NO975729D0 - Forbindelser og peptider som binder til etytropoietinreseptoren - Google Patents

Forbindelser og peptider som binder til etytropoietinreseptoren

Info

Publication number
NO975729D0
NO975729D0 NO975729A NO975729A NO975729D0 NO 975729 D0 NO975729 D0 NO 975729D0 NO 975729 A NO975729 A NO 975729A NO 975729 A NO975729 A NO 975729A NO 975729 D0 NO975729 D0 NO 975729D0
Authority
NO
Norway
Prior art keywords
hoc
amino
receptor
ethytropoietin
compounds
Prior art date
Application number
NO975729A
Other languages
English (en)
Other versions
NO975729L (no
NO318783B1 (no
Inventor
Nicholas C Wrighton
William J Dower
Ray S Chang
Arun K Kashyap
Linda K Jolliffe
Dana Johnson
Original Assignee
Ortho Pharma Corp
Affymax Yechnologies Nv
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
Priority claimed from US08/484,631 external-priority patent/US5830851A/en
Priority claimed from US08/484,635 external-priority patent/US5773569A/en
Application filed by Ortho Pharma Corp, Affymax Yechnologies Nv filed Critical Ortho Pharma Corp
Publication of NO975729D0 publication Critical patent/NO975729D0/no
Publication of NO975729L publication Critical patent/NO975729L/no
Publication of NO318783B1 publication Critical patent/NO318783B1/no

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475Growth factors; Growth regulators
    • C07K14/505Erythropoietin [EPO]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/02Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06Antianaemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/14Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04Linear peptides containing only normal peptide links
    • C07K7/06Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04Linear peptides containing only normal peptide links
    • C07K7/08Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64Cyclic peptides containing only normal peptide links
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Zoology (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Toxicology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
NO19975729A 1995-06-07 1997-12-05 Peptid som binder til erytropoietinreseptoren og anvendelse derav, samt farmasoytiske blandinger som inneholder peptidet. NO318783B1 (no)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/484,631 US5830851A (en) 1993-11-19 1995-06-07 Methods of administering peptides that bind to the erythropoietin receptor
US08/484,635 US5773569A (en) 1993-11-19 1995-06-07 Compounds and peptides that bind to the erythropoietin receptor
PCT/US1996/009810 WO1996040749A1 (en) 1995-06-07 1996-06-07 Compounds and peptides that bind to the erythropoietin receptor

Publications (3)

Publication Number Publication Date
NO975729D0 true NO975729D0 (no) 1997-12-05
NO975729L NO975729L (no) 1998-02-05
NO318783B1 NO318783B1 (no) 2005-05-09

Family

ID=27048076

Family Applications (1)

Application Number Title Priority Date Filing Date
NO19975729A NO318783B1 (no) 1995-06-07 1997-12-05 Peptid som binder til erytropoietinreseptoren og anvendelse derav, samt farmasoytiske blandinger som inneholder peptidet.

Country Status (18)

Country Link
EP (2) EP0886648B8 (no)
JP (3) JP4050314B2 (no)
KR (1) KR100459984B1 (no)
CN (1) CN1192748A (no)
AT (1) ATE254138T1 (no)
AU (1) AU712713B2 (no)
BR (1) BR9609006A (no)
CA (1) CA2223833C (no)
CZ (1) CZ391097A3 (no)
DE (1) DE69630708T2 (no)
ES (1) ES2210374T3 (no)
HU (1) HUP9901069A2 (no)
IL (1) IL122417A0 (no)
NO (1) NO318783B1 (no)
NZ (1) NZ310804A (no)
PL (1) PL185040B1 (no)
TR (1) TR199701557T2 (no)
WO (1) WO1996040749A1 (no)

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5830851A (en) * 1993-11-19 1998-11-03 Affymax Technologies N.V. Methods of administering peptides that bind to the erythropoietin receptor
US5773569A (en) * 1993-11-19 1998-06-30 Affymax Technologies N.V. Compounds and peptides that bind to the erythropoietin receptor
US5767078A (en) * 1995-06-07 1998-06-16 Johnson; Dana L. Agonist peptide dimers
US6121416A (en) * 1997-04-04 2000-09-19 Genentech, Inc. Insulin-like growth factor agonist molecules
DE19904406A1 (de) * 1999-02-04 2000-08-10 Bayer Ag Substituierte Pyrazolcarbonsäuren
DE19904396A1 (de) * 1999-02-04 2000-08-10 Bayer Ag Substituierte Pyrazolbenzylamin-Derivate
US7179638B2 (en) 1999-07-30 2007-02-20 Large Scale Biology Corporation Microarrays and their manufacture by slicing
US6713309B1 (en) 1999-07-30 2004-03-30 Large Scale Proteomics Corporation Microarrays and their manufacture
US6703480B1 (en) 1999-11-24 2004-03-09 Palani Balu Peptide dimers as agonists of the erythropoientin (EPO) receptor, and associated methods of synthesis and use
US7259146B2 (en) 2000-05-26 2007-08-21 Ortho-Mcneil Pharmaceutical, Inc. Neuroprotective peptides
GB0208742D0 (en) 2002-04-17 2002-05-29 Bradford Particle Design Ltd Particulate materials
EP1581260B1 (en) 2002-12-31 2014-09-17 Nektar Therapeutics Polymeric reagents comprising a ketone or a related functional group
CN1820024B (zh) 2003-05-12 2011-06-22 阿费麦克斯公司 新的聚(乙二醇)修饰的化合物及其用途
ATE428727T1 (de) 2003-05-12 2009-05-15 Affymax Inc Neue, an den erythropoietinrezeptor bindende peptide
US7919118B2 (en) 2003-05-12 2011-04-05 Affymax, Inc. Spacer moiety for poly (ethylene glycol) modified peptide based compounds
AU2004238868B2 (en) * 2003-05-12 2010-01-21 Affymax, Inc. Peptides that bind to the erythropoietin receptor
EP2644206B1 (en) 2003-05-23 2019-04-03 Nektar Therapeutics PEG derivatives containing two PEG chains
CA2537336C (en) 2003-09-17 2013-02-26 Nektar Therapeutics Al, Corporation Multi-arm polymer prodrugs
WO2005058367A2 (en) 2003-12-16 2005-06-30 Nektar Therapeutics Al, Corporation Pegylated small molecules
DE602005012575D1 (en) * 2004-03-17 2009-03-19 Aplagen Gmbh Isostere transformation
WO2005107815A2 (en) 2004-05-03 2005-11-17 Nektar Therapeutics Al, Corporation Polymer derivatives comprising an imide branching point
WO2005108463A2 (en) 2004-05-03 2005-11-17 Nektar Therapeutics Al, Corporation Branched polyethylen glycol derivates comprising an acetal or ketal branching point
CA2586915A1 (en) * 2004-11-10 2006-05-18 Aplagen Gmbh Molecules which promote hematopoiesis
US7589063B2 (en) 2004-12-14 2009-09-15 Aplagen Gmbh Molecules which promote hematopoiesis
JP2008519858A (ja) * 2004-11-11 2008-06-12 アフィーマックス・インコーポレイテッド エリスロポエチンレセプターに結合する新規ペプチド
EP1884235A1 (en) * 2005-04-26 2008-02-06 Ajinomoto Co., Inc. Myeloerythroid progenitor differentiation inducer
US7550433B2 (en) 2005-06-03 2009-06-23 Affymax, Inc. Erythropoietin receptor peptide formulations and uses
WO2006136450A2 (en) * 2005-06-23 2006-12-28 Aplagen Gmbh Supravalent compounds
SI2540309T1 (en) * 2005-08-05 2018-04-30 Araim Pharmaceuticals, Inc. Tissue protective peptides and their uses
SG170086A1 (en) * 2006-03-09 2011-04-29 Aplagen Gmbh De Modified molecules which promote hematopoiesis
CN101528263B (zh) 2006-06-30 2013-01-23 Sku资产管理有限公司 用于癌症的先天性免疫方法的缀合物
EP2118127A4 (en) 2007-01-31 2010-12-01 Affymax Inc NICKET-BASED LINKER FOR BONDING MODIFYING GROUPS OF POLYPEPTIDES AND OTHER MACROMOLECULES
EP2018835B1 (de) 2007-07-09 2014-03-05 Augustinus Bader Wirkstoff abgebendes Pflaster
CN101456911A (zh) * 2007-12-12 2009-06-17 江苏豪森药业股份有限公司 促红细胞生成素模拟肽衍生物及其可药用盐和其制备方法与用途
US20110105400A1 (en) * 2008-03-26 2011-05-05 Orthologic Corp. Methods for treating acute myocardial infarction
WO2010014258A2 (en) 2008-08-01 2010-02-04 Nektar Therapeutics Al, Corporation Conjugates having a releasable linkage
AU2009282413B2 (en) 2008-08-11 2014-07-17 Nektar Therapeutics Multi-arm polymeric alkanoate conjugates
JP5766118B2 (ja) 2008-09-11 2015-08-19 ウェルズ ファーゴ バンク ナショナル アソシエイション ポリマー性アルファ−ヒドロキシアルデヒドおよびケトン反応剤ならびに抱合方法
WO2010033240A2 (en) 2008-09-19 2010-03-25 Nektar Therapeutics Carbohydrate-based drug delivery polymers and conjugates thereof
BR122012024318A2 (pt) * 2008-09-26 2019-07-30 Ambrx, Inc. Polipeptídeos modificados de eritropoetina animal e seus usos
JP6059014B2 (ja) * 2009-06-19 2017-01-11 アリゾナ ボード オブ リージェンツ ア ボディー コーポレート アクティング オン ビハーフ オブ アリゾナ ステイト ユニバーシティARIZONA BOARD OF REGENTS,a body corporate acting on behalf of ARIZONA STATE UNIVERSITY 試料の構成成分の検出において使用されるデバイスを製造する方法およびペプチドアレイ
WO2011012306A2 (en) 2009-07-30 2011-02-03 Aplagen Gmbh Use of emps for antagonising epo-stimulatory effects on epo-responsive tumors while maintaining erythropoiesis
WO2012003960A1 (en) 2010-07-06 2012-01-12 Augustinus Bader Topical application of erythropoietin for the treatment of eye disorders and injuries
WO2012088422A1 (en) 2010-12-22 2012-06-28 Nektar Therapeutics Multi-arm polymeric prodrug conjugates of taxane-based compounds
WO2012088445A1 (en) 2010-12-22 2012-06-28 Nektar Therapeutics Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds
US20140088021A1 (en) 2011-05-27 2014-03-27 Nektar Therapeutics Water-Soluble Polymer-Linked Binding Moiety and Drug Compounds
WO2013171810A1 (ja) 2012-05-14 2013-11-21 パナソニック株式会社 耐熱性抗体提示ファージを得る方法
CN103450348B (zh) * 2012-05-29 2016-03-30 中国人民解放军军事医学科学院毒物药物研究所 一种促红细胞生成素模拟肽、其制备方法和用途
CN106608906A (zh) * 2015-10-22 2017-05-03 天津药物研究院有限公司 一种具有刺激红细胞生成功能的环形多肽的制备及其应用
CN106928338A (zh) * 2015-12-31 2017-07-07 杭州阿德莱诺泰制药技术有限公司 促红细胞生成素肽及衍生物和聚合物、制备方法和应用
GB201609083D0 (en) 2016-05-24 2016-07-06 Syntab Therapeutics Gmbh Synthetic compound
JP7445978B2 (ja) * 2018-09-14 2024-03-08 エポメッド株式会社 抗エリスロポエチン受容体ペプチド
CA3142758A1 (en) 2019-06-10 2020-12-17 Respira Therapeutics,Inc. Carrier-based formulations and related methods
WO2025262329A1 (en) 2024-06-21 2025-12-26 Syntab Therapeutics Gmbh Synthetic molecules comprising tlr2 ligands

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ210501A (en) * 1983-12-13 1991-08-27 Kirin Amgen Inc Erythropoietin produced by procaryotic or eucaryotic expression of an exogenous dna sequence
WO1990008822A1 (en) * 1989-02-03 1990-08-09 Genetics Institute, Inc. Erythropoietin receptor
DE3924746A1 (de) * 1989-07-26 1991-01-31 Behringwerke Ag Erythropoietin (epo)-peptide und dagegen gerichtete antikoerper
US5767078A (en) * 1995-06-07 1998-06-16 Johnson; Dana L. Agonist peptide dimers

Also Published As

Publication number Publication date
CA2223833A1 (en) 1996-12-19
EP0886648B8 (en) 2004-03-03
AU712713B2 (en) 1999-11-11
KR100459984B1 (ko) 2005-06-20
JP4050314B2 (ja) 2008-02-20
PL185040B1 (pl) 2003-02-28
ES2210374T3 (es) 2004-07-01
WO1996040749A1 (en) 1996-12-19
EP1510524A2 (en) 2005-03-02
JP2009280616A (ja) 2009-12-03
ATE254138T1 (de) 2003-11-15
DE69630708T2 (de) 2004-08-05
CA2223833C (en) 2010-12-21
IL122417A0 (en) 1998-06-15
HUP9901069A2 (hu) 1999-07-28
NZ310804A (en) 1998-10-28
EP0886648A4 (en) 2000-01-12
KR19990022656A (ko) 1999-03-25
PL323858A1 (en) 1998-04-27
NO975729L (no) 1998-02-05
EP0886648B1 (en) 2003-11-12
NO318783B1 (no) 2005-05-09
EP0886648A1 (en) 1998-12-30
CZ391097A3 (cs) 1998-07-15
DE69630708D1 (de) 2003-12-18
JPH11507367A (ja) 1999-06-29
AU6166796A (en) 1996-12-30
TR199701557T2 (xx) 2002-06-21
EP1510524A3 (en) 2006-06-07
BR9609006A (pt) 1999-12-14
CN1192748A (zh) 1998-09-09
JP2007277264A (ja) 2007-10-25

Similar Documents

Publication Publication Date Title
NO975729D0 (no) Forbindelser og peptider som binder til etytropoietinreseptoren
NO961115D0 (no) Humane metabotrope glutamatreseptorsubtyper (HMR4, HMR6, HMR7) og relaterte DNA forbindelser
DK0765394T3 (da) Oprensede Myceliopthora-laccaser og nukleinsyrer der koder for disse
FI954805A0 (fi) Menetelmiä insuliininkaltaisen kasvutekijän sitojaproteiinien käyttämiseksi
NO910982L (no) Uratoksydase-aktivt protein, rekombinant gen som koder for det, ekspresjonsvektor, mikroorganismer og transformerteceller.
DE59409672D1 (de) Festphasensynthese von Oligoribonucleotiden
NO950477D0 (no) Aminosyrederivater
DK0990703T3 (da) Nyt polypeptid, DNA, som koder herfor, samt anvendelse heraf
AU4375493A (en) Isolated protein receptors, antibodies which bind thereto, nucleic acid sequence coding therefor, and uses thereof
SE9602822D0 (sv) New receptor
DE69929454D1 (de) Neue aminosäuresequenzen, deren kodierende dns, antikörper dagegen und deren verwendungen
DK0923644T3 (da) G-koblet receptor, der udviser selektiv selektivitet for ATP
CA2199403A1 (en) Novel PKA-Binding Proteins and Uses Thereof
DE69315730D1 (de) Verfahren zur Herstellung von Peptiden und neue Zwischenverbindungen dazu
NO974713L (no) Gener som koder for lymfocyttinterferon-regulatorisk faktor (LSIRF) polypeptider
CA2199843A1 (en) Novel PKA-Binding Proteins and Uses Thereof
DK0938555T3 (da) Konstruktioner og komplekser af cyclin E
ES2059801T3 (es) Nuevas linfoquinas, secuencias de adn que codifican para estas linfoquinas, y composiciones farmaceuticas conteniendo estas linfoquinas.
EP0588036A3 (en) Composition for the isolation of apamine receptor, apamine binding protein and its uses.
FR2710241B3 (fr) Composition énergétique à base d'acides aminés glycogéniques.
EP0716146A3 (en) A novel stem cell marker protein, antibodies thereto, compositions thereof and nucleotide sequences encoding said protein
WO2004054907A3 (en) Ftsz-polypeptides as a target for herbicidal compounds

Legal Events

Date Code Title Description
MM1K Lapsed by not paying the annual fees