SG11201811338VA - A novel botulinum neurotoxin and its derivatives - Google Patents
A novel botulinum neurotoxin and its derivativesInfo
- Publication number
- SG11201811338VA SG11201811338VA SG11201811338VA SG11201811338VA SG11201811338VA SG 11201811338V A SG11201811338V A SG 11201811338VA SG 11201811338V A SG11201811338V A SG 11201811338VA SG 11201811338V A SG11201811338V A SG 11201811338VA SG 11201811338V A SG11201811338V A SG 11201811338VA
- Authority
- SG
- Singapore
- Prior art keywords
- international
- boston
- pct
- bont
- botulinum neurotoxin
- Prior art date
Links
- 108030001720 Bontoxilysin Proteins 0.000 title abstract 5
- 231100001103 botulinum neurotoxin Toxicity 0.000 title abstract 5
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 229920001184 polypeptide Polymers 0.000 abstract 2
- 102000004196 processed proteins & peptides Human genes 0.000 abstract 2
- 108090000765 processed proteins & peptides Proteins 0.000 abstract 2
- 241001112695 Clostridiales Species 0.000 abstract 1
- 101000761935 Clostridium botulinum Botulinum neurotoxin type X Proteins 0.000 abstract 1
- 230000008520 organization Effects 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
Classifications
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- 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)
- C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
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- 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)
- C12Y304/24—Metalloendopeptidases (3.4.24)
- C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P27/02—Ophthalmic agents
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- 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]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
- A61P37/08—Antiallergic agents
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- 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
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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
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/035—Fusion polypeptide containing a localisation/targetting motif containing a signal for targeting to the external surface of a cell, e.g. to the outer membrane of Gram negative bacteria, GPI- anchored eukaryote proteins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/20—Fusion polypeptide containing a tag with affinity for a non-protein ligand
- C07K2319/21—Fusion polypeptide containing a tag with affinity for a non-protein ligand containing a His-tag
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/20—Fusion polypeptide containing a tag with affinity for a non-protein ligand
- C07K2319/22—Fusion polypeptide containing a tag with affinity for a non-protein ligand containing a Strep-tag
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/20—Fusion polypeptide containing a tag with affinity for a non-protein ligand
- C07K2319/23—Fusion polypeptide containing a tag with affinity for a non-protein ligand containing a GST-tag
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/20—Fusion polypeptide containing a tag with affinity for a non-protein ligand
- C07K2319/24—Fusion polypeptide containing a tag with affinity for a non-protein ligand containing a MBP (maltose binding protein)-tag
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
- C07K2319/41—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation containing a Myc-tag
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
- C07K2319/42—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation containing a HA(hemagglutinin)-tag
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
- C07K2319/43—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation containing a FLAG-tag
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/50—Fusion polypeptide containing protease site
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/55—Fusion polypeptide containing a fusion with a toxin, e.g. diphteria toxin
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization 1111111111111111111111111111 31111111111111111111111111111111111111111111111111111 International Bureau (10) International Publication Number (43) International Publication Date .....0\"\" WO 2018/009903 A2 11 January 2018 (11.01.2018) W I PO I PCT (51) International Patent Classification: (74) C07K 14/33 (2006.01) A61K 38/48 (2006.01) Agent: EL-HAYEK, Roque; Wolf, Greenfield & Sacks, P.C., 600 Atlantic Avenue, Boston, MA 02210-2206 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US2017/041255 kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: 07 July 2017 (07.07.2017) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (25) Filing Language: English HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (26) Publication Language: English KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (30) Priority Data: 62/360,239 08 July 2016 (08.07.2016) US OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant. CHILDREN'S MEDICAL CENTER COR- PORATION [US/US]; 55 Shattuck Street, Boston, MA (84) Designated States (unless otherwise indicated, for every 02115 (US). kind of regional protection available): ARIPO (BW, GH, (72) Inventor; and GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (71) Applicant: STENMARK, Paul [SE/SE]; Svantearrhenius- vag 16C, 10691 Stockholm (SE). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Inventors: DONG, MM; 12 Croft Lane, Weatogue, CT 06089 (US). ZHANG, Sicai; EN 1070, 300 Longwood Ave, Boston, MA (US). (72) MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). — = = Title: A NOVEL BOTULINUM NEUROTOXIN AND ITS DERIVATIVES (54) FIG. IE = = . 0 ' = = = = = = = = ei en © C:r C:r © © ...... 1 J W 1 0 (57) : Provided herein are Clostridial Botulinum neurotoxin (BoNT) polypeptides of a novel serotype (BoNT/X) and methods \" of making and using the BoNT polypeptides, e.g., in therapeutic applications. C [Continued on next page] WO 2018/009903 A2 MIDEDIMOM0101011MERIONHOHOIMOIMIDOME110IS Published: — without international search report and upon receipt of that report (Rule 48.2(g)) to be republished — with sequence listing part of description (Rule 5.2(a))
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662360239P | 2016-07-08 | 2016-07-08 | |
PCT/US2017/041255 WO2018009903A2 (en) | 2016-07-08 | 2017-07-07 | A novel botulinum neurotoxin and its derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
SG11201811338VA true SG11201811338VA (en) | 2019-01-30 |
Family
ID=59384231
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SG10201912102WA SG10201912102WA (en) | 2016-07-08 | 2017-07-07 | A novel botulinum neurotoxin and its derivatives |
SG11201811338VA SG11201811338VA (en) | 2016-07-08 | 2017-07-07 | A novel botulinum neurotoxin and its derivatives |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SG10201912102WA SG10201912102WA (en) | 2016-07-08 | 2017-07-07 | A novel botulinum neurotoxin and its derivatives |
Country Status (21)
Country | Link |
---|---|
US (2) | US11286473B2 (en) |
EP (2) | EP4212545A1 (en) |
JP (2) | JP7158371B2 (en) |
KR (1) | KR102530925B1 (en) |
CN (1) | CN109803980B (en) |
AU (2) | AU2017292922B9 (en) |
BR (1) | BR112019000278A2 (en) |
CA (1) | CA3030155A1 (en) |
DK (1) | DK3481852T3 (en) |
EA (1) | EA201990229A1 (en) |
ES (1) | ES2939001T3 (en) |
FI (1) | FI3481852T3 (en) |
HU (1) | HUE061429T2 (en) |
IL (2) | IL263754B2 (en) |
MX (1) | MX2019000151A (en) |
PL (1) | PL3481852T3 (en) |
PT (1) | PT3481852T (en) |
SG (2) | SG10201912102WA (en) |
UA (1) | UA125965C2 (en) |
WO (1) | WO2018009903A2 (en) |
ZA (1) | ZA201900341B (en) |
Families Citing this family (51)
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JP6088438B2 (en) | 2010-12-22 | 2017-03-01 | プレジデント アンド フェローズ オブ ハーバード カレッジ | Continuous directed evolution |
KR102083371B1 (en) | 2012-11-21 | 2020-03-04 | 입센 바이오이노베이션 리미티드 | Methods for the manufacture of proteolytically processed polypeptides |
US10920208B2 (en) | 2014-10-22 | 2021-02-16 | President And Fellows Of Harvard College | Evolution of proteases |
US11299729B2 (en) | 2015-04-17 | 2022-04-12 | President And Fellows Of Harvard College | Vector-based mutagenesis system |
WO2016170501A1 (en) * | 2015-04-24 | 2016-10-27 | Consiglio Nazionale Delle Ricerche | A new therapeutic use of the botulinum neurotoxin serotype a |
US10392674B2 (en) | 2015-07-22 | 2019-08-27 | President And Fellows Of Harvard College | Evolution of site-specific recombinases |
WO2017015559A2 (en) | 2015-07-23 | 2017-01-26 | President And Fellows Of Harvard College | Evolution of bt toxins |
US10612011B2 (en) | 2015-07-30 | 2020-04-07 | President And Fellows Of Harvard College | Evolution of TALENs |
GB201607901D0 (en) * | 2016-05-05 | 2016-06-22 | Ipsen Biopharm Ltd | Chimeric neurotoxins |
CA3024331A1 (en) * | 2016-05-16 | 2017-11-23 | President And Fellows Of Harvard College | Method for purification and activation of botulinum neurotoxin |
EP4212545A1 (en) | 2016-07-08 | 2023-07-19 | Children's Medical Center Corporation | A novel botulinum neurotoxin and its derivatives |
US11129906B1 (en) | 2016-12-07 | 2021-09-28 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
US11040090B2 (en) * | 2016-12-08 | 2021-06-22 | Prime Bio, Inc | Botulinum neurotoxin compositions |
US11447809B2 (en) | 2017-07-06 | 2022-09-20 | President And Fellows Of Harvard College | Evolution of tRNA synthetases |
US11624130B2 (en) | 2017-09-18 | 2023-04-11 | President And Fellows Of Harvard College | Continuous evolution for stabilized proteins |
EP3687566A2 (en) * | 2017-09-29 | 2020-08-05 | Children's Medical Center Corporation | A neurotoxin-like toxin and uses thereof |
CA3089834A1 (en) * | 2018-01-30 | 2019-08-08 | Children's Medical Center Corporation | Production of botulinum neurotoxins using bacillus systems |
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 |
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GB201900621D0 (en) | 2019-01-16 | 2019-03-06 | Ipsen Biopharm Ltd | Labelled polypeptides |
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GB201907016D0 (en) | 2019-05-17 | 2019-07-03 | Ipsen Biopharm Ltd | Screening method to determine suitability for participation in a clinical trial |
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CN110938150B (en) * | 2019-12-16 | 2021-08-31 | 中国人民解放军军事科学院军事医学研究院 | Preparation method and application of E-type botulinum toxin recombinant L-HN antigen |
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WO2022140249A1 (en) * | 2020-12-21 | 2022-06-30 | Children's Medical Center Corporation | Improved receptor-binding domain of botulinum neurotoxin a and uses thereof |
GB202100566D0 (en) | 2021-01-15 | 2021-03-03 | Ipsen Biopharm Ltd | Treatment of brain damage |
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GB202104294D0 (en) | 2021-03-26 | 2021-05-12 | Ipsen Biopharm Ltd | Clostridial neurotoxins comprising an exogenous activation loop |
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AU2022247196A1 (en) | 2021-03-30 | 2023-10-05 | Ipsen Biopharm Limited | Treatment of pain & inflammatory disorders |
CN117561075A (en) * | 2021-04-26 | 2024-02-13 | 上海科技大学 | Intramuscular injection composition of botulinum neurotoxin |
CN117795080A (en) * | 2021-08-06 | 2024-03-29 | 花王株式会社 | Nucleic acid constructs using SNARE |
GB202116795D0 (en) | 2021-11-22 | 2022-01-05 | Ipsen Biopharm Ltd | Treatment of visceral pain |
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