AU2017277905B2 - Engineered Botulinum neurotoxins - Google Patents
Engineered Botulinum neurotoxins Download PDFInfo
- Publication number
- AU2017277905B2 AU2017277905B2 AU2017277905A AU2017277905A AU2017277905B2 AU 2017277905 B2 AU2017277905 B2 AU 2017277905B2 AU 2017277905 A AU2017277905 A AU 2017277905A AU 2017277905 A AU2017277905 A AU 2017277905A AU 2017277905 B2 AU2017277905 B2 AU 2017277905B2
- Authority
- AU
- Australia
- Prior art keywords
- bont
- seq
- modified
- polypeptide
- amino acid
- 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.)
- Ceased
Links
Classifications
-
- 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)
-
- 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)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
- A61K38/4893—Botulinum neurotoxin (3.4.24.69)
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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]
-
- 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
-
- 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
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Neurology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Neurosurgery (AREA)
- Toxicology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Dermatology (AREA)
- Ophthalmology & Optometry (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662347579P | 2016-06-08 | 2016-06-08 | |
| US62/347,579 | 2016-06-08 | ||
| PCT/US2017/036628 WO2017214447A1 (en) | 2016-06-08 | 2017-06-08 | Engineered botulinum neurotoxins |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2017277905A1 AU2017277905A1 (en) | 2018-12-20 |
| AU2017277905B2 true AU2017277905B2 (en) | 2022-04-14 |
Family
ID=59227906
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2017277905A Ceased AU2017277905B2 (en) | 2016-06-08 | 2017-06-08 | Engineered Botulinum neurotoxins |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US11104891B2 (enExample) |
| EP (1) | EP3468985A1 (enExample) |
| JP (2) | JP7152392B2 (enExample) |
| KR (1) | KR20190025906A (enExample) |
| CN (1) | CN109476713A (enExample) |
| AU (1) | AU2017277905B2 (enExample) |
| BR (1) | BR112018075363A2 (enExample) |
| CA (1) | CA3026492A1 (enExample) |
| EA (1) | EA201892784A1 (enExample) |
| IL (1) | IL263058B2 (enExample) |
| MX (1) | MX2018015254A (enExample) |
| SG (2) | SG10201912099TA (enExample) |
| WO (1) | WO2017214447A1 (enExample) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2847241T3 (es) | 2012-05-30 | 2021-08-02 | Harvard College | Neurotoxina botulínica genéticamente modificada |
| CN115925835A (zh) * | 2015-03-26 | 2023-04-07 | 哈佛大学校长及研究员协会 | 工程改造的肉毒杆菌神经毒素 |
| US10676723B2 (en) | 2015-05-11 | 2020-06-09 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
| TW201718627A (zh) * | 2015-06-11 | 2017-06-01 | 梅茲製藥有限兩合公司 | 重組梭菌神經毒素及其使用與形成方法、包括其之醫藥組合物及對應其之前驅物、編碼前驅物之核酸序列及其獲得方法與前驅物之形成方法、載體與包括核酸序列之重組宿主細胞 |
| GB201607901D0 (en) | 2016-05-05 | 2016-06-22 | Ipsen Biopharm Ltd | Chimeric neurotoxins |
| EA201892643A1 (ru) * | 2016-05-16 | 2019-06-28 | Президент Энд Феллоуз Оф Гарвард Колледж | Способ очистки и активации ботулинического нейротоксина |
| PL3481852T3 (pl) * | 2016-07-08 | 2023-07-24 | Children's Medical Center Corporation | Nowa neurotoksyna botulinowa i jej pochodne |
| US11117935B2 (en) | 2016-08-24 | 2021-09-14 | President And Fellows Of Harvard College | Engineered botulinum neurotoxin |
| US11129906B1 (en) | 2016-12-07 | 2021-09-28 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
| US12098169B2 (en) | 2017-09-29 | 2024-09-24 | Children's Medical Center Corporation | Enterococcus faecium neurotoxin (BoNT/EN) and derivatives thereof |
| TWI810228B (zh) * | 2017-12-20 | 2023-08-01 | 英商艾普森生物製藥有限公司 | 自主神經系統障礙之治療 |
| KR20200115584A (ko) | 2018-01-30 | 2020-10-07 | 칠드런'즈 메디컬 센터 코포레이션 | 바실루스 시스템을 이용한 보툴리눔 신경독소의 생산 |
| US11707510B2 (en) * | 2018-02-16 | 2023-07-25 | Preclinics Discovery Gmbh | Nucleic acid-based botulinum neurotoxin for therapeutic use |
| SE542539C2 (en) * | 2018-02-26 | 2020-06-02 | Toxotech Ab | Chimeric botulinum neurotoxin heavy chain binding domain |
| 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 |
| KR20230001254A (ko) | 2021-06-28 | 2023-01-04 | (주)메디톡스 | 재조합 보툴리눔 독소 타입 a 경쇄, 재조합 보툴리눔 독소 및 이의 조성물, 용도 및 방법 |
| KR20230001260A (ko) | 2021-06-28 | 2023-01-04 | (주)메디톡스 | 재조합 보툴리눔 독소 타입 a 경쇄, 재조합 보툴리눔 독소 및 이의 조성물, 용도 및 방법 |
| WO2023068485A1 (ko) * | 2021-10-22 | 2023-04-27 | 비피메드(주) | 보툴리눔 유래 펩타이드를 포함하는 탈모개선용 조성물 |
| KR20240116485A (ko) * | 2021-11-22 | 2024-07-29 | 입센 바이오팜 리미티드 | 통증의 치료 |
| CN114369623B (zh) * | 2022-01-12 | 2023-07-07 | 中国人民解放军空军军医大学 | 一种基于Cre-lox重组系统的Synaptotagmin2-RNAi及其应用 |
| CN114410683B (zh) * | 2022-01-12 | 2023-11-28 | 中国人民解放军空军军医大学 | 一种基于Cre-lox重组系统的RIM3-RNAi及其应用 |
| GB202206348D0 (en) * | 2022-04-29 | 2022-06-15 | Ipsen Biopharm Ltd | Treatment of limb spasticity |
| KR102728382B1 (ko) * | 2022-10-12 | 2024-11-14 | 주식회사 알케미어 | 보툴리눔 독소의 경쇄 변이체 |
| WO2025065012A1 (en) * | 2023-09-21 | 2025-03-27 | The Medical College Of Wisconsin, Inc. | Botulinum neurotoxin variants, constructs, compositions, and methods of use |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013180799A1 (en) * | 2012-05-30 | 2013-12-05 | President And Fellows Of Harvard College | Engineered botulinum neurotoxin |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880635B1 (en) | 1984-08-08 | 1996-07-02 | Liposome Company | Dehydrated liposomes |
| US5807715A (en) | 1984-08-27 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin |
| US4921757A (en) | 1985-04-26 | 1990-05-01 | Massachusetts Institute Of Technology | System for delayed and pulsed release of biologically active substances |
| US4920016A (en) | 1986-12-24 | 1990-04-24 | Linear Technology, Inc. | Liposomes with enhanced circulation time |
| JPH0825869B2 (ja) | 1987-02-09 | 1996-03-13 | 株式会社ビタミン研究所 | 抗腫瘍剤包埋リポソ−ム製剤 |
| US4917951A (en) | 1987-07-28 | 1990-04-17 | Micro-Pak, Inc. | Lipid vesicles formed of surfactants and steroids |
| US4911928A (en) | 1987-03-13 | 1990-03-27 | Micro-Pak, Inc. | Paucilamellar lipid vesicles |
| US5053005A (en) | 1989-04-21 | 1991-10-01 | Gary E. Borodic | Chemomodulation of curvature of the juvenile spine |
| DE69526340T2 (de) | 1994-05-09 | 2002-11-14 | William J. Binder | Botulinumtoxin ZUR REDUKTION VON Migraine -KOPFSCHMERZEN |
| GB9508204D0 (en) | 1995-04-21 | 1995-06-07 | Speywood Lab Ltd | A novel agent able to modify peripheral afferent function |
| US5721215A (en) | 1996-03-20 | 1998-02-24 | Allergan | Injectable therapy for control of muscle spasms and pain related to muscle spasms |
| US6113915A (en) | 1999-10-12 | 2000-09-05 | Allergan Sales, Inc. | Methods for treating pain |
| US20040033241A1 (en) | 2000-06-02 | 2004-02-19 | Allergan, Inc. | Controlled release botulinum toxin system |
| DE102005019302A1 (de) * | 2005-04-26 | 2006-11-16 | Toxogen Gmbh | Carrier zum Targeting von Nervenzellen |
| JP5709356B2 (ja) * | 2006-01-13 | 2015-04-30 | アメリカ合衆国 | 哺乳動物細胞における発現のためのコドン最適化IL−15およびIL−15R−α遺伝子 |
| US8273865B2 (en) * | 2006-03-15 | 2012-09-25 | Allergan, Inc. | Multivalent clostridial toxins |
| US9913875B2 (en) | 2015-03-16 | 2018-03-13 | California Institute Of Technology | Botulinum neurotoxin-specific capture agents, compositions, and methods of using and making |
| GB201607901D0 (en) * | 2016-05-05 | 2016-06-22 | Ipsen Biopharm Ltd | Chimeric neurotoxins |
-
2017
- 2017-06-08 KR KR1020197000585A patent/KR20190025906A/ko not_active Ceased
- 2017-06-08 JP JP2019516917A patent/JP7152392B2/ja active Active
- 2017-06-08 WO PCT/US2017/036628 patent/WO2017214447A1/en not_active Ceased
- 2017-06-08 CN CN201780035648.4A patent/CN109476713A/zh active Pending
- 2017-06-08 SG SG10201912099TA patent/SG10201912099TA/en unknown
- 2017-06-08 IL IL263058A patent/IL263058B2/en unknown
- 2017-06-08 BR BR112018075363-7A patent/BR112018075363A2/pt not_active IP Right Cessation
- 2017-06-08 SG SG11201810210UA patent/SG11201810210UA/en unknown
- 2017-06-08 CA CA3026492A patent/CA3026492A1/en active Pending
- 2017-06-08 EP EP17733667.4A patent/EP3468985A1/en not_active Withdrawn
- 2017-06-08 MX MX2018015254A patent/MX2018015254A/es unknown
- 2017-06-08 EA EA201892784A patent/EA201892784A1/ru unknown
- 2017-06-08 AU AU2017277905A patent/AU2017277905B2/en not_active Ceased
- 2017-06-08 US US16/308,146 patent/US11104891B2/en active Active
-
2022
- 2022-03-18 JP JP2022044568A patent/JP2022112031A/ja active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013180799A1 (en) * | 2012-05-30 | 2013-12-05 | President And Fellows Of Harvard College | Engineered botulinum neurotoxin |
Non-Patent Citations (2)
| Title |
|---|
| A. RUMMEL ET AL, "Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, (2007-01-02), vol. 104, no. 1, pages 359 - 364 * |
| BERNTSSON RONNIE PER-ARNE ET AL, "Crystal Structures of Botulinum Neurotoxin DC in Complex with Its Protein Receptors Synaptotagmin I and II", STRUCTURE, (2013-09-03), vol. 21, no. 9, pages 1602 - 1611 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2019523015A (ja) | 2019-08-22 |
| JP2022112031A (ja) | 2022-08-01 |
| CN109476713A (zh) | 2019-03-15 |
| JP7152392B2 (ja) | 2022-10-12 |
| IL263058A (en) | 2018-12-31 |
| KR20190025906A (ko) | 2019-03-12 |
| MX2018015254A (es) | 2019-08-16 |
| IL263058B1 (en) | 2023-07-01 |
| IL263058B2 (en) | 2023-11-01 |
| EP3468985A1 (en) | 2019-04-17 |
| WO2017214447A1 (en) | 2017-12-14 |
| CA3026492A1 (en) | 2017-12-14 |
| BR112018075363A2 (pt) | 2019-03-19 |
| US20190300869A1 (en) | 2019-10-03 |
| EA201892784A1 (ru) | 2019-05-31 |
| AU2017277905A1 (en) | 2018-12-20 |
| SG11201810210UA (en) | 2018-12-28 |
| SG10201912099TA (en) | 2020-02-27 |
| US11104891B2 (en) | 2021-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2017277905B2 (en) | Engineered Botulinum neurotoxins | |
| JP7402916B2 (ja) | 新規ボツリヌスニューロトキシンおよびその誘導体 | |
| TWI725963B (zh) | 工程化之肉毒桿菌神經毒素 | |
| KR102060355B1 (ko) | 가공된 보툴리눔 신경독소 | |
| US20200255481A1 (en) | Neurotoxin-like toxin and uses thereof | |
| US20240158773A1 (en) | Engineered botulinum neurotoxin a protease domain with improved efficacy | |
| US20240082369A1 (en) | Improved receptor-binding domain of botulinum neurotoxin a and uses thereof | |
| WO2024073664A2 (en) | Modified bont/a2 receptor-binding domains | |
| US20240216487A1 (en) | Intramuscular compositions of botulinum neurotoxins |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |