JP5870088B2 - 共役血液凝固第viii因子 - Google Patents
共役血液凝固第viii因子 Download PDFInfo
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- JP5870088B2 JP5870088B2 JP2013506735A JP2013506735A JP5870088B2 JP 5870088 B2 JP5870088 B2 JP 5870088B2 JP 2013506735 A JP2013506735 A JP 2013506735A JP 2013506735 A JP2013506735 A JP 2013506735A JP 5870088 B2 JP5870088 B2 JP 5870088B2
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- 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
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
-
- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
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- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Medicinal Chemistry (AREA)
- Public Health (AREA)
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- Animal Behavior & Ethology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Description
(a)FVIIIの2つのシステイン残基間のもとのジスルフィド結合を還元して、2つの遊離チオール基を生成し;
(b)共役二重結合を有する共役試薬および脱離基の第1のチオレート付加反応(thiolate addition reaction)を行い;
(c)前記脱離基の脱離によって、共役二重結合を生成し;さらに
(d)第2のチオレート付加反応を行い、2つの硫黄原子間に3−炭素架橋を形成する
ことを含む。
ヒトFVIIIのジスルフィドPEG化を、Shaunak et al. in Nat Chem Biol. 2006; 2(6):312-31に記載される方法を改変した方法に従って行う。
TheraPEG(商標)PEG化方法は、ジスルフィド結合の還元が必要である。還元は、セレノシスタミン(SeCys)の存在または不存在下のいずれかにおいて、ジチオトレイトール(DTT)、2−メルカプトエタノール、またはトリス(2−カルボキシエチル)ホスフィン(TCEP)等の好適な還元剤を用いて行われる。用いられる還元剤の濃度は、例えば、0.5〜5mmのDTTまたは低い過剰モルのTCEPである。
FVIIIのPEG化のためにTheraPEG(商標)を使用する最初の評価が小スケール反応(例えば、5〜20μg FVIII)で行われる。これにより、PEG試薬を用いてPEG化FVIIIを再現性良く調製するのに使用される条件を同定できる。タンパク質分解を防止、またはタンパク質の安定性を支援するために、ベンズアミジンまたは他の添加剤が添加されうる。
FVIIIおよびPEG化FVIIIの活性は、クロマトグラフィーアッセイおよび修飾活性化部分トロンボプラスチン時間凝固アッセイを用いて測定される。
前記クロマトグラフィーアッセイ(Hypen Biomed catalogue number The chromogenic assay (Hyphen Biomed, catalogue no. 221402)は、着色基質の形成によってFVIIIの活性を測定するものであり、凝固形成を伴わない。発色アッセイに係る工程の概略図である図3を参照。
凝固FVIIIの試験方法は、活性化部分トロンボプラスチン時間(aPTT)に基づく一段階アッセイである。FVIIIは、第IXa因子、カルシウム、およびリン脂質の存在下、第X因子の第Xa因子への酵素的変換において、補酵素として作用する。凝固物の形成にかかる時間(秒)と、FVIII濃度の対数との間には、反比例の関係がある。
1.第VIII因子欠損血漿、Helena Biosciences、カタログ番号5193
2.aPTT−ES試薬、Helena Biosciences、カタログ番号5397
3.塩化カルシウム溶液、0.025mol/L
希釈した試験サンプル25μlをインキュベートし、FVIII欠損血漿25μlを、予め加温したaPTT−ES試薬50μlとともにインキュベートさせる。活性化剤により接触システムが開始する。次いで、リン脂質の存在下、内因性経路の残りが行われる。37℃で正確に3分インキュベーションを行った後、0.025mol/Lの塩化カルシウム50μlを添加し、凝固を開始させる。前記凝固時間は、Sysmex CA50凝固分析器(Sysmex CA50 coagulation analyser)で測定した。
Claims (23)
- FVIIIでジスルフィド結合を形成した2つのシステイン残基の硫黄原子を架橋するリンカー基によって1つ以上のポリエチレングリコール基が第VIII因子に共役してなり、以下の構造を有する、第VIII因子−ポリエチレングリコール共役体:
- 前記アルキレン基がC 1−10 アルキレン基である、請求項1に記載の第VIII因子−ポリエチレングリコール共役体。
- 前記ポリエチレングリコールが5〜100kDaの分子量を有する、請求項1または2に記載の第VIII因子−ポリエチレングリコール共役体。
- 請求項1〜3のいずれか1項に記載の第VIII因子−ポリエチレングリコール共役体を含む、薬剤組成物。
- 製薬上許容できる希釈剤、アジュバント、または担体を含む、請求項4に記載の薬剤組成物。
- 他の薬剤活性のある物質(pharmaceutically active agent)をさらに含む、請求項4または5に記載の薬剤組成物。
- 非経口投与に適する、請求項4〜6のいずれか1項に記載の薬剤組成物。
- 皮内、皮下、および筋肉内注射、並びに静脈内または骨内注入に適する、請求項4〜7のいずれか1項に記載の薬剤組成物。
- 溶液、懸濁液、またはエマルジョンの形態を有する、請求項4〜8のいずれか1項に記載の薬剤組成物。
- 前記共役体が、未修飾のFVIIIと比べて長い半減期を有する、請求項4〜9のいずれか1項に記載の薬剤組成物。
- 前記共役体が、未修飾のFVIIIと比べて高いAUCを有する、請求項4〜10のいずれか1項に記載の薬剤組成物。
- 前記共役体が、未修飾のFVIIIと比べて高いバイオアベイラビリティを有する、請求項4〜11のいずれか1項に記載の薬剤組成物。
- 前記共役体が、未修飾のFVIIIと比べて低い免疫原性を有する、請求項4〜12のいずれか1項に記載の薬剤組成物。
- 血液凝固疾患(blood clotting disease)または外傷(trauma)の治療に用いられる、請求項4〜13のいずれか1項に記載の薬剤組成物。
- 前記血液凝固疾患が、血友病Aまたは血友病Bである、請求項14に記載の薬剤組成物。
- 血友病A、血友病Bまたは外傷を有する哺乳動物の関節血症、出血、胃腸出血、および月経過多症の危険性を低減するのに用いられる、請求項4〜13のいずれか1項に記載の薬剤組成物。
- 皮下に投与されて用いられる、請求項16に記載の薬剤組成物。
- 静脈内に投与されて用いられる、請求項16に記載の薬剤組成物。
- 1〜14日に1度投与されて用いられる、請求項16に記載の薬剤組成物。
- FVIIIの機能の欠損の特徴を有する血液凝固疾患(blood clotting disease)の治療、または外傷の治療に使用される、請求項1〜3のいずれか1項に記載の第VIII因子−ポリエチレングリコール共役体。
- 以下の構造を有する、第VIII因子−ポリエチレングリコール共役体:
の調製方法であって、
(a)FVIIIの2つのシステイン残基間のもとのジスルフィド結合を還元して、2つの遊離チオール基を生成し;
(b)共役二重結合を有する共役試薬および脱離基の第1のチオレート付加反応(thiolate addition reaction)を行い;
(c)前記脱離基の脱離によって、共役二重結合を生成し;さらに
(d)第2のチオレート付加反応を行い、2つの硫黄原子間に3−炭素架橋を形成する
ことを含む、方法。 - 前記共役試薬は、下記式:
を有する、請求項21に記載の方法。 - 前記アルキレン基がC 1−10 アルキレン基である、請求項21または22に記載の調製方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1007357.5 | 2010-04-30 | ||
GBGB1007357.5A GB201007357D0 (en) | 2010-04-30 | 2010-04-30 | Conjugated factor VIII |
PCT/GB2011/000662 WO2011135307A1 (en) | 2010-04-30 | 2011-04-28 | Conjugated blood coagulation factor viii |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2013525414A JP2013525414A (ja) | 2013-06-20 |
JP2013525414A5 JP2013525414A5 (ja) | 2014-06-19 |
JP5870088B2 true JP5870088B2 (ja) | 2016-02-24 |
Family
ID=42289987
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013506735A Expired - Fee Related JP5870088B2 (ja) | 2010-04-30 | 2011-04-28 | 共役血液凝固第viii因子 |
Country Status (26)
Country | Link |
---|---|
US (1) | US20130150302A1 (ja) |
EP (1) | EP2563402A1 (ja) |
JP (1) | JP5870088B2 (ja) |
KR (1) | KR20130055619A (ja) |
CN (1) | CN102939108A (ja) |
AP (1) | AP2012006575A0 (ja) |
AU (1) | AU2011247147B2 (ja) |
BR (1) | BR112012027590A2 (ja) |
CA (1) | CA2797058A1 (ja) |
CL (1) | CL2012003039A1 (ja) |
CO (1) | CO6660443A2 (ja) |
CR (1) | CR20120579A (ja) |
EA (1) | EA201290938A1 (ja) |
EC (1) | ECSP12012314A (ja) |
GB (2) | GB201007357D0 (ja) |
HK (1) | HK1173946A1 (ja) |
IL (1) | IL222566A (ja) |
MX (1) | MX2012012683A (ja) |
MY (1) | MY160922A (ja) |
NI (1) | NI201200160A (ja) |
NZ (1) | NZ603939A (ja) |
PE (1) | PE20130254A1 (ja) |
RU (1) | RU2012144555A (ja) |
SG (1) | SG184906A1 (ja) |
WO (1) | WO2011135307A1 (ja) |
ZA (1) | ZA201208989B (ja) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8637007B2 (en) | 2006-12-15 | 2014-01-28 | Baxter International Inc. | Factor VIIa-polysialic acid conjugate having prolonged in vivo half-life |
CA2769326A1 (en) | 2009-07-27 | 2011-02-10 | Baxter International Inc. | Blood coagulation protein conjugates |
ES2856055T3 (es) | 2009-07-27 | 2021-09-27 | Baxalta GmbH | Glicopolisialilación de proteínas diferentes de las proteínas de coagulación de la sangre |
US8642737B2 (en) | 2010-07-26 | 2014-02-04 | Baxter International Inc. | Nucleophilic catalysts for oxime linkage |
ES2590679T3 (es) | 2009-07-27 | 2016-11-23 | Lipoxen Technologies Limited | Glicopolisialilación de proteínas diferentes a proteínas de coagulación de la sangre |
US8809501B2 (en) | 2009-07-27 | 2014-08-19 | Baxter International Inc. | Nucleophilic catalysts for oxime linkage |
KR102025442B1 (ko) | 2010-12-22 | 2019-09-25 | 박스알타 인코퍼레이티드 | 단백질에 수용성 지방산 유도체를 접합하기 위한 물질 및 방법 |
WO2013156488A2 (en) * | 2012-04-16 | 2013-10-24 | Leverton Licence Holdings Limited | Optimised subcutaneous therapeutic agents |
GB201417589D0 (en) | 2014-10-06 | 2014-11-19 | Cantab Biopharmaceuticals Patents Ltd | Pharmaceutical Formulations |
GB201518172D0 (en) | 2015-10-14 | 2015-11-25 | Cantab Biopharmaceuticals Patents Ltd | Colloidal particles for use in medicine |
GB201518170D0 (en) | 2015-10-14 | 2015-11-25 | Cantab Biopharmaceuticals Patents Ltd | Colloidal particles for subcutaneous administration with intravenous administration of therapeutic agent |
GB201518171D0 (en) | 2015-10-14 | 2015-11-25 | Cantab Biopharmaceuticals Patents Ltd | Colloidal particles for topical administration with therapeutic agent |
KR20190086269A (ko) * | 2018-01-12 | 2019-07-22 | 재단법인 목암생명과학연구소 | 체내 지속형 재조합 당단백질 및 이의 제조방법 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2788505C (en) * | 2003-02-26 | 2018-09-04 | Nektar Therapeutics | Polymer-factor viii moiety conjugates |
GB0316294D0 (en) | 2003-07-11 | 2003-08-13 | Polytherics Ltd | Conjugated biological molecules and their preparation |
SI3130601T1 (sl) * | 2004-11-12 | 2020-11-30 | Bayer Healthcare Llc | Usmerjena modifikacija FVIII |
WO2006071801A2 (en) * | 2004-12-27 | 2006-07-06 | Baxter International Inc | Polymer-von willebrand factor-conjugates |
AU2007245190B2 (en) * | 2006-03-31 | 2011-07-21 | Takeda Pharmaceutical Company Limited | Pegylated factor VIII |
EP2209494B1 (en) | 2007-10-09 | 2016-07-20 | Polytherics Limited | Novel conjugated proteins and peptides |
WO2009130602A2 (en) | 2008-04-24 | 2009-10-29 | Celtic Pharma Peg Ltd. | Factor ix conjugates with extended half-lives |
EP2326349B1 (en) | 2008-07-21 | 2015-02-25 | Polytherics Limited | Novel reagents and method for conjugating biological molecules |
GB0912485D0 (en) * | 2009-07-17 | 2009-08-26 | Polytherics Ltd | Improved conjugation method |
-
2010
- 2010-04-30 GB GBGB1007357.5A patent/GB201007357D0/en not_active Ceased
-
2011
- 2011-04-28 JP JP2013506735A patent/JP5870088B2/ja not_active Expired - Fee Related
- 2011-04-28 NZ NZ603939A patent/NZ603939A/xx not_active IP Right Cessation
- 2011-04-28 CN CN2011800218881A patent/CN102939108A/zh active Pending
- 2011-04-28 EA EA201290938A patent/EA201290938A1/ru unknown
- 2011-04-28 AU AU2011247147A patent/AU2011247147B2/en not_active Ceased
- 2011-04-28 US US13/643,287 patent/US20130150302A1/en not_active Abandoned
- 2011-04-28 WO PCT/GB2011/000662 patent/WO2011135307A1/en active Application Filing
- 2011-04-28 EP EP11719040A patent/EP2563402A1/en not_active Withdrawn
- 2011-04-28 PE PE2012002104A patent/PE20130254A1/es not_active Application Discontinuation
- 2011-04-28 KR KR1020127031386A patent/KR20130055619A/ko not_active Application Discontinuation
- 2011-04-28 GB GB201220667A patent/GB2492935B8/en not_active Expired - Fee Related
- 2011-04-28 CA CA2797058A patent/CA2797058A1/en active Pending
- 2011-04-28 BR BR112012027590A patent/BR112012027590A2/pt not_active IP Right Cessation
- 2011-04-28 SG SG2012077087A patent/SG184906A1/en unknown
- 2011-04-28 AP AP2012006575A patent/AP2012006575A0/xx unknown
- 2011-04-28 MX MX2012012683A patent/MX2012012683A/es not_active Application Discontinuation
- 2011-04-28 MY MYPI2012004710A patent/MY160922A/en unknown
- 2011-04-28 RU RU2012144555/15A patent/RU2012144555A/ru not_active Application Discontinuation
-
2012
- 2012-10-21 IL IL222566A patent/IL222566A/en not_active IP Right Cessation
- 2012-10-29 CL CL2012003039A patent/CL2012003039A1/es unknown
- 2012-10-29 NI NI201200160A patent/NI201200160A/es unknown
- 2012-11-14 CR CR20120579A patent/CR20120579A/es unknown
- 2012-11-28 EC ECSP12012314 patent/ECSP12012314A/es unknown
- 2012-11-28 ZA ZA2012/08989A patent/ZA201208989B/en unknown
- 2012-11-29 CO CO12216949A patent/CO6660443A2/es unknown
-
2013
- 2013-01-18 HK HK13100809.6A patent/HK1173946A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
PE20130254A1 (es) | 2013-03-16 |
GB2492935B8 (en) | 2014-10-29 |
GB201007357D0 (en) | 2010-06-16 |
GB2492935B (en) | 2014-04-30 |
AU2011247147B2 (en) | 2014-09-18 |
IL222566A0 (en) | 2012-12-31 |
WO2011135307A1 (en) | 2011-11-03 |
US20130150302A1 (en) | 2013-06-13 |
NI201200160A (es) | 2013-04-19 |
GB201220667D0 (en) | 2013-01-02 |
ECSP12012314A (es) | 2013-05-31 |
AU2011247147A1 (en) | 2013-01-10 |
EA201290938A1 (ru) | 2013-04-30 |
ZA201208989B (en) | 2014-02-26 |
GB2492935A (en) | 2013-01-16 |
MY160922A (en) | 2017-03-31 |
MX2012012683A (es) | 2013-04-03 |
KR20130055619A (ko) | 2013-05-28 |
NZ603939A (en) | 2013-08-30 |
HK1173946A1 (en) | 2013-05-31 |
EP2563402A1 (en) | 2013-03-06 |
SG184906A1 (en) | 2012-11-29 |
CA2797058A1 (en) | 2011-11-03 |
GB2492935A8 (en) | 2014-10-29 |
CR20120579A (es) | 2013-04-25 |
IL222566A (en) | 2017-12-31 |
CL2012003039A1 (es) | 2014-01-24 |
AP2012006575A0 (en) | 2012-12-31 |
RU2012144555A (ru) | 2014-06-10 |
JP2013525414A (ja) | 2013-06-20 |
CN102939108A (zh) | 2013-02-20 |
BR112012027590A2 (pt) | 2016-08-09 |
CO6660443A2 (es) | 2013-04-30 |
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