JP6437458B2 - 第Ｘａ因子の阻害を中和するための組成物および方法 - Google Patents

第Ｘａ因子の阻害を中和するための組成物および方法 Download PDF

Info

Publication number
JP6437458B2
JP6437458B2 JP2015555829A JP2015555829A JP6437458B2 JP 6437458 B2 JP6437458 B2 JP 6437458B2 JP 2015555829 A JP2015555829 A JP 2015555829A JP 2015555829 A JP2015555829 A JP 2015555829A JP 6437458 B2 JP6437458 B2 JP 6437458B2
Authority
JP
Japan
Prior art keywords
fxa
factor
rivaroxaban
variant
apixaban
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.)
Expired - Fee Related
Application number
JP2015555829A
Other languages
English (en)
Japanese (ja)
Other versions
JP2016511755A (ja
JP2016511755A5 (cg-RX-API-DMAC10.html
Inventor
カミール ロッドニー
カミール ロッドニー
フルビス ジョアキム
フルビス ジョアキム
ディ． ピットマン デブラ
ディ． ピットマン デブラ
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.)
Children's Hospital of Philadelphia
Original Assignee
Children's Hospital of Philadelphia
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 Children's Hospital of Philadelphia filed Critical Children's Hospital of Philadelphia
Publication of JP2016511755A publication Critical patent/JP2016511755A/ja
Publication of JP2016511755A5 publication Critical patent/JP2016511755A5/ja
Application granted granted Critical
Publication of JP6437458B2 publication Critical patent/JP6437458B2/ja
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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)
    • C12N9/6432—Coagulation factor Xa (3.4.21.6)
    • 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)
    • C12Y304/21006—Coagulation factor Xa (3.4.21.6)

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Dermatology (AREA)
JP2015555829A 2013-01-31 2014-01-23 第Ｘａ因子の阻害を中和するための組成物および方法 Expired - Fee Related JP6437458B2 (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201361759332P 2013-01-31 2013-01-31
US61/759,332 2013-01-31
PCT/IB2014/058494 WO2014118677A1 (en) 2013-01-31 2014-01-23 Compositions and methods for counteracting factor xa inhibition

Related Child Applications (1)

Application Number Title Priority Date Filing Date
JP2018190856A Division JP2019077677A (ja) 2013-01-31 2018-10-09 第Ｘａ因子の阻害を中和するための組成物および方法

Publications (3)

Publication Number Publication Date
JP2016511755A JP2016511755A (ja) 2016-04-21
JP2016511755A5 JP2016511755A5 (cg-RX-API-DMAC10.html) 2017-03-30
JP6437458B2 true JP6437458B2 (ja) 2018-12-12

Family

ID=50114451

Family Applications (2)

Application Number Title Priority Date Filing Date
JP2015555829A Expired - Fee Related JP6437458B2 (ja) 2013-01-31 2014-01-23 第Ｘａ因子の阻害を中和するための組成物および方法
JP2018190856A Withdrawn JP2019077677A (ja) 2013-01-31 2018-10-09 第Ｘａ因子の阻害を中和するための組成物および方法

Family Applications After (1)

Application Number Title Priority Date Filing Date
JP2018190856A Withdrawn JP2019077677A (ja) 2013-01-31 2018-10-09 第Ｘａ因子の阻害を中和するための組成物および方法

Country Status (12)

Country Link
US (3) US20150343034A1 (cg-RX-API-DMAC10.html)
EP (1) EP2950813B1 (cg-RX-API-DMAC10.html)
JP (2) JP6437458B2 (cg-RX-API-DMAC10.html)
KR (1) KR20150103205A (cg-RX-API-DMAC10.html)
CN (1) CN104994868A (cg-RX-API-DMAC10.html)
AU (1) AU2014210830A1 (cg-RX-API-DMAC10.html)
CA (1) CA2897672A1 (cg-RX-API-DMAC10.html)
ES (1) ES2761730T3 (cg-RX-API-DMAC10.html)
HK (1) HK1215196A1 (cg-RX-API-DMAC10.html)
IL (1) IL240147A0 (cg-RX-API-DMAC10.html)
MX (1) MX2015008813A (cg-RX-API-DMAC10.html)
WO (1) WO2014118677A1 (cg-RX-API-DMAC10.html)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HK1215196A1 (zh) 2013-01-31 2016-08-19 辉瑞公司 用於抵消因子xa抑制的组合物和方法
CN112195169A (zh) 2013-09-24 2021-01-08 辉瑞大药厂 包含重组人凝血因子Xa蛋白的异质性群体的组合物
US20160235824A1 (en) * 2013-11-01 2016-08-18 The Children's Hospital Philadelphia Compositions and Methods for Increasing the Half-Life of Factor XA
CN105934250A (zh) * 2014-01-24 2016-09-07 辉瑞公司 治疗脑内出血的组合物和方法
NZ727444A (en) 2014-05-26 2021-12-24 Academisch Ziekenhuis Leiden Prohemostatic proteins for the treatment of bleeding
JP6776221B2 (ja) 2014-07-31 2020-10-28 ヘモネティクス・コーポレーションＨａｅｍｏｎｅｔｉｃｓ Ｃｏｒｐｏｒａｔｉｏｎ 凝固分析を使用した抗凝固剤の検出および分類
WO2016028872A2 (en) 2014-08-19 2016-02-25 The Children's Hospital Of Philadelphia Compositions and methods for modulating factor ix function
CN105440127B (zh) * 2015-12-30 2018-10-16 上海莱士血液制品股份有限公司 一种以人血浆Cohn组分III为原料的FEIBA的制备方法
TW201802121A (zh) 2016-05-25 2018-01-16 諾華公司 抗因子XI/XIa抗體之逆轉結合劑及其用途
KR102616666B1 (ko) 2016-12-23 2023-12-27 노파르티스 아게 인자 xi 항체 및 사용 방법
US12703762B2 (en) 2018-12-18 2026-08-11 Novartis Ag Reversal binding agents for anti-factor XI/XIa antibodies and uses thereof
WO2020163685A1 (en) * 2019-02-07 2020-08-13 Portola Pharmaceuticals, Inc. Methods for treating intracranial hemorrhage and assessing efficacy
CN114681597A (zh) * 2022-03-11 2022-07-01 兆科药业（合肥）有限公司 蝰蛇蛇毒血凝酶在制备用于逆转凝血因子Xa抑制剂的抗凝作用的药物中的应用

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5597799A (en) 1990-09-04 1997-01-28 Cor Therapeutics, Inc. Recombinant agents affecting thrombosis
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
AT405517B (de) 1997-02-27 1999-09-27 Immuno Ag Faktor x-deletionsmutanten und analoge davon
AT405516B (de) 1997-02-27 1999-09-27 Immuno Ag Faktor x-analoge mit modifizierter proteasespaltstelle
US6133256A (en) 1997-04-14 2000-10-17 Cor Therapeutics Inc Selective factor Xa inhibitors
GB9908838D0 (en) 1998-09-11 1999-06-16 Univ London Fibroblast inhibitor
AT410216B (de) 1999-08-10 2003-03-25 Baxter Ag Faktor x-analogon mit verbesserter aktivierbarkeit
AU2001249389A1 (en) 2000-03-22 2001-10-03 The Children's Hospital Of Philadelphia Modified blood clotting factors and methods of use
US6905683B2 (en) 2000-05-03 2005-06-14 Novo Nordisk Healthcare A/G Human coagulation factor VII variants
FR2831170B1 (fr) 2001-10-19 2004-03-19 Inst Nat Sante Rech Med Proteines c modifiees activables directement par la thrombine
FR2841904B1 (fr) 2002-07-03 2004-08-20 Inst Nat Sante Rech Med Analogues de facteurs x clivables par la thrombine
EP1728798A1 (en) 2005-06-01 2006-12-06 ZLB Behring GmbH Coagulation factor X polypeptides with modified activation properties
DE102005028018A1 (de) * 2005-06-16 2006-12-21 Dade Behring Marburg Gmbh Verfahren zur Standardisierung von Gerinnungstesten
MX336958B (es) 2005-11-15 2016-02-05 Philadelphia Children Hospital Metodos y composiciones para modular la hemostasia.
EP1820508A1 (en) 2006-02-21 2007-08-22 CSL Behring GmbH Coagulation factor X polypeptides with modified activation properties
EP1867660A1 (en) 2006-06-14 2007-12-19 CSL Behring GmbH Proteolytically cleavable fusion protein comprising a blood coagulation factor
KR102069498B1 (ko) 2007-09-28 2020-01-23 포톨라 파마슈티컬스, 인코포레이티드 인자 Ｘａ 저해제에 대한 안티도트 및 그것을 사용하는 방법
WO2009061697A1 (en) 2007-11-09 2009-05-14 The Board Of Trustees Of The University Of Illinois Anticoagulant antagonist and hemophilia procoagulant
CA2743496C (en) 2008-11-14 2018-03-27 Portola Pharmaceuticals, Inc. Antidotes for factor xa inhibitors and methods of using the same in combination with blood coagulating agents
JP5833448B2 (ja) 2008-12-19 2015-12-16 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル セリンプロテアーゼ誘導体および血液凝固疾患の予防または処置における使用
PL3604510T3 (pl) 2009-03-30 2025-07-28 Alexion Pharmaceuticals, Inc. Antidota na inhibitory czynnika xa i sposoby ich stosowania
EP2453910B1 (en) * 2009-07-15 2016-08-31 Portola Pharmaceuticals, Inc. Unit dose formulation of antidote for factor xa inhibitors for use in preventing bleeding
GB2485590A (en) 2010-11-22 2012-05-23 Univ Ruprecht Karis Heidelberg Method for detecting at least one direct factor Xa inhibitors
FR2972114B1 (fr) 2011-03-01 2013-03-15 Univ Grenoble 1 Un nouveau leurre moleculaire procoagulant pour le traitement des hemophiles a ou b avec ou sans inhibiteur
JP6514893B2 (ja) 2011-09-30 2019-05-15 ザ・チルドレンズ・ホスピタル・オブ・フィラデルフィアＴｈｅ Ｃｈｉｌｄｒｅｎ’Ｓ Ｈｏｓｐｉｔａｌ Ｏｆ Ｐｈｉｌａｄｅｌｐｈｉａ 止血を調節するための組成物および方法
WO2013123248A1 (en) 2012-02-16 2013-08-22 Portola Pharmaceuticals, Inc. MODULATION OF FACTOR Xa INHIBITOR MEDIATED BLOOD LOSS BY PARTIAL AND TRANSIENT ADMINISTRATION OF ANTIDOTE
FR3000895B1 (fr) 2013-01-11 2017-02-24 Laboratoire Francais Du Fractionnement Et Des Biotechnologies Sa Utilisation d'antidotes d'inhibiteurs de la coagulation indiques dans la prevention ou le traitement de pathologies thromboemboliques
HK1215196A1 (zh) 2013-01-31 2016-08-19 辉瑞公司 用於抵消因子xa抑制的组合物和方法
CN112195169A (zh) 2013-09-24 2021-01-08 辉瑞大药厂 包含重组人凝血因子Xa蛋白的异质性群体的组合物
US20160235824A1 (en) * 2013-11-01 2016-08-18 The Children's Hospital Philadelphia Compositions and Methods for Increasing the Half-Life of Factor XA
CN105934250A (zh) 2014-01-24 2016-09-07 辉瑞公司 治疗脑内出血的组合物和方法

Also Published As

Publication number Publication date
US20210000930A1 (en) 2021-01-07
US20150343034A1 (en) 2015-12-03
ES2761730T3 (es) 2020-05-20
AU2014210830A1 (en) 2015-07-16
IL240147A0 (en) 2015-09-24
HK1215196A1 (zh) 2016-08-19
JP2016511755A (ja) 2016-04-21
MX2015008813A (es) 2016-03-31
CA2897672A1 (en) 2014-08-07
KR20150103205A (ko) 2015-09-09
WO2014118677A1 (en) 2014-08-07
CN104994868A (zh) 2015-10-21
US20180344819A1 (en) 2018-12-06
JP2019077677A (ja) 2019-05-23
US10588950B2 (en) 2020-03-17
EP2950813B1 (en) 2019-09-04
EP2950813A1 (en) 2015-12-09

Similar Documents

Publication Publication Date Title
US10588950B2 (en) Compositions and methods for counteracting Factor Xa inhibition
JP7000394B2 (ja) 補因子の非存在下で凝固活性を有する、及び／又は、第ｉｘ因子凝固活性が増加した第ｉｘ因子変異体、並びに、出血性疾患を処置するためのその使用
AU763466B2 (en) A pharmaceutical preparation for treating blood coagulation disorders
EP2680876B1 (fr) Facteur xa depourvu de domaine gla pour le traitement des hemophilies a ou b avec ou sans anticorps
KR20160070163A (ko) 출혈 또는 응고성 저하와 관련된 상태의 치료 또는 예방용 요법
EP2001504A2 (en) Use of thrombin mutants to inhibit the anticoagulation effect of thrombin inhibitors
US20190231856A1 (en) Compositions and methods for treating intracerebral hemorrhage
JP6535036B2 (ja) 出血性疾患の治療における止血を改善するためのヒトプロトロンビン及び活性化第ｘ因子の組成物
JP6826040B2 (ja) 安全かつ効果的な血栓溶解（Ｔｈｒｏｍｂｏｌｙｓｉｓ）のための方法および組成物
CN108348776A (zh) 基于测定蛋白水解通路对阿尔茨海默病进行的诊断检验
JP6629744B2 (ja) 第Ｘａ因子の半減期を延ばす組成物および方法
US20240002861A1 (en) Compositions and methods for treatment of bleeding disorders
Ye et al. Murine Recombinant ACE2: Effect on angiotensin II dependent hypertension and distinctive ACE2 inhibitor characteristics on rodent and human ACE2
HK40040435A (en) Compositions and methods for treating intracerebral hemorrhage
WO2005034990A1 (ja) アンチトロンビンｉｉｉ含有止血用組成物
HK1228257A1 (en) Compositions and methods for treating intracerebral hemorrhage

Legal Events

Date Code Title Description
A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20150825

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20150903

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20170123

A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20170123

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20170222

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20170920

A601 Written request for extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A601

Effective date: 20171215

A601 Written request for extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A601

Effective date: 20180215

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20180319

A02 Decision of refusal

Free format text: JAPANESE INTERMEDIATE CODE: A02

Effective date: 20180611

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20181009

A911 Transfer to examiner for re-examination before appeal (zenchi)

Free format text: JAPANESE INTERMEDIATE CODE: A911

Effective date: 20181016

TRDD Decision of grant or rejection written
A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

Effective date: 20181112

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20181114

R150 Certificate of patent or registration of utility model

Ref document number: 6437458

Country of ref document: JP

Free format text: JAPANESE INTERMEDIATE CODE: R150

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

LAPS Cancellation because of no payment of annual fees