class et al. Patent application title: REVERSIBLE HEPARIN MOLECULES AND METHODS OF MAKING AND USING THE SAME Inventors: Jian Liu (Chapel Hill, NC, US) Yongmei Xu (Durham, NC, US) Robert J. Linhardt (Albany, NY, US) Robert J. Linhardt (Albany, NY, US) Edward Harris (Lincoln, NE, US)
EP2690178B1 (en) Targeted glycosaminoglycan polymers by polymer grafting and methods of making and using same
AU2013237670B2 (en) Targeted glycosaminoglycan polymers by polymer grafting and methods of making and using same
US20230151339A1 (en) Engineered aryl sulfate-dependent enzymes
Xu et al. Design of homogeneous and reversible low molecular weight heparins
KR20220032086A (ko) 항응고제 다당류의 합성 방법

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
TA01 Transfer of patent application right

Effective date of registration: 20180907

Address after: North Carolina

Applicant after: The University of North Carolina AT Chapel Hill

Applicant after: RENSSELAER POLYTECH INST

Applicant after: Knob Tyke Wen Tusi company

Address before: North Carolina

Applicant before: The University of North Carolina AT Chapel Hill

Applicant before: RENSSELAER POLYTECH INST

Applicant before: Board of Regents of the University of Nebraska

TA01 Transfer of patent application right
GR01 Patent grant
GR01 Patent grant