JP2007190024A - 哺乳類細胞培養によって生産されるタンパク質のシアリル化を制御する方法 - Google Patents

哺乳類細胞培養によって生産されるタンパク質のシアリル化を制御する方法 Download PDF

Info

Publication number
JP2007190024A
JP2007190024A JP2007050848A JP2007050848A JP2007190024A JP 2007190024 A JP2007190024 A JP 2007190024A JP 2007050848 A JP2007050848 A JP 2007050848A JP 2007050848 A JP2007050848 A JP 2007050848A JP 2007190024 A JP2007190024 A JP 2007190024A
Authority
JP
Japan
Prior art keywords
tnfr1
igg
cell
host cell
cell culture
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.)
Granted
Application number
JP2007050848A
Other languages
English (en)
Other versions
JP4348376B2 (ja
Inventor
Tina Etcheverry
エッチェベリー ティナ
Thomas Ryll
ライル トーマス
Werner Lesslauer
レスローアー ヴェルナー
Thomas Schreitmuller
シュライトムラー トーマス
Wolfgang Richter
ヴォルフガング　リヒター
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Genentech Inc
Original Assignee
F Hoffmann La Roche AG
Genentech Inc
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=23863440&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=JP2007190024(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by F Hoffmann La Roche AG, Genentech Inc filed Critical F Hoffmann La Roche AG
Publication of JP2007190024A publication Critical patent/JP2007190024A/ja
Application granted granted Critical
Publication of JP4348376B2 publication Critical patent/JP4348376B2/ja
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/005—Glycopeptides, glycoproteins
    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7151—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for tumor necrosis factor [TNF], for lymphotoxin [LT]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0018—Culture media for cell or tissue culture
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • 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
    • C12N2500/00—Specific components of cell culture medium
    • C12N2500/30—Organic components
    • C12N2500/36—Lipids
    • 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
    • C12N2500/00—Specific components of cell culture medium
    • C12N2500/60—Buffer, e.g. pH regulation, osmotic pressure

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Cell Biology (AREA)
  • Biomedical Technology (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

【課題】ＴＮＦ介在性病状の治療に有用な製剤を含む治療組成物の提供。
【解決手段】哺乳類宿主細胞培養によって生産される哺乳類糖タンパク質のオリゴ糖側鎖上に存在するシアル酸の量を制御する方法であって、ｉ）その細胞培養に０．１ｍＭ〜２０ｍＭの濃度の３〜６個の炭素原子を有するアルカン酸又はその塩を添加し、
ｉｉ）その細胞培養の重量オスモル濃度を２５０〜６００ｍＯｓｍに維持し、
ｉｉｉ）培養温度を３０℃〜３５℃の温度に維持することを特徴とする該培養の生産相で哺乳類宿主細胞を培養することを含む方法。
【選択図】なし

Description
本発明によって以下が提供される。
図１Ａ及び図１Ｂ：図１Ａと図１Ｂは、代表的細胞培養法の生産相における比生産能を計算するために使用した方法を示す。比生産能は、図１Ａに示すように生存可能細胞数（生存可能細胞・日数）の関数として、あるいは図１Ｂに示すようにパック細胞容積（ＰＣＶ）の関数として表わすことができる。比生産速度には９０％の信頼区間が与えられる。 図２Ａ及び図２Ｂ：図２Ａ及び図２Ｂは、生産相における生存可能細胞・日数（図２Ａ）及びパック細胞容量（ＰＣＶ）（図２Ｂ）に基づく比生産能と収集した産物のシアル酸（ＮＡＮＡ）含量の間の相関関係を示す。９種類の方法（Ａ〜Ｉ）に関する値を示す。データ点は表Ｉに記載の独立した生産法を表す。

Claims (20)

  1. 哺乳類宿主細胞培養によって生産される哺乳類糖タンパク質のオリゴ糖側鎖上に存在するシアル酸の量を制御する方法であって、
    ｉ）その細胞培養に０．１ｍＭ〜２０ｍＭの濃度の３〜６個の炭素原子を有するアルカン酸又はその塩を添加し、
    ｉｉ）その細胞培養の重量オスモル濃度を２５０〜６００ｍＯｓｍに維持し、
    ｉｉｉ）培養温度を３０℃〜３５℃の温度に維持することを特徴とする該培養の生産相で哺乳類宿主細胞を培養することを含む方法。
  2. 宿主細胞を１〜６ｍＭの濃度の前記３〜６個の炭素原子を有するアルカン酸又はその塩で培養し、その重量オスモル濃度を３００〜４５０ｍＯｓｍに維持することによって細胞培養の細胞比生産能を減じ、糖タンパク質のオリゴ糖側鎖上に存在するシアル酸の量を増大させる請求項１の方法。
  3. 宿主細胞がＣＨＯ細胞である請求項２の方法。
  4. 前記３〜６個の炭素原子を有するアルカン酸又はその塩が酪酸ナトリウムである請求項３の方法。
  5. 糖タンパク質が腫瘍壊死因子受容体−免疫グロブリンキメラである請求項１の方法。
  6. 宿主細胞が可溶性１型腫瘍壊死因子受容体−免疫グロブリンＴＮＦＲ１−ＩｇＧ１キメラをコードするｃＤＮＡを保持するベクターでトランスフェクションされた細胞である請求項５の方法。
  7. 宿主細胞を６ｍＭ〜１２ｍＭの濃度の前記３〜６個の炭素原子を有するアルカン酸又はその塩で培養し、その重量オスモル濃度を４５０〜６００ｍＯｓｍに維持することによって細胞培養の細胞比生産能を増大させ、糖タンパク質のオリゴ糖側鎖上に存在するシアル酸の量を減少させる請求項１の方法。
  8. 宿主細胞がＣＨＯ細胞である請求項７の方法。
  9. 前記３〜６個の炭素原子を有するアルカン酸又はその塩が酪酸ナトリウムである請求項８の方法。
  10. 糖タンパク質が腫瘍壊死因子受容体−免疫グロブリンキメラである請求項９の方法。
  11. 宿主細胞が可溶性１型腫瘍壊死因子受容体−免疫グロブリンＴＮＦＲ１−ＩｇＧ１キメラのｃＤＮＡを保持するベクターでトランスフェクションされた細胞である請求項１０の方法。
  12. （ｉ）６ｍＭ〜１２ｍＭの濃度の酪酸ナトリウムの存在下に、
    （ｉｉ）重量オスモル濃度を４５０〜６００ｍＯｓｍに維持しながら、生産相で宿主細胞を培養することを含むヒト可溶性１型腫瘍壊死因子受容体−免疫グロブリンＴＮＦＲ１−ＩｇＧ１キメラタンパク質を生産するための請求項１の方法。
  13. （ｉ）０．１ｍＭ〜６ｍＭの濃度の酪酸ナトリウムの存在下に、
    （ｉｉ）重量オスモル濃度を３００〜４５０ｍＯｓｍに維持しながら、生産相で宿主細胞を培養することを含むヒト可溶性１型腫瘍壊死因子受容体−免疫グロブリンＴＮＦＲ１−ＩｇＧ１キメラタンパク質を生産するための請求項１の方法。
  14. 宿主細胞がＣＨＯ細胞である請求項１３の方法。
  15. 宿主細胞がｄｈｆｒ−ＣＨＯ細胞である請求項１４の方法。
  16. タンパク質に対するシアル酸のモル比が４〜７のＴＮＦＲ１−ＩｇＧ１分子を含む請求項１３の方法により製造されるＴＮＦＲ１−ＩｇＧ１製剤。
  17. ＴＮＦＲ１−ＩｇＧ１タンパク質１モルにつき１〜２モルの露出したＮ一アセチルグルコサミン残基を持つＴＮＦＲ１−ＩｇＧ１分子を含む請求項１３の方法により製造されるＴＮＦＲ１−ＩｇＧ１製剤。
  18. Ｎ−アセチルグルコサミンに対するシアル酸のモル比が０．３５〜０．５であるＴＮＦＲ１−ＩｇＧ１分子を含む請求項１３の方法により製造されるＴＮＦＲ１−ＩｇＧ１製剤。
  19. Ｎ−アセチルグルコサミンに対するシアル酸のモル比が０．３９〜０．４５である請求項１８のＴＮＦＲ１−ＩｇＧ１製剤。
  20. 請求項１６〜１９のいずれかのＴＮＦＲ１−ＩｇＧ１製剤と医薬的に許容できる賦形剤とを含む治療用組成物。
JP2007050848A 1995-06-06 2007-02-28 哺乳類細胞培養によって生産されるタンパク質のシアリル化を制御する方法 Expired - Lifetime JP4348376B2 (ja)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08/469,348 US5705364A (en) 1995-06-06 1995-06-06 Mammalian cell culture process

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
JP9501638A Division JPH11507523A (ja) 1995-06-06 1996-06-06 哺乳類細胞培養によって生産されるタンパク質のシアリル化を制御する方法

Publications (2)

Publication Number Publication Date
JP2007190024A true JP2007190024A (ja) 2007-08-02
JP4348376B2 JP4348376B2 (ja) 2009-10-21

Family

ID=23863440

Family Applications (2)

Application Number Title Priority Date Filing Date
JP9501638A Withdrawn JPH11507523A (ja) 1995-06-06 1996-06-06 哺乳類細胞培養によって生産されるタンパク質のシアリル化を制御する方法
JP2007050848A Expired - Lifetime JP4348376B2 (ja) 1995-06-06 2007-02-28 哺乳類細胞培養によって生産されるタンパク質のシアリル化を制御する方法

Family Applications Before (1)

Application Number Title Priority Date Filing Date
JP9501638A Withdrawn JPH11507523A (ja) 1995-06-06 1996-06-06 哺乳類細胞培養によって生産されるタンパク質のシアリル化を制御する方法

Country Status (36)

Country Link
US (1) US5705364A (ja)
EP (2) EP1609853B2 (ja)
JP (2) JPH11507523A (ja)
KR (1) KR100496356B1 (ja)
CN (1) CN1166772C (ja)
AR (2) AR004940A1 (ja)
AT (2) ATE302266T1 (ja)
AU (1) AU717847B2 (ja)
BG (1) BG63213B1 (ja)
BR (1) BR9609150A (ja)
CA (1) CA2220684C (ja)
CZ (1) CZ293719B6 (ja)
DE (2) DE69637867D1 (ja)
DK (2) DK1609853T4 (ja)
EA (1) EA001215B1 (ja)
ES (2) ES2248812T5 (ja)
GE (1) GEP20012519B (ja)
HK (2) HK1017903A1 (ja)
HU (1) HU226420B1 (ja)
IL (1) IL122398A (ja)
IS (1) IS2614B (ja)
MY (1) MY113496A (ja)
NO (1) NO322276B1 (ja)
NZ (1) NZ310202A (ja)
OA (1) OA10753A (ja)
PL (1) PL185484B1 (ja)
PT (1) PT1609853E (ja)
RO (1) RO120267B1 (ja)
SA (1) SA96170351B1 (ja)
SI (2) SI0832189T2 (ja)
SK (1) SK282658B6 (ja)
TR (1) TR199701543T1 (ja)
TW (2) TW426734B (ja)
UA (1) UA47428C2 (ja)
WO (1) WO1996039488A1 (ja)
ZA (1) ZA964776B (ja)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017516484A (ja) * 2014-06-03 2017-06-22 ルピン・リミテッド タンパク質生産のための細胞培養工程

Families Citing this family (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0939121T4 (da) 1989-09-12 2008-02-04 Ahp Mfg B V TNF-bindende proteiner
US6656466B1 (en) * 1995-06-06 2003-12-02 Genetech, Inc. Human tumor necrosis factor—immunoglobulin(TNFR1-IgG1) chimera composition
US5705364A (en) † 1995-06-06 1998-01-06 Genentech, Inc. Mammalian cell culture process
JP4306813B2 (ja) 1995-09-19 2009-08-05 アスビオファーマ株式会社 動物細胞の新規培養方法
CA2253557A1 (en) * 1996-05-08 1997-11-13 Louis Martin Renzetti Treatment of asthma with tnfr-ig
US6673575B1 (en) * 1997-12-03 2004-01-06 Roche Diagnostics Gmbh Method for preparing polypeptides with appropriate glycosilation
US6140445A (en) * 1998-04-17 2000-10-31 Crompton Corporation Silane functional oligomer
ATE314485T1 (de) * 1998-05-29 2006-01-15 Genentech Inc Zellkulturverfahren für die produktion von glycoproteinen
US6528286B1 (en) * 1998-05-29 2003-03-04 Genentech, Inc. Mammalian cell culture process for producing glycoproteins
TR200504220T2 (tr) * 1998-12-17 2007-04-24 Biogen Idec Ma Inc. Aktif limfotoksin-beta reseptör imunoglobülin şimeAktif limfotoksin-beta reseptör imunoglobülin şimerik proteinlerinin yüksek düzey ifadesi ve saflaştrik proteinlerinin yüksek düzey ifadesi ve saflaştırılması için bir yöntem.ırılması için bir yöntem.
GB9828624D0 (en) * 1998-12-23 1999-02-17 Glaxo Group Ltd Production of proteins
KR100475417B1 (ko) * 1998-12-30 2005-07-18 씨제이 주식회사 시알산 함량이 높은 재조합 당단백질의 제조방법
US7294481B1 (en) * 1999-01-05 2007-11-13 Immunex Corporation Method for producing recombinant proteins
EP1171615B1 (en) 1999-04-26 2006-12-13 Genentech, Inc. Cell culture process for glycoproteins
US6261805B1 (en) * 1999-07-15 2001-07-17 Boyce Thompson Institute For Plant Research, Inc. Sialyiation of N-linked glycoproteins in the baculovirus expression vector system
KR100394474B1 (ko) * 1999-12-18 2003-08-09 동아제약 주식회사 동물세포에서 재조합 당단백질의 연속식 대량생산 방법
WO2001087922A2 (en) * 2000-05-16 2001-11-22 Lipoxen Technologies Limited Derivatisation of proteins in aqueous solution
WO2002002793A1 (fr) * 2000-07-05 2002-01-10 Japan As Represented By Secretary Of Osaka University Processus de production de glycoproteine
US20030040095A1 (en) * 2001-03-16 2003-02-27 Achille Arini Method for the production of pharmaceutically active recombinant proteins
US20030087372A1 (en) * 2001-06-13 2003-05-08 Genentech, Inc. Methods of culturing animal cells and polypeptide production in animal cells
PL376821A1 (pl) * 2002-03-27 2006-01-09 Immunex Corporation Sposoby zwiększania produkcji polipeptydów
US20030190710A1 (en) * 2002-03-28 2003-10-09 Devries Ruth L. Control of glycoforms in IgG
US6924124B1 (en) * 2002-08-23 2005-08-02 Immunex Corporation Feeding strategies for cell culture
US7067279B1 (en) 2002-08-23 2006-06-27 Immunex Corporation Cell culture performance with betaine
US6974681B1 (en) 2002-08-23 2005-12-13 Immunex Corporation Cell culture performance with vanadate
ES2347239T3 (es) * 2002-12-02 2010-10-27 Amgen Fremont Inc. Anticuerpos dirigidos al factor de necrosis tumoral y usos de los mismos.
ES2354610T5 (es) * 2002-12-23 2020-09-14 Bristol Myers Squibb Co Mejora de la calidad del producto en procedimientos de cultivo de células de mamífero para la producción de proteína
WO2004058800A2 (en) * 2002-12-23 2004-07-15 Bristol-Myers Squibb Company Mammalian cell culture processes for protein production
AU2004234377A1 (en) * 2003-04-25 2004-11-11 Immunex Corporation Inducers of recombinant protein expression
WO2005040377A2 (en) 2003-10-24 2005-05-06 Selexis S.A. High efficiency gene transfer and expression in mammalian cells by a multiple transfection procedure of matrix attachment region sequences
EP1697414A2 (en) * 2003-12-23 2006-09-06 Applied Research Systems ARS Holding N.V. Process for the production of tumor necrosis factor-binding proteins
EP1709185A1 (en) * 2003-12-31 2006-10-11 Samyang Genex Corporation Method for mass production of secondary metabolites in plant cell culture by treatment of an alkanoic acid or salt thereof
US8609370B2 (en) * 2004-02-13 2013-12-17 Glycotope Gmbh Highly active glycoproteins-process conditions and an efficient method for their production
US7335491B2 (en) * 2004-08-27 2008-02-26 Wyeth Research Ireland Limited Production of anti-abeta
TWI364458B (en) * 2004-08-27 2012-05-21 Wyeth Res Ireland Ltd Production of tnfr-lg
TWI384069B (zh) * 2004-08-27 2013-02-01 Pfizer Ireland Pharmaceuticals 多胜肽之製法
MX2007014148A (es) * 2005-05-19 2008-01-11 Amgen Inc Composiciones y metodos para incrementar la estabilidad de anticuerpos.
JP2008541746A (ja) * 2005-06-03 2008-11-27 ビオヴィトルム・アクチボラゲット（プブリクト） 新規プロセス
KR100670105B1 (ko) 2005-06-29 2007-01-17 주식회사 셀트리온 콩가수분해물의 저분자량 분획을 이용하여 시알산 함량이증가된 에리스로포이에틴을 생산하는 방법 및 그에 의하여생산된 시알산 함량이 증가된 에리스로포이에틴
US8470318B2 (en) 2005-11-07 2013-06-25 The Rockefeller University Polypeptides with enhanced anti-inflammatory and decreased cytotoxic properties and relating methods
WO2008057634A2 (en) * 2006-10-26 2008-05-15 The Rockefeller University Polypeptides with enhanced anti-inflammatory and decreased cytotoxic properties and relating methods
PL2253644T3 (pl) 2005-12-20 2014-04-30 Bristol Myers Squibb Co Kompozycje i sposoby wytwarzania kompozycji
AR058568A1 (es) 2005-12-20 2008-02-13 Bristol Myers Squibb Co Metodos para producir una composicion con moleculas ctla4-ig a partir de un medio de cultivo
US20070190057A1 (en) 2006-01-23 2007-08-16 Jian Wu Methods for modulating mannose content of recombinant proteins
JP5199886B2 (ja) * 2006-01-26 2013-05-15 レコファーマ アーベー ウイルスの接着を阻害するための組成物および方法
EP3456351A1 (en) * 2006-04-05 2019-03-20 The Rockefeller University Polypeptides with enhanced anti-inflammatory and decreased cytotoxic properties and relating methods
CN101541950A (zh) 2006-07-13 2009-09-23 惠氏公司 糖蛋白的产生
AU2007294731B2 (en) 2006-09-13 2014-04-17 Abbvie Inc. Cell culture improvements
US8911964B2 (en) 2006-09-13 2014-12-16 Abbvie Inc. Fed-batch method of making human anti-TNF-alpha antibody
US20080145893A1 (en) * 2006-09-17 2008-06-19 Excellegene Sa Method for producing a recombinant protein at high specific productivity, high batch yield and high volumetric yield by means of transient transfection
WO2008069244A1 (ja) * 2006-12-05 2008-06-12 Kyowa Hakko Kogyo Co., Ltd. 糖蛋白質組成物の製造方法
JP5175336B2 (ja) * 2007-04-16 2013-04-03 モメンタ ファーマシューティカルズ インコーポレイテッド 細胞表面グリコシル化に関連する方法
TW200902708A (en) 2007-04-23 2009-01-16 Wyeth Corp Methods of protein production using anti-senescence compounds
US20090023186A1 (en) * 2007-07-22 2009-01-22 Excellgene Sa Use of valproic acid for enhancing production of recombinant proteins in mammalian cells
EP3327132A3 (en) * 2007-08-09 2018-07-18 Wyeth LLC Use of perfusion to enhance production of fed-batch cell culture in bioreactors
EP3760715B1 (en) * 2008-03-06 2021-08-04 Halozyme, Inc. Large-scale production of soluble hyaluronidase
TWI395593B (zh) 2008-03-06 2013-05-11 Halozyme Inc 可活化的基質降解酵素之活體內暫時性控制
EP2283043B1 (en) * 2008-04-07 2014-08-13 Bayer HealthCare, LLC Methods of recombinant production of glycoproteins
US7846744B2 (en) 2008-04-22 2010-12-07 Ravetch Jeffrey V Methods of identifying anti-inflammatory compounds
BRPI0913475B8 (pt) 2008-09-15 2019-05-07 Genentech Inc vetor
NZ592097A (en) 2008-10-20 2013-01-25 Abbott Lab Viral inactivation during purification of il-12 and il-18 antibodies
CA2911256A1 (en) * 2008-10-20 2010-12-09 Robert K. Hickman Isolation and purification of antibodies using protein a affinity chromatography
CN102307993B (zh) 2008-12-09 2014-06-25 哈洛齐梅公司 延长的可溶性ph20多肽及其用途
EP2403523A1 (en) * 2009-03-06 2012-01-11 Halozyme, Inc. Temperature sensitive mutants of matrix metalloprotease 1 und uses thereof
US9540426B2 (en) * 2009-10-06 2017-01-10 Bristol-Myers Squibb Company Mammalian cell culture processes for protein production
BR112012009828B8 (pt) 2009-10-26 2022-10-25 Hoffmann La Roche Método para a produção de uma imunoglobulina glicosilada e seu uso
EP3255153A1 (en) 2009-11-17 2017-12-13 E. R. Squibb & Sons, L.L.C. Methods for enhanced protein production
CA2782320A1 (en) * 2009-12-02 2011-06-09 Acceleron Pharma Inc. Compositions and methods for increasing serum half-life of fc fusion proteins
NZ601790A (en) * 2010-02-24 2014-03-28 Zymenex As Process for production and purification of recombinant lysosomal alpha-mannosidase
JPWO2012017925A1 (ja) 2010-08-02 2013-10-03 協和発酵キリン株式会社 物質の製造方法
EP2686423A4 (en) 2011-03-14 2015-01-28 Nat Res Council Canada METHOD FOR PRODUCING VIRUSES IN CELLS
WO2012149197A2 (en) 2011-04-27 2012-11-01 Abbott Laboratories Methods for controlling the galactosylation profile of recombinantly-expressed proteins
MY169935A (en) 2011-04-29 2019-06-18 Biocon Biologics India Ltd "a method for reducing heterogeneity of antibodies and a process of producing the antibodies thereof"
US8883982B2 (en) 2011-06-08 2014-11-11 Acceleron Pharma, Inc. Compositions and methods for increasing serum half-life
US9067990B2 (en) 2013-03-14 2015-06-30 Abbvie, Inc. Protein purification using displacement chromatography
WO2013158273A1 (en) 2012-04-20 2013-10-24 Abbvie Inc. Methods to modulate c-terminal lysine variant distribution
US9334319B2 (en) 2012-04-20 2016-05-10 Abbvie Inc. Low acidic species compositions
WO2013176754A1 (en) 2012-05-24 2013-11-28 Abbvie Inc. Novel purification of antibodies using hydrophobic interaction chromatography
CN102839157A (zh) * 2012-07-12 2012-12-26 扬州大学 稳定共表达hST3GalIV和β1-4GalT1的MDCK细胞系及构建方法和应用
US9512214B2 (en) 2012-09-02 2016-12-06 Abbvie, Inc. Methods to control protein heterogeneity
KR20150043523A (ko) 2012-09-02 2015-04-22 애브비 인코포레이티드 단백질 불균일성의 제어 방법
NO2760138T3 (ja) 2012-10-01 2018-08-04
US20140106405A1 (en) * 2012-10-15 2014-04-17 Bristol-Myers Squibb Company Mammalian cell culture processes for protein production
WO2014062535A1 (en) 2012-10-15 2014-04-24 Bristol-Myers Squibb Company Mammalian cell culture processes for protein production
SG11201507230PA (en) 2013-03-12 2015-10-29 Abbvie Inc Human antibodies that bind human tnf-alpha and methods of preparing the same
WO2014159579A1 (en) 2013-03-14 2014-10-02 Abbvie Inc. MUTATED ANTI-TNFα ANTIBODIES AND METHODS OF THEIR USE
US9017687B1 (en) 2013-10-18 2015-04-28 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9217168B2 (en) 2013-03-14 2015-12-22 Momenta Pharmaceuticals, Inc. Methods of cell culture
WO2014151878A2 (en) 2013-03-14 2014-09-25 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosacharides
AR095196A1 (es) 2013-03-15 2015-09-30 Regeneron Pharma Medio de cultivo celular libre de suero
JP6563910B2 (ja) 2013-07-04 2019-08-21 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 血清サンプル中の抗薬物抗体を検出するための干渉抑制イムノアッセイ
BR112015032800A2 (pt) 2013-07-06 2017-07-25 Cadila Healthcare Ltd “processo para a produção de um anticorpo”
US9598667B2 (en) 2013-10-04 2017-03-21 Abbvie Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
US8946395B1 (en) 2013-10-18 2015-02-03 Abbvie Inc. Purification of proteins using hydrophobic interaction chromatography
US9085618B2 (en) 2013-10-18 2015-07-21 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9181337B2 (en) 2013-10-18 2015-11-10 Abbvie, Inc. Modulated lysine variant species compositions and methods for producing and using the same
WO2015073884A2 (en) 2013-11-15 2015-05-21 Abbvie, Inc. Glycoengineered binding protein compositions
RU2712562C2 (ru) * 2014-02-27 2020-01-29 Ф.Хоффманн-Ля Рош Аг Модулирование клеточного роста и гликозилирования при производстве рекомбинантных гликопротеинов
JP6652334B2 (ja) 2014-05-31 2020-02-19 Ｊｃｒファーマ株式会社 ウリジンとｎ−アセチル−ｄ−マンノサミンとを含有する培地
US20160130324A1 (en) 2014-10-31 2016-05-12 Shire Human Genetic Therapies, Inc. C1 Inhibitor Fusion Proteins and Uses Thereof
KR102007930B1 (ko) * 2014-12-31 2019-08-06 주식회사 엘지화학 재조합 당단백질의 글리코실화 조절 방법
TW202340452A (zh) 2015-08-04 2023-10-16 美商再生元醫藥公司 補充牛磺酸之細胞培養基及用法
MA43270A (fr) 2015-11-19 2021-06-02 Takeda Pharmaceuticals Co Inhibiteur de la c1 estérase humaine recombinante et ses utilisations
CN108882740A (zh) * 2015-12-29 2018-11-23 N·V·努特里奇亚 含有不可消化寡糖的发酵配方物
US20200385673A1 (en) * 2017-11-30 2020-12-10 Hoffmann-La Roche Inc. Process for culturing mammalian cells
BR112021008879A2 (pt) 2018-11-13 2021-10-26 Janssen Biotech, Inc. Controle de oligometais durante a produção de anticorpos anti-cd38
CN114206924A (zh) 2019-12-06 2022-03-18 瑞泽恩制药公司 抗vegf蛋白组合物及其制备方法
IL300828A (en) 2020-08-31 2023-04-01 Regeneron Pharma Asparagine feeding strategies to improve cell culture performance and reduce asparagine sequence variants
CN116761880A (zh) 2021-01-20 2023-09-15 瑞泽恩制药公司 改进细胞培养物中的蛋白质滴度的方法
CA3230985A1 (en) 2021-10-07 2023-04-13 Ross BROWNE Ph meter calibration and correction
US20230116199A1 (en) 2021-10-07 2023-04-13 Regeneron Pharmaceuticals, Inc. Systems and methods of ph modeling and control
US20240010737A1 (en) 2022-03-02 2024-01-11 Regeneron Pharmaceuticals, Inc. Manufacturing process for high titer antibody

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3926723A (en) 1974-08-08 1975-12-16 Massachusetts Inst Technology Method of controllably releasing glucose to a cell culture medium
JPS5938488B2 (ja) 1979-05-07 1984-09-17 株式会社東芝 空気調和機
GB2122207B (en) * 1982-06-21 1986-02-12 Wellcome Found Interferon production
US4560655A (en) 1982-12-16 1985-12-24 Immunex Corporation Serum-free cell culture medium and process for making same
US4657866A (en) 1982-12-21 1987-04-14 Sudhir Kumar Serum-free, synthetic, completely chemically defined tissue culture media
US4767704A (en) 1983-10-07 1988-08-30 Columbia University In The City Of New York Protein-free culture medium
US4724206A (en) * 1984-02-13 1988-02-09 Damon Biotech, Inc. Protein production using hypertonic media
GB8516415D0 (en) 1985-06-28 1985-07-31 Celltech Ltd Culture of animal cells
JPH0639919B2 (ja) 1985-08-29 1994-05-25 トヨタ自動車株式会社 過給機付き内燃機関の異常判別装置
GB8606386D0 (en) * 1986-03-14 1986-04-23 Celltech Ltd Production of protein
US4927762A (en) 1986-04-01 1990-05-22 Cell Enterprises, Inc. Cell culture medium with antioxidant
WO1988001643A1 (en) 1986-08-29 1988-03-10 Endotronics, Inc. Method of culturing cells
JPH01257492A (ja) * 1987-03-05 1989-10-13 Green Cross Corp:The 異種蛋白質の生産増強方法
IL87737A (en) * 1987-09-11 1993-08-18 Genentech Inc Method for culturing polypeptide factor dependent vertebrate recombinant cells
JPH066054B2 (ja) 1987-10-15 1994-01-26 帝人株式会社 動物細胞の培養方法
CA1312030C (en) * 1987-11-18 1992-12-29 Brian Maiorella Method to increase antibody titer
US5151359A (en) * 1988-05-19 1992-09-29 Mitsui Toatsu Chemicals Incorporated Method for producing of human tissue type plasminogen activator
ATE135397T1 (de) 1988-09-23 1996-03-15 Cetus Oncology Corp Zellenzuchtmedium für erhöhtes zellenwachstum, zur erhöhung der langlebigkeit und expression der produkte
KR0132666B1 (en) * 1989-03-14 1998-04-14 Hitachi Kk Method for controlling cultivation conditions for animal cells
JPH0396383A (ja) 1989-09-08 1991-04-22 Riso Kagaku Corp 画像形成装置
DK0939121T4 (da) 1989-09-12 2008-02-04 Ahp Mfg B V TNF-bindende proteiner
US5096816A (en) * 1990-06-05 1992-03-17 Cetus Corporation In vitro management of ammonia's effect on glycosylation of cell products through pH control
US5122469A (en) * 1990-10-03 1992-06-16 Genentech, Inc. Method for culturing Chinese hamster ovary cells to improve production of recombinant proteins
GB9022545D0 (en) * 1990-10-17 1990-11-28 Wellcome Found Culture medium
GB2251249B (en) * 1990-12-28 1995-06-21 Mogam Biotech Res Inst High-density medium for animal cell culture
WO1993010260A1 (en) * 1991-11-21 1993-05-27 The Board Of Trustees Of The Leland Stanford Junior University Controlling degradation of glycoprotein oligosaccharides by extracellular glycosisases
US5447851B1 (en) * 1992-04-02 1999-07-06 Univ Texas System Board Of Dna encoding a chimeric polypeptide comprising the extracellular domain of tnf receptor fused to igg vectors and host cells
WO1994006476A1 (en) * 1992-09-15 1994-03-31 Immunex Corporation Method of treating tnf-dependent inflammation using tumor necrosis factor antagonists
JP3523293B2 (ja) † 1993-07-19 2004-04-26 住友製薬株式会社 インターフェロンの産生増強法
US5705364A (en) † 1995-06-06 1998-01-06 Genentech, Inc. Mammalian cell culture process
JP5515221B2 (ja) † 2008-01-28 2014-06-11 日油株式会社 ポリオキシエチレンソルビタン脂肪酸エステルの製造方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017516484A (ja) * 2014-06-03 2017-06-22 ルピン・リミテッド タンパク質生産のための細胞培養工程

Also Published As

Publication number Publication date
BG63213B1 (bg) 2001-06-29
IL122398A0 (en) 1998-06-15
SI0832189T1 (sl) 2006-02-28
DE69637867D1 (de) 2009-04-23
OA10753A (en) 2002-12-11
BR9609150A (pt) 1999-02-23
SK282658B6 (sk) 2002-11-06
HU226420B1 (en) 2008-12-29
EP1609853B1 (en) 2009-03-11
SI1609853T2 (sl) 2020-07-31
NO975674D0 (no) 1997-12-05
CN1166772C (zh) 2004-09-15
UA47428C2 (uk) 2002-07-15
EP0832189B1 (en) 2005-08-17
CA2220684C (en) 2002-11-12
DK1609853T4 (da) 2020-04-06
ATE302266T1 (de) 2005-09-15
ZA964776B (en) 1997-12-08
TR199701543T1 (xx) 1998-05-21
ES2248812T5 (es) 2008-12-16
AU6095296A (en) 1996-12-24
AR004940A1 (es) 1999-04-07
KR19990022473A (ko) 1999-03-25
SI0832189T2 (sl) 2008-12-31
BG102101A (en) 1998-07-31
DK0832189T3 (da) 2005-11-21
JPH11507523A (ja) 1999-07-06
ES2248812T3 (es) 2006-03-16
KR100496356B1 (ko) 2005-11-25
RO120267B1 (ro) 2005-11-30
NO322276B1 (no) 2006-09-04
MX9709452A (es) 1998-06-30
GEP20012519B (en) 2001-08-27
IL122398A (en) 2001-12-23
ES2324046T5 (es) 2020-09-14
DK1609853T3 (da) 2009-06-02
PL185484B1 (pl) 2003-05-30
AR011439A2 (es) 2000-08-16
DK0832189T4 (da) 2008-10-27
CN1186514A (zh) 1998-07-01
JP4348376B2 (ja) 2009-10-21
PL323737A1 (en) 1998-04-14
NZ310202A (en) 1999-10-28
HUP9900920A2 (hu) 1999-07-28
CZ293719B6 (cs) 2004-07-14
SA96170351B1 (ar) 2006-07-04
HUP9900920A3 (en) 2001-06-28
MY113496A (en) 2002-03-30
HK1017903A1 (en) 1999-12-03
SI1609853T1 (sl) 2009-08-31
DE69635076T3 (de) 2009-01-15
EP1609853A1 (en) 2005-12-28
ES2324046T3 (es) 2009-07-29
SK167097A3 (en) 1998-07-08
EA001215B1 (ru) 2000-12-25
DE69635076D1 (de) 2005-09-22
AU717847B2 (en) 2000-04-06
EA199700364A1 (ru) 1998-04-30
CA2220684A1 (en) 1996-12-12
US5705364A (en) 1998-01-06
EP1609853B2 (en) 2020-01-22
TW516962B (en) 2003-01-11
CZ390997A3 (cs) 1998-06-17
EP0832189A1 (en) 1998-04-01
IS2614B (is) 2010-04-15
PT1609853E (pt) 2009-06-09
HK1087151A1 (en) 2006-10-06
IS4626A (is) 1997-12-03
NO975674L (no) 1998-02-06
ATE425245T2 (de) 2009-03-15
DE69635076T2 (de) 2006-06-01
EP0832189B2 (en) 2008-07-09
TW426734B (en) 2001-03-21
WO1996039488A1 (en) 1996-12-12

Similar Documents

Publication Publication Date Title
JP2007190024A (ja) 哺乳類細胞培養によって生産されるタンパク質のシアリル化を制御する方法
EP1128847B1 (en) Antibody-serum protein hybrids
JPH05502380A (ja) 低―動物毒性と高殺細胞活性の改良シュードモナス外毒素
JP2008507283A (ja) 疾患処置におけるｍｇｄ−ｃｓｆのための組成物およびその使用方法
CS270558B2 (en) Method of carbacycline derivatives' cyclodextrin's clathrates production
JPH01153628A (ja) メルファラン製剤
JP2021120393A5 (ja)
JPH0412277B2 (ja)
CA2272356C (en) Soluble polypeptides
JP2001120262A (ja) 生理活性物質の産生増強方法
CN1303387A (zh) 铂配合物、其制备和治疗应用
JPH07508501A (ja) 含フッ素ビタミンｄ↓３類縁体
Wolfrom et al. L-Fructose1
AU683104B2 (en) Improved cell cultivation method and medium
WO1990013557A1 (en) New s-adenosylmethionine derivative
US20060166927A1 (en) Compounds that bind to the interferon-gamma, preparation method thereof and medicaments containing same
CA2401032A1 (en) Memno peptides, a process for their preparation and their use
JP3694868B2 (ja) ヒアルロン酸ナトリウム注射液組成物
JPH0262885A (ja) 有機ゲルマニウム化合物及びその製造方法
JP3362468B2 (ja) Ｎ−混合飽和脂肪酸アシル中性アミノ酸の製造法
JPS62120375A (ja) チアゾリジン誘導体、その製法および医薬組成物
CN1022912C (zh) 激光合成维生素d
JP2683946B2 (ja) 細胞培養によるタンパク質産生方法
JP2777455B2 (ja) Ｎ―長鎖アシル酸性アミノ酸の製造方法
AU2003273727B2 (en) Method of obtaining cell lines in a protein-free medium and cell lines thus obtained

Legal Events

Date Code Title Description
RD03 Notification of appointment of power of attorney

Free format text: JAPANESE INTERMEDIATE CODE: A7423

Effective date: 20071108

RD04 Notification of resignation of power of attorney

Free format text: JAPANESE INTERMEDIATE CODE: A7424

Effective date: 20071114

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20081104

A601 Written request for extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A601

Effective date: 20090204

A602 Written permission of extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A602

Effective date: 20090209

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20090501

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: 20090623

A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20090717

R150 Certificate of patent or registration of utility model

Free format text: JAPANESE INTERMEDIATE CODE: R150

FPAY Renewal fee payment (event date is renewal date of database)

Free format text: PAYMENT UNTIL: 20120724

Year of fee payment: 3

FPAY Renewal fee payment (event date is renewal date of database)

Free format text: PAYMENT UNTIL: 20120724

Year of fee payment: 3

FPAY Renewal fee payment (event date is renewal date of database)

Free format text: PAYMENT UNTIL: 20130724

Year of fee payment: 4

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

EXPY Cancellation because of completion of term