ATE517182T1 - Angiostatin und verfahren zu seiner nutzung zur vermeidung der angiogenese - Google Patents

Angiostatin und verfahren zu seiner nutzung zur vermeidung der angiogenese

Info

Publication number
ATE517182T1
ATE517182T1 AT07003963T AT07003963T ATE517182T1 AT E517182 T1 ATE517182 T1 AT E517182T1 AT 07003963 T AT07003963 T AT 07003963T AT 07003963 T AT07003963 T AT 07003963T AT E517182 T1 ATE517182 T1 AT E517182T1
Authority
AT
Austria
Prior art keywords
kilodaltons
amino acid
molecule
endothelial inhibitor
angiostatin
Prior art date
Application number
AT07003963T
Other languages
English (en)
Inventor
Michael S O'reilly
Judah M Folkman
Kim Lee Sim
Yihai Cao
Original Assignee
Childrens Medical Center
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=22939956&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=ATE517182(T1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Childrens Medical Center filed Critical Childrens Medical Center
Application granted granted Critical
Publication of ATE517182T1 publication Critical patent/ATE517182T1/de

Links

Classifications

    • 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
    • G01N33/57557—Immunoassay; Biospecific binding assay; Materials therefor for cancer of other specific parts of the body, e.g. brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6435—Plasmin (3.4.21.7), i.e. fibrinolysin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21007—Plasmin (3.4.21.7), i.e. fibrinolysin
    • 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
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • 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

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Cell Biology (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Physics & Mathematics (AREA)
  • Zoology (AREA)
  • Food Science & Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • General Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Ophthalmology & Optometry (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
AT07003963T 1994-04-26 1995-04-26 Angiostatin und verfahren zu seiner nutzung zur vermeidung der angiogenese ATE517182T1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/248,629 US5639725A (en) 1994-04-26 1994-04-26 Angiostatin protein
US08/326,785 US5792845A (en) 1994-04-26 1994-10-20 Nucleotides encoding angiostatin protein and method of use

Publications (1)

Publication Number Publication Date
ATE517182T1 true ATE517182T1 (de) 2011-08-15

Family

ID=22939956

Family Applications (1)

Application Number Title Priority Date Filing Date
AT07003963T ATE517182T1 (de) 1994-04-26 1995-04-26 Angiostatin und verfahren zu seiner nutzung zur vermeidung der angiogenese

Country Status (8)

Country Link
US (4) US5639725A (de)
EP (1) EP1783215B1 (de)
KR (1) KR100336452B1 (de)
AT (1) ATE517182T1 (de)
DK (1) DK1783215T3 (de)
ES (1) ES2370155T3 (de)
PT (1) PT1783215E (de)
ZA (1) ZA953419B (de)

Families Citing this family (213)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040248799A1 (en) * 1993-05-27 2004-12-09 Holaday John W. Compositions and methods for treating cancer and hyperproliferative disorders
EP0702563B1 (de) * 1993-05-27 2003-08-06 EntreMed, Inc. Zubereitungen und verfahren für die behandlung von krebs und hyperproliferierenden krankheiten
US6805865B1 (en) 1993-05-27 2004-10-19 Entremed, Inc. Compositions and methods for treating cancer and hyperproliferative disorders
US20040214807A1 (en) * 1993-08-06 2004-10-28 D'amato Robert J. Estrogenic compounds as anti-mitotic agents
US6908910B2 (en) 1993-08-06 2005-06-21 The Children's Medical Center Corporation Estrogenic compounds as anti-mitotic agents
US5504074A (en) * 1993-08-06 1996-04-02 Children's Medical Center Corporation Estrogenic compounds as anti-angiogenic agents
US20010055581A1 (en) 1994-03-18 2001-12-27 Lawrence Tamarkin Composition and method for delivery of biologically-active factors
US5945403A (en) * 1997-05-30 1999-08-31 The Children's Medical Center Corporation Angiostatin fragments and method of use
US6949511B1 (en) 1994-04-26 2005-09-27 The Children's Medical Center Corporation Methods of inhibiting angiogenesis via increasing in vivo concentrations of kringle region fragments of plasminogen
US5837682A (en) * 1996-03-08 1998-11-17 The Children's Medical Center Corporation Angiostatin fragments and method of use
US20040265288A1 (en) * 1995-03-08 2004-12-30 Gilman Michael Z. New applications of gene therapy technology
US6346510B1 (en) 1995-10-23 2002-02-12 The Children's Medical Center Corporation Therapeutic antiangiogenic endostatin compositions
EP0857210B1 (de) * 1995-10-23 2003-09-03 The Children's Medical Center Corporation Therapeutische antiangiogenische zusammensetzungen und verfahren
US5854221A (en) * 1996-12-12 1998-12-29 The Children's Medical Center Corporation Endothelial cell proliferation inhibitor and method of use
US5801146A (en) * 1996-05-03 1998-09-01 Abbott Laboratories Compound and method for inhibiting angiogenesis
CA2255865C (en) * 1996-05-24 2008-10-14 The Regents Of The University Of Minnesota Synthesis of soluble beta-sheet forming peptides
US6080728A (en) * 1996-07-16 2000-06-27 Mixson; A. James Carrier: DNA complexes containing DNA encoding anti-angiogenic peptides and their use in gene therapy
US5700821A (en) * 1996-07-30 1997-12-23 University Of Pittsburgh Phosphatase inhibitors and methods of use thereof
US5801012A (en) * 1996-09-17 1998-09-01 Northwestern University Methods and compositions for generating angiostatin
US6593291B1 (en) 1997-02-06 2003-07-15 Entremed, Inc. Compositions and methods of use of ligands that bind components of the blood coagulation/clotting pathway for the treatment of cancer and angiogenic-based disease
AU6578298A (en) 1997-03-21 1998-10-20 President And Fellows Of Harvard College Antisense inhibition of angiogenin expression
US7220557B2 (en) * 1997-04-24 2007-05-22 Human Genome Sciences, Inc. METH1 polynucleotides
AU753781B2 (en) 1997-04-28 2002-10-31 Aventis Pharma S.A. Adenovirus-mediated intratumoral delivery of an angiogenesis antagonist for the treatment of tumors
WO1999006073A1 (en) * 1997-07-31 1999-02-11 St. Elizabeth's Medical Center Of Boston, Inc. Method for the treatment of grafts
AU8918898A (en) 1997-08-25 1999-03-16 Harold Brem Prevention of adhesions and excessive scar formation using angiogenesis inhibi tors
US20020002294A1 (en) * 1997-09-24 2002-01-03 D' Amato Robert J. Estrogenic compounds as antiangiogenic agents
DE69824750T2 (de) 1997-10-31 2005-07-07 Children's Medical Center Corp., Boston Methoden zur regulierung der grösse und des wachstums von durchblutetem normalem gewebe
US6407218B1 (en) * 1997-11-10 2002-06-18 Cytimmune Sciences, Inc. Method and compositions for enhancing immune response and for the production of in vitro mabs
US7229841B2 (en) * 2001-04-30 2007-06-12 Cytimmune Sciences, Inc. Colloidal metal compositions and methods
WO1999026480A1 (en) * 1997-11-20 1999-06-03 Genetix Pharmaceuticals, Inc. Anti-angiogenic gene therapy vectors and their use in treating angiogenesis-related diseases
ES2221717T3 (es) 1997-12-08 2005-01-01 Emd Lexigen Research Center Corp. Proteinas de fusion heterodimeras utiles para inmunoterapia dirigida e inmunoestimulacion general.
US20030105294A1 (en) * 1998-02-25 2003-06-05 Stephen Gillies Enhancing the circulating half life of antibody-based fusion proteins
CN1318092C (zh) * 1998-04-15 2007-05-30 利思进药品公司 含有抗体－细胞因子融合蛋白和血管生成抑制剂的免疫治疗用组合物
AU3980499A (en) 1998-05-11 1999-11-29 Endowment for Research in Human Biology, Inc., The Use of neomycin for treating angiogenesis-related diseases
US20040022788A1 (en) 1998-05-19 2004-02-05 Moser Tammy L. Compositions and methods for promoting or inhibiting angiogenesis
WO1999059620A1 (en) * 1998-05-19 1999-11-25 Duke University Angiostatin receptor
US6620382B1 (en) 1998-05-22 2003-09-16 Biopheresis Technologies, Llc. Method and compositions for treatment of cancers
US20030012792A1 (en) * 1998-05-22 2003-01-16 Holaday John W. Compositions and methods for inhibiting endothelial cell proliferation and regulating angiogenesis using cancer markers
US8197430B1 (en) * 1998-05-22 2012-06-12 Biopheresis Technologies, Inc. Method and system to remove cytokine inhibitor in patients
JP2002518341A (ja) * 1998-06-15 2002-06-25 アーチ・デヴェロップメント・コーポレイション 放射線療法と抗血管形成因子の組み合わせ
AU5087799A (en) * 1998-07-06 2000-01-24 Beth Israel Deaconess Medical Center Methods of inhibiting proliferative diseases by inhibiting tgf-beta mediated angiogenesis
EP1096955B9 (de) 1998-07-13 2006-07-05 Board of Regents, The University of Texas System Verwendung von antikörper gegen aminophospholipide zur krebsbehandlung
WO2000003726A1 (en) * 1998-07-14 2000-01-27 Bristol-Myers Squibb Company Lysine binding fragments of angiostatin
US6365364B1 (en) 1998-08-20 2002-04-02 University Of Vermont And State Agriculture College Angiogenesis inhibitors and uses thereof
US6949081B1 (en) * 1998-08-26 2005-09-27 Non-Invasive Technology, Inc. Sensing and interactive drug delivery
US7317003B2 (en) * 1998-09-04 2008-01-08 National University Of Singapore Small peptides having anti-angiogenic and endothelial cell inhibition activity
EP1234585A3 (de) 1998-09-04 2004-01-21 The Regents Of The University Of Michigan Zusammensetzungen zur Vorbeugung oder Behandlung von Krebs
US6703050B1 (en) * 1998-09-04 2004-03-09 The Regents Of The University Of Michigan Methods and compositions for the prevention or treatment of cancer
US6200954B1 (en) 1998-09-04 2001-03-13 National University Of Singapore Small peptides having potent anti-angiogenic activity
US6537554B1 (en) 1998-09-10 2003-03-25 Curagen Corporation Nucleotide sequences and amino acid sequences of secreted proteins involved in angiogenesis
US6248327B1 (en) 1998-09-11 2001-06-19 Vanderbilt University Modulation of endothelial cell surface receptor activity in the regulation of angiogenesis
US7176289B1 (en) 1998-09-11 2007-02-13 Vanderbilt University Modulation of endothelial cell surface receptor activity in the regulation of angiogenesis
US6596690B2 (en) * 1998-10-06 2003-07-22 The United States Of America As Represented By The Department Of Health And Human Services Vasostatin as marrow protectant
DK1656952T3 (da) 1998-10-16 2014-01-20 Biogen Idec Inc Polyalkylenglycolkonjugater af interferon beta-1A og anvendelser deraf
US6218361B1 (en) 1998-11-18 2001-04-17 Children's Medical Center Corporation Treatment of chronic allograft rejection with anti-angiogenic agents
US6201104B1 (en) * 1998-12-04 2001-03-13 Entremed, Inc. Angiogenesis—inhibiting protein binding peptides and proteins and methods of use
AU2990300A (en) * 1999-02-10 2000-08-29 Children's Medical Center Corporation Deglycosylated kringle 1-5 region fragments of plasminogen and methods of use
US6465424B1 (en) 1999-02-17 2002-10-15 Bristol-Myers Squibb Company Anti-angiogenic agent and method for inhibiting angiogenesis
US6420345B1 (en) 1999-03-01 2002-07-16 Cell Genesys, Inc. Methods and reagents for inhibiting angiogenesis
US6943153B1 (en) 1999-03-15 2005-09-13 The Regents Of The University Of California Use of recombinant gene delivery vectors for treating or preventing diseases of the eye
CA2367375A1 (en) * 1999-03-15 2000-09-21 Chiron Corporation Use of recombinant gene delivery vectors for treating or preventing diseases of the eye
US7829064B2 (en) * 1999-05-10 2010-11-09 Immunomedics, Inc. Anti-CD74 immunoconjugates and methods
US8119101B2 (en) * 1999-05-10 2012-02-21 The Ohio State University Anti-CD74 immunoconjugates and methods of use
US8383081B2 (en) * 1999-05-10 2013-02-26 Immunomedics, Inc. Anti-CD74 immunoconjugates and methods of use
PT1180121E (pt) * 1999-05-17 2004-03-31 Conjuchem Inc Peptidos insulinotropicos de longa duracao
US7144854B1 (en) 1999-09-10 2006-12-05 Conjuchem, Inc. Long lasting anti-angiogenic peptides
US6890904B1 (en) 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
JP2003500041A (ja) * 1999-05-25 2003-01-07 ヒューマン ジノーム サイエンシーズ， インコーポレイテッド Ｍｅｔｈ１およびｍｅｔｈ２ポリヌクレオチドおよびポリペプチド
US6673843B2 (en) * 1999-06-30 2004-01-06 Emory University Curcumin and curcuminoid inhibition of angiogenesis
US7067110B1 (en) 1999-07-21 2006-06-27 Emd Lexigen Research Center Corp. Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens
SK782002A3 (en) * 1999-07-21 2003-08-05 Lexigen Pharm Corp FC fusion proteins for enhancing the immunogenicity of protein and peptide antigens
WO2001010912A1 (en) * 1999-08-09 2001-02-15 Lexigen Pharmaceuticals Corp. Multiple cytokine-antibody complexes
US7087592B1 (en) * 1999-08-23 2006-08-08 Entre Med, Inc. Compositions comprising purified 2-methoxyestradiol and methods of producing same
CA2384929C (en) 1999-09-15 2006-12-05 Mogam Biotechnology Research Institute A novel angiogenesis inhibitor
US20080241835A1 (en) * 1999-11-01 2008-10-02 Genentech, Inc. Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same
DE60043156D1 (de) 1999-11-10 2009-11-26 Biopheresis Technologies Inc Verfahren und system zur entfernung von zytokininhibitoren in patienten
CA2391080A1 (en) 1999-11-12 2001-05-25 Merck Patent Gesellschaft Mit Beschraenkter Haftung Erythropoietin forms with improved properties
US6379708B1 (en) * 1999-11-20 2002-04-30 Cytologic, Llc Method for enhancing immune responses in mammals
EP1218495A2 (de) * 1999-12-03 2002-07-03 EntreMed, Inc. Methode zur herstellung und reinigung von angiostatin-m(3)
US6723536B2 (en) 1999-12-03 2004-04-20 Entremed, Inc. Method of producing and purifying angiostatin
US6380253B1 (en) 2000-01-05 2002-04-30 Efa Sciences Llc Method of stabilizing and potentiating the action of anti-angiogenic substances
CA2398901C (en) * 2000-02-10 2010-11-16 Massachusetts Eye And Ear Infirmary Methods and compositions for treating conditions of the eye
JP5179689B2 (ja) * 2000-02-11 2013-04-10 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング 抗体ベース融合タンパク質の循環系内半減期の増強
AU2001238499A1 (en) * 2000-02-18 2001-08-27 New York Medical College Nitroacridine/tumor inhibitor compositions
US6825167B1 (en) 2000-04-03 2004-11-30 Regents Of The University Of Minnesota Genetic modification of endostatin
CZ2003214A3 (cs) * 2000-06-29 2003-08-13 Merck Patent Gmbh Zesílení odpovědi mediovaných fúzním proteinem protilátka-cytokin kombinovanou léčbou pomocí činidel zvyšujících uptake imunocytokinu
US20050192258A1 (en) * 2000-08-18 2005-09-01 Agoston Gregory E. Antiangiogenic agents
US6995278B2 (en) * 2000-08-18 2006-02-07 Entre Med, Inc. Antiangiogenic agents
US7135581B2 (en) * 2000-08-18 2006-11-14 Entremed, Inc. Antiangiogenic agents
US7160858B2 (en) * 2000-09-01 2007-01-09 Philadelphia, Health And Education Corporation Methods and compositions for inhibiting angiogenesis
EP1313504B1 (de) * 2000-09-01 2006-11-29 Philadelphia, Health and Education Corporation Verfahren und zusammensetzungen zur inhibition der angiogenese
AU8591901A (en) 2000-09-05 2002-03-22 Karolinska Innovations Ab Materials and methods relating to endothelial cell growth inhibitors
US20030104573A1 (en) * 2000-09-11 2003-06-05 Shimkets Richard A. Nucleotide sequences and amino acid sequences of secreted proteins involved in angiogenesis
US20020159992A1 (en) * 2000-09-29 2002-10-31 Jack Henkin Antiangiogenic polypeptides and methods for inhibiting angiogenesis
DE60134885D1 (de) 2000-11-28 2008-08-28 David M Waisman Antiangiogene polypeptide
CA2430669C (en) * 2000-11-30 2011-06-14 The Children's Medical Center Corporation Synthesis of 3-amino-thalidomide and its enantiomers
US20040121945A1 (en) * 2000-12-15 2004-06-24 Hong Liang Compositions and methods for inhibiting endothelial cell proliferation
CN1455682A (zh) * 2001-01-05 2003-11-12 百疗医株式会社 包括编码抗－血管生成蛋白或者其部分的基因的用于类风湿性关节炎的基因治疗的组合物
US6632835B2 (en) 2001-02-22 2003-10-14 Nanodesign Inc. Dibenzo[c]chromen-6-one derivatives as anti-cancer agents
DK1366067T3 (da) * 2001-03-07 2012-10-22 Merck Patent Gmbh Ekspressionsteknologi for proteiner indeholdende en hybrid isotype-antistof-enhed
US6992174B2 (en) 2001-03-30 2006-01-31 Emd Lexigen Research Center Corp. Reducing the immunogenicity of fusion proteins
BR0209177A (pt) 2001-05-03 2004-10-05 Merck Patent Gmbh Anticorpo especìfico a tumor recombinante e uso do mesmo
US20030129164A1 (en) * 2001-12-03 2003-07-10 Flannery John G. Expression of glial-derived neurotrophic factor for treatment of diseases of the eye
EP1454138B1 (de) * 2001-12-04 2012-01-18 Merck Patent GmbH Immunocytokine mit modulierter selektivität
PT3025726T (pt) 2002-01-18 2020-01-09 Biogen Ma Inc Compostos do polímero polialquileno e utilizações dos mesmos
US20030236439A1 (en) * 2002-01-30 2003-12-25 Gregory Agoston Non-steroidal analogs of 2-methoxyestradiol
US7255986B2 (en) * 2002-01-31 2007-08-14 The Board Of Trustees Operating Michigan State University Compositions for the diagnosis and treatment of epizootic catarrhal enteritis in ferrets
US7056514B2 (en) 2002-02-20 2006-06-06 Regents Of The University Of Minnesota Partial peptide mimetics and methods
US9770517B2 (en) 2002-03-01 2017-09-26 Immunomedics, Inc. Anti-Trop-2 antibody-drug conjugates and uses thereof
JP2005529080A (ja) * 2002-03-08 2005-09-29 エモリー　ユニバーシティ 腫瘍の増殖および脈管形成のサプレッサとしての新規のクルクミノイド−第ＶＩＩａ因子構築物
US7285277B2 (en) * 2002-03-15 2007-10-23 Mogam Biotechnology Research Institute Anticancer agent
AU2003299509A1 (en) * 2002-06-21 2004-05-13 University Of Utah Research Foundation Crosslinked compounds and methods of making and using thereof
US20040091465A1 (en) * 2002-06-26 2004-05-13 Zachary Yim Therapeutic antiangiogenic compositions and methods
JP2005537245A (ja) * 2002-06-26 2005-12-08 エントレメッド インコーポレイテッド タンパク質活性化レセプターのアンタゴニストを含む組成物および方法
DE60335383D1 (de) 2002-07-15 2011-01-27 Univ Texas Antikörper mit bindung an anionische phospholipide und aminophospholipide und ihre verwendung bei der behandlung von virusinfektionen
US7189865B2 (en) * 2002-07-23 2007-03-13 Attenuon, Llc Thiomolybdate analogues and uses thereof
GEP20074270B (en) 2002-07-23 2007-12-25 Univ Michigan Tetrapropylammonium tetrathiomolybdate and related compounds for anti-angiogenic therapies
US8071569B2 (en) * 2002-09-20 2011-12-06 Mousa Shaker A Oxidized heparin fractions and their use in inhibiting angiogenesis
US20030153013A1 (en) * 2002-11-07 2003-08-14 Ruo-Pan Huang Antibody-based protein array system
CA2507045A1 (en) * 2002-11-25 2004-06-10 Attenuon, Llc Peptides which inhibit angiogenesis, cell migration, cell invasion and cell proliferation, compositions and uses thereof
US8420086B2 (en) 2002-12-13 2013-04-16 Immunomedics, Inc. Camptothecin conjugates of anti-CD22 antibodies for treatment of B cell diseases
CA2514873C (en) * 2002-12-13 2012-01-03 David Waisman Compositions and methods for inhibiting tumor growth and metastasis
ATE471946T1 (de) * 2002-12-17 2010-07-15 Merck Patent Gmbh Humanisierter antikörper (h14.18) des maus antikörpers 14.18, der gd2 bindet und seine fusion mit il-2
WO2004093892A2 (en) * 2003-04-16 2004-11-04 Genentech, Inc. Stanniocalcin-1, variant or antagonists thereof for selective modulation of vascularization
CN101137388A (zh) 2003-05-15 2008-03-05 犹他卅大学研究基金会 抗粘连复合材料及其应用方法
EA200501865A1 (ru) * 2003-05-27 2006-08-25 Атеньюон, Ллк Аналоги тиовольфраматов и их применение
WO2005030120A2 (en) * 2003-05-28 2005-04-07 Entremed, Inc. Antiangiogenic agents
WO2004113361A2 (en) * 2003-06-20 2004-12-29 The Regents Of The University Of California Novel prokineticin receptor isoforms and methods of use
US20070020234A1 (en) * 2003-07-07 2007-01-25 Vande Woude George F Inhibition of tumor angiogenesis by combination of thrombospondin-1 and inhibitors of vascular endothelial growth factor
US20050143300A1 (en) * 2003-10-10 2005-06-30 Ma Jian-Xing Compounds useful in inhibiting vascular leakage, inflammation and fibrosis and methods of making and using same
US20050250694A1 (en) * 2003-10-10 2005-11-10 Ma Jian-Xing Compounds useful in inhibiting vascular leakage, inflammation and fibrosis and methods of making and using same
JP2008504216A (ja) * 2003-12-02 2008-02-14 サイトイミューン サイエンシズ インコーポレイテッド モノクローナル抗体の生成のための方法および組成物
EP1694712A1 (de) 2003-12-04 2006-08-30 University of Utah Research Foundation Modifizierte makromoleküle und verfahren zu ihrer herstellung und verwendung
US20100330143A1 (en) 2003-12-04 2010-12-30 University Of Utah Research Foundation Modified macromolecules and methods of making and using thereof
US20050130897A1 (en) * 2003-12-11 2005-06-16 Ma Jian-Xing Compounds useful in inhibiting vascular leakage, inflammation and fibrosis and methods of making and using same
HRP20130459T1 (en) 2004-01-22 2013-06-30 University Of Miami Topical co-enzyme q10 formulations and methods of use
JP4833862B2 (ja) * 2004-01-28 2011-12-07 サイトイミューン サイエンシズ インコーポレイテッド 官能化コロイド金属組成物および方法
US8883160B2 (en) * 2004-02-13 2014-11-11 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) complexes for therapeutic and diagnostic use
US20110171126A1 (en) * 2010-01-11 2011-07-14 Center For Molecular Medicine And Immunology Enhanced Cytotoxicity of Anti-CD74 and Anti-HLA-DR Antibodies with Interferon-Gamma
US9550838B2 (en) 2004-02-13 2017-01-24 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) complexes for therapeutic and diagnostic use
EP1729784A1 (de) * 2004-02-23 2006-12-13 Attenuon, LLC Formulierungen von thiomolybdat oder thiowolframat-verbindungen und ihre verwendungen
AU2005222934B2 (en) * 2004-03-12 2010-06-17 Entremed, Inc. Antiangiogenic agents
US20070004689A1 (en) * 2004-03-12 2007-01-04 Agoston Gregory E Antiangiogenic agents
US20060204951A1 (en) * 2004-04-26 2006-09-14 Judah Folkman Platelet biomarkers for the detection of disease
AU2005240082B2 (en) * 2004-04-30 2009-07-23 Innatus Corporation Method and system to remove soluble TNFR1,TNFR2, and IL2 in patients
US8618054B2 (en) * 2004-05-05 2013-12-31 Valorisation-Rechereche Société en Commandite Interleukin-1 receptor antagonists, compositions, and methods of treatment
CA2576971A1 (en) * 2004-08-20 2006-03-02 Entremed, Inc. Compositions and methods comprising proteinase activated receptor antagonists
CA2588449A1 (en) * 2004-11-24 2006-06-01 Therakine Corporation An implant for intraocular drug delivery
US20060116360A1 (en) * 2004-11-29 2006-06-01 Fogler William E Method of administering anti-angiogenic agents and a method of treating disease using same
WO2006084016A1 (en) 2005-02-01 2006-08-10 Attenuon, Llc ACID ADDITION SALTS OF Ac-PHSCN-NH2
US9707302B2 (en) 2013-07-23 2017-07-18 Immunomedics, Inc. Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer
US10058621B2 (en) 2015-06-25 2018-08-28 Immunomedics, Inc. Combination therapy with anti-HLA-DR antibodies and kinase inhibitors in hematopoietic cancers
US8475794B2 (en) 2005-04-06 2013-07-02 Ibc Pharmaceuticals, Inc. Combination therapy with anti-CD74 antibodies provides enhanced toxicity to malignancies, Autoimmune disease and other diseases
US8349332B2 (en) 2005-04-06 2013-01-08 Ibc Pharmaceuticals, Inc. Multiple signaling pathways induced by hexavalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases
AU2006264567A1 (en) 2005-05-05 2007-01-11 Valorisation Hsj, Societe En Commandite Cytokine receptor modulators and uses thereof
US20070065514A1 (en) * 2005-09-22 2007-03-22 Howell Mark D Method for enhancing immune responses in mammals
EP1948674A4 (de) 2005-11-02 2009-02-04 Protiva Biotherapeutics Inc Modifizierte sirna-moleküle und anwendungen davon
WO2007059111A2 (en) * 2005-11-14 2007-05-24 Entremed, Inc. Anti-angiogenic activity of 2-methoxyestradiol in combination with anti-cancer agents
AR059066A1 (es) * 2006-01-27 2008-03-12 Amgen Inc Combinaciones del inhibidor de la angiopoyetina -2 (ang2) y el inhibidor del factor de crecimiento endotelial vascular (vegf)
US20070176403A1 (en) * 2006-02-01 2007-08-02 Dennis Calderone Air adjustable seat
US8399440B2 (en) * 2006-03-20 2013-03-19 Entremed, Inc. Disease modifying anti-arthritic activity of 2-methoxyestradiol
US8747870B2 (en) 2006-04-20 2014-06-10 University Of Utah Research Foundation Polymeric compositions and methods of making and using thereof
AU2007240613B2 (en) * 2006-04-20 2013-11-28 University Of Utah Research Foundation Polymeric compositions and methods of making and using thereof
CN101511876A (zh) * 2006-07-11 2009-08-19 犹他大学研究基金会 用亲电子基团修饰的大分子及其制备和使用方法
US20080075690A1 (en) * 2006-09-22 2008-03-27 Mark Douglas Howell Method for enhancing immune responses in mammals
WO2008094665A1 (en) * 2007-01-31 2008-08-07 Entremed, Inc. Method of treating amyloidosis mediated diseases
US20080287341A1 (en) * 2007-05-18 2008-11-20 Danyang Chen Treatment of vascular abnormalities using nanoparticles
US20110014118A1 (en) * 2007-09-21 2011-01-20 Lawrence Tamarkin Nanotherapeutic colloidal metal compositions and methods
JP2011520769A (ja) * 2007-09-21 2011-07-21 サイトイミューン サイエンシズ インコーポレイテッド ナノ治療コロイド金属組成物および方法
WO2009062151A1 (en) 2007-11-08 2009-05-14 Cytimmune Sciences, Inc. Compositions and methods for generating antibodies
WO2009060198A1 (en) 2007-11-09 2009-05-14 Peregrine Pharmaceuticals, Inc. Anti-vegf antibody compositions and methods
EP2279254B1 (de) 2008-04-15 2017-07-05 Protiva Biotherapeutics Inc. Neue lipidformulierungen zur nukleinsäurezuführung
WO2010005527A1 (en) 2008-06-30 2010-01-14 Angioblast Systems, Inc. Treatment of eye diseases and excessive neovascularization using a combined therapy
WO2010051531A1 (en) 2008-10-31 2010-05-06 University Of Louisville Reserch Foundation, Inc. Olfactory epithelial-derived stem cells and methods of use therefor
CA2795698A1 (en) * 2010-03-05 2011-09-09 Angstrom Pharmaceuticals, Inc. Modulation of intracellular signaling
US10865383B2 (en) 2011-07-12 2020-12-15 Lineage Cell Therapeutics, Inc. Methods and formulations for orthopedic cell therapy
US8921533B2 (en) 2011-07-25 2014-12-30 Chromatin Technologies Glycosylated valproic acid analogs and uses thereof
US9757458B2 (en) 2011-12-05 2017-09-12 Immunomedics, Inc. Crosslinking of CD22 by epratuzumab triggers BCR signaling and caspase-dependent apoptosis in hematopoietic cancer cells
US9192664B2 (en) 2011-12-05 2015-11-24 Immunomedics, Inc. Therapeutic use of anti-CD22 antibodies for inducing trogocytosis
EP2628748A1 (de) 2012-02-14 2013-08-21 Szilak Laboratories Bioinformatics & Molecule-Design Ltd. Angiostatin-Chimäre und deren Verwendungen
TWI698240B (zh) 2012-05-15 2020-07-11 澳大利亞商艾佛蘭屈澳洲私營有限公司 使用腺相關病毒(aav)sflt-1治療老年性黃斑部退化(amd)
US20240148873A1 (en) 2012-12-13 2024-05-09 Immunomedics, Inc. Dosages of immunoconjugates of antibodies and sn-38 for improved efficacy and decreased toxicity
US10206918B2 (en) 2012-12-13 2019-02-19 Immunomedics, Inc. Efficacy of anti-HLA-DR antiboddy drug conjugate IMMU-140 (hL243-CL2A-SN-38) in HLA-DR positive cancers
US10137196B2 (en) 2012-12-13 2018-11-27 Immunomedics, Inc. Dosages of immunoconjugates of antibodies and SN-38 for improved efficacy and decreased toxicity
US10744129B2 (en) 2012-12-13 2020-08-18 Immunomedics, Inc. Therapy of small-cell lung cancer (SCLC) with a topoisomerase-I inhibiting antibody-drug conjugate (ADC) targeting Trop-2
US9931417B2 (en) 2012-12-13 2018-04-03 Immunomedics, Inc. Antibody-SN-38 immunoconjugates with a CL2A linker
CN107753954A (zh) 2012-12-13 2018-03-06 免疫医疗公司 功效改进且毒性降低的抗体与sn‑38的免疫缀合物的剂量
US10413539B2 (en) 2012-12-13 2019-09-17 Immunomedics, Inc. Therapy for metastatic urothelial cancer with the antibody-drug conjugate, sacituzumab govitecan (IMMU-132)
WO2015012904A2 (en) 2012-12-13 2015-01-29 Immunomedics, Inc. Antibody-sn-38 immunoconjugates with a cl2a linker
US9492566B2 (en) 2012-12-13 2016-11-15 Immunomedics, Inc. Antibody-drug conjugates and uses thereof
US12310958B2 (en) 2012-12-13 2025-05-27 Immunomedics, Inc. Antibody-drug conjugates and uses thereof
BR112015019509A2 (pt) 2013-02-13 2017-07-18 Cartiheal 2009 Ltd substratos sólidos para atenuar ou prevenir a adesão e vascularização de tecidos e células
US11253606B2 (en) 2013-07-23 2022-02-22 Immunomedics, Inc. Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, Bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer
US10064940B2 (en) 2013-12-11 2018-09-04 Siva Therapeutics Inc. Multifunctional radiation delivery apparatus and method
ES2822551T3 (es) 2014-03-17 2021-05-04 Adverum Biotechnologies Inc Composiciones y métodos para la expresión génica mejorada en células de los conos
FI3265178T3 (fi) 2015-03-02 2026-08-03 Adverum Biotechnologies Inc Koostumuksia ja menetelmiä polynukleotidien viemiseksi intravitreaalisesti retinaalisiin tappisoluihin
EP3286224A4 (de) 2015-04-22 2018-11-14 Immunomedics, Inc. Isolierung, detektion, diagnose und/oder charakterisierung von zirkulierenden trop-2-positiven krebszellen
US11241394B2 (en) * 2015-06-19 2022-02-08 The Regents Of The University Of California Treating vasculature related diseases or disorders using nanoparticles
US10195175B2 (en) 2015-06-25 2019-02-05 Immunomedics, Inc. Synergistic effect of anti-Trop-2 antibody-drug conjugate in combination therapy for triple-negative breast cancer when used with microtubule inhibitors or PARP inhibitors
GB2545763A (en) 2015-12-23 2017-06-28 Adverum Biotechnologies Inc Mutant viral capsid libraries and related systems and methods
CN108601841A (zh) 2016-02-10 2018-09-28 免疫医疗公司 Abcg2抑制剂与sacituzumab govitecan(immu-132)的组合克服表达trop-2的癌中对sn-38的抗性
RU2725292C2 (ru) 2016-04-27 2020-06-30 Иммьюномедикс, Инк. Эффективность конъюгатов антитела против trop-2 с лекарственным средством sn-38 для терапии рецидивирующих/рефрактерных к ингибиторам контрольной точки опухолей
RU2758234C2 (ru) 2017-03-27 2021-10-26 Иммьюномедикс, Инк. ЛЕЧЕНИЕ ТРИЖДЫ НЕГАТИВНОГО РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ, ХАРАКТЕРИЗУЮЩЕГОСЯ ЭКСПРЕССИЕЙ Trop-2, С ПОМОЩЬЮ САЦИТУЗУМАБА ГОВИТЕКАНА И ИНГИБИТОРА Rad51
CA3044082A1 (en) 2017-04-03 2018-10-11 Immunomedics, Inc. Subcutaneous administration of antibody-drug conjugates for cancer therapy
EP3746151B1 (de) 2018-02-28 2024-04-24 Plas-Free Ltd. Extrakorporale und matrix zur entfernung von fibrinolytischen proteinen aus biologischen flüssigkeiten, verfahren und verwendungen davon
JP7709981B2 (ja) 2020-03-17 2025-07-17 ジェネヴァント サイエンシズ ゲーエムベーハー 肝星細胞への治療薬の脂質ナノ粒子送達のためのカチオン性脂質
CN115885049A (zh) * 2020-08-20 2023-03-31 泰伦基国际有限公司 一种治疗肿瘤的方法和药物
AU2021403156A1 (en) 2020-12-18 2023-07-13 Genevant Sciences Gmbh Peg lipids and lipid nanoparticles
KR20240146674A (ko) 2022-01-31 2024-10-08 제네반트 사이언시즈 게엠베하 지질 나노입자를 위한 이온화 가능한 양이온성 지질
WO2025052278A1 (en) 2023-09-05 2025-03-13 Genevant Sciences Gmbh Pyrrolidine based cationic lipids for lipid nanoparticle delivery of therapeutics to hepatic stellate cells
WO2025133951A1 (en) 2023-12-21 2025-06-26 Genevant Sciences Gmbh Ionizable lipids suitable for lipid nanoparticles
WO2026022656A2 (en) 2024-07-22 2026-01-29 Genevant Sciences Gmbh Lipid particle formulations with permanently charged cationic lipids
WO2026022677A1 (en) 2024-07-22 2026-01-29 Genevant Sciences Gmbh Permanently charged cationic lipids

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5192744A (en) * 1990-01-12 1993-03-09 Northwestern University Method of inhibiting angiogenesis of tumors

Also Published As

Publication number Publication date
EP1783215B1 (de) 2011-07-20
DK1783215T3 (da) 2011-10-31
EP1783215A1 (de) 2007-05-09
KR100336452B1 (ko) 2002-12-26
US5733876A (en) 1998-03-31
US5639725A (en) 1997-06-17
PT1783215E (pt) 2011-10-31
ES2370155T3 (es) 2011-12-13
US5776704A (en) 1998-07-07
US5792845A (en) 1998-08-11
ZA953419B (en) 1996-01-11

Similar Documents

Publication Publication Date Title
ATE355379T1 (de) Angiostatin und verfahren zu seiner nutzung zur vermeidung der angiogenese
DK1783215T3 (da) Angiostatin og fremgangsmåde til anvendelse til inhibering af angiogenese
RU95110871A (ru) Способы определения нуклеотидной последовательности
YU8997A (sh) Prečišćen protein koji ima serinsku proteaznu inhibitorsku aktivnost i farmaceutski preparat koji ga sadrži
DE69731084D1 (de) REINIGUNG DES GEWEBE PLASMINOGENAKTIVATORS (tPA)
PT737207E (pt) Inibidores de plasmina humana derivados de dominios kunitz
ATE152126T1 (de) Osteogene faktoren
FI942625A7 (fi) Peptidisiä fosfinyylioksimetyyliketoneja interleukiini-1beta-muuttuvan entsyymin inhibiittoreina
DK430486A (da) Fremgangsmaade til udvinding af protein
EP0205475A4 (de) Rekombinantverfahren zur herstellung von serinproteaseinhibitoren, sowie dns-sequenzen dazu.
DE69637463D1 (de) Kontrolle der schotendehiszenz
DE69433357D1 (de) Rekombinantes Mersacidin und Verfahren zu seiner Herstellung
DE59914580D1 (de) Verfahren zur chromatographischen reinigung von insulinen
WO1998003652A3 (en) P300/cbp-associated transcriptional co-factor p/caf and uses thereof
ATE333469T1 (de) Verfahren zur reinigung hochanionischer proteine
SE8005498L (sv) Homogent fibroblastinterferon och framstellning derav
Shigeta et al. Fragmentation of a 70000-dalton calpastatin molecule upon its complex formation with calpain
ATE237636T1 (de) Reinigung von molekülen
DE69637941D1 (de) Modifizierte hämoglobinähnliche verbindungen und verfahren zu deren reinigung
Dalet-Fumeron et al. High-performance liquid chromatographic method for the simultaneous purification of cathepsins B, H and L from human liver
ATE195502T1 (de) Verfahren zur reinigung von pentafluorethan
DE3674955D1 (de) Im blut identifiziertes protein, ein verfahren zu seiner zubereitung, ein verfahren fuer die bestimmung dieses proteins und ebenfalls des t-pa-hemmungsfaktors und pharmazeutische zusammensetzungen, die dieses protein enthalten.
FI946031A7 (fi) Kringleä sisältävien proteiinien puhdistus ja etenkin t-PA:n
US5700365A (en) Crosslinked polyacrylamide gels with high monomer: crosslinker ratios
FR2654430B1 (fr) Nouveaux derives de peptides, utilisables comme inhibiteurs des collagenases bacteriennes.

Legal Events

Date Code Title Description
UEP Publication of translation of european patent specification

Ref document number: 1783215

Country of ref document: EP