JP2012518403A5 - - Google Patents
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- JP2012518403A5 JP2012518403A5 JP2011550638A JP2011550638A JP2012518403A5 JP 2012518403 A5 JP2012518403 A5 JP 2012518403A5 JP 2011550638 A JP2011550638 A JP 2011550638A JP 2011550638 A JP2011550638 A JP 2011550638A JP 2012518403 A5 JP2012518403 A5 JP 2012518403A5
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| UA128185C2 (uk) | 2018-01-29 | 2024-05-01 | Іпсен Біофарм Лімітед | Ботулінічний нейротоксин, який розщеплює ненейронний snare |
| WO2019241649A1 (en) | 2018-06-14 | 2019-12-19 | President And Fellows Of Harvard College | Evolution of cytidine deaminases |
| GB201815844D0 (en) | 2018-09-28 | 2018-11-14 | Ipsen Biopharm Ltd | Therapeutic & comestic uses of botulinum neurotoxin serotype e |
| GB201815817D0 (en) | 2018-09-28 | 2018-11-14 | Ispen Biopharm Ltd | Clostridial neurotoxins comprising and exogenous activation loop |
| KR102174197B1 (ko) * | 2019-06-12 | 2020-11-04 | 주식회사 앤씨비아이티 | 생산성이 향상된 비독성 프로테아제 |
| WO2022133266A1 (en) * | 2020-12-18 | 2022-06-23 | The Broad Institute, Inc. | Evolution of botulinum neurotoxin proteases |
| CN114957482B (zh) * | 2021-02-26 | 2024-09-24 | 重庆誉颜制药有限公司 | 一种经修饰的神经毒素的单链多肽及其用途 |
| GB202103372D0 (en) | 2021-03-11 | 2021-04-28 | Ipsen Biopharm Ltd | Modified clostridial neurotoxins |
| GB202104294D0 (en) | 2021-03-26 | 2021-05-12 | Ipsen Biopharm Ltd | Clostridial neurotoxins comprising an exogenous activation loop |
| GB202214229D0 (en) | 2022-09-28 | 2022-11-09 | Ipsen Biopharm Ltd | Clostridial neurotoxins comprising an activating endosomal protease cleavage site |
| GB202214232D0 (en) | 2022-09-28 | 2022-11-09 | Ispen Biopharm Ltd | Clostridial neurotoxins comprising an activating exogenous protease cleavage site |
| KR20250069883A (ko) | 2022-09-30 | 2025-05-20 | 입센 바이오팜 리미티드 | 방광 통증 증후군 치료에 사용되는 클로스트리디움 신경독소 |
| GB202318884D0 (en) | 2023-12-11 | 2024-01-24 | Ipsen Biopharm Ltd | Formulation |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2380457A1 (en) | 1999-08-25 | 2001-03-01 | Allergan Sales, Inc. | Activatable recombinant neurotoxins |
| GB9921592D0 (en) | 1999-09-13 | 1999-11-17 | Microbiological Res Authority | Preparation of highly pure toxin fragments |
| US20080038274A1 (en) | 1999-09-23 | 2008-02-14 | Foster Keith A | Inhibition of secretion from non-neuronal cells |
| US7273722B2 (en) * | 2000-11-29 | 2007-09-25 | Allergan, Inc. | Neurotoxins with enhanced target specificity |
| GB0321344D0 (en) * | 2003-09-11 | 2003-10-15 | Health Prot Agency | Re-targeted toxin conjugates |
| US6991789B2 (en) * | 2004-06-29 | 2006-01-31 | Allergas, Inc. | Methods of modulating intracellular degradation rates of toxins |
| US20060024331A1 (en) | 2004-08-02 | 2006-02-02 | Ester Fernandez-Salas | Toxin compounds with enhanced membrane translocation characteristics |
| WO2006026780A1 (en) | 2004-09-01 | 2006-03-09 | Allergan, Inc. | Degradable clostridial toxins |
| GB0426397D0 (en) | 2004-12-01 | 2005-01-05 | Health Prot Agency | Fusion proteins |
| EP2310029B1 (en) | 2008-06-12 | 2019-04-03 | Ipsen Bioinnovation Limited | Fusion proteins for use in the treatment of cancer |
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2009
- 2009-02-23 GB GBGB0903006.5A patent/GB0903006D0/en not_active Ceased
- 2009-12-16 WO PCT/GB2009/002892 patent/WO2010094905A1/en not_active Ceased
- 2009-12-16 CA CA2753101A patent/CA2753101C/en not_active Expired - Fee Related
- 2009-12-16 US US13/202,696 patent/US9849163B2/en active Active
- 2009-12-16 JP JP2011550638A patent/JP5764072B2/ja not_active Expired - Fee Related
- 2009-12-16 ES ES09799683.9T patent/ES2537338T5/es active Active
- 2009-12-16 EP EP09799683.9A patent/EP2398495B2/en active Active
- 2009-12-16 AU AU2009340404A patent/AU2009340404B2/en not_active Ceased
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2016
- 2016-04-28 US US15/141,268 patent/US10744190B2/en active Active
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