MX2018008078A - Tecnologia de sinergismo anticuerpo-farmaco para el tratamiento de enfermedades. - Google Patents
Tecnologia de sinergismo anticuerpo-farmaco para el tratamiento de enfermedades.Info
- Publication number
- MX2018008078A MX2018008078A MX2018008078A MX2018008078A MX2018008078A MX 2018008078 A MX2018008078 A MX 2018008078A MX 2018008078 A MX2018008078 A MX 2018008078A MX 2018008078 A MX2018008078 A MX 2018008078A MX 2018008078 A MX2018008078 A MX 2018008078A
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- antibody
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- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- 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
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6845—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon
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- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
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- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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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
- 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
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61K9/08—Solutions
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- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- 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
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Dermatology (AREA)
- Cell Biology (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Botany (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
Abstract
Un método para producir una eficacia sinérgica y potenciada en el tratamiento de una enfermedad en un sujeto que incluye proporcionar un anticuerpo, el anticuerpo que es un anticuerpo clásico o una molécula biológica modificada que bloquea un primer objetivo en el sujeto; proporcionar un fármaco, el fármaco que es un agente de molécula pequeña que bloquea el primer objetivo o un segundo objetivo en el sujeto; conectar el anticuerpo y el fármaco con un enlazador para formar un compuesto de Sinergismo Anticuerpo-Fármaco (ADS); y tratar la enfermedad con el compuesto de ADS. El enlazador se hidroliza en el sujeto durante un determinado tiempo de manera que tanto el anticuerpo como el fármaco ejercen sus funciones simultáneamente, y el compuesto de ADS confiere mejor eficacia que el anticuerpo o el fármaco solo debido al sinergismo del compuesto de ADS.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662291361P | 2016-02-04 | 2016-02-04 | |
| PCT/US2017/016107 WO2017136486A1 (en) | 2016-02-04 | 2017-02-02 | Antibody-drug synergism technology for treating diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX2018008078A true MX2018008078A (es) | 2018-11-29 |
| MX394623B MX394623B (es) | 2025-03-24 |
Family
ID=59501050
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2018008078A MX394623B (es) | 2016-02-04 | 2017-02-02 | Tecnología de sinergismo anticuerpo-fármaco para el tratamiento de enfermedades. |
Country Status (10)
| Country | Link |
|---|---|
| US (2) | US10835617B2 (es) |
| EP (1) | EP3411399A4 (es) |
| JP (1) | JP7081818B2 (es) |
| KR (1) | KR20180105235A (es) |
| CN (1) | CN108602879A (es) |
| AU (2) | AU2017214475B2 (es) |
| BR (1) | BR112018014467A2 (es) |
| CA (1) | CA3010623A1 (es) |
| MX (1) | MX394623B (es) |
| WO (1) | WO2017136486A1 (es) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3302379B1 (en) | 2015-06-06 | 2023-11-22 | Cloudbreak Therapeutics, LLC | Compositions and methods for treating pterygium |
| KR102408596B1 (ko) | 2016-06-02 | 2022-06-13 | 에이디에스 테라퓨틱스 엘엘씨 | 비정상적 신생혈관이 있는 안구 질환 치료를 위한, 닌테다닙을 사용하는 조성물 및 방법 |
| US11278546B2 (en) | 2016-07-22 | 2022-03-22 | Aiviva Biopharma, Inc. | Multikinase inhibitors and uses in ocular fibrosis |
| US20200345637A1 (en) * | 2018-01-19 | 2020-11-05 | Aiviva Biopharma, Inc. | Suspension compositions of multi-target inhibitors |
| KR20220061147A (ko) * | 2019-09-10 | 2022-05-12 | 클라우드브레이크 테라퓨틱스, 엘엘씨 | 눈 외양에 대한 익상편-관련 걱정을 경감하기 위한 방법 |
| US20230210770A1 (en) * | 2020-06-01 | 2023-07-06 | Ads Therapeutics Llc | Topical ophthalmological compositions and methods for treating abnormal angiogenesis |
| KR20230104188A (ko) * | 2020-11-03 | 2023-07-07 | 에이디에스 테라퓨틱스 엘엘씨 | 안구용 항체-약물 접합체 |
| CN115325959B (zh) * | 2022-10-13 | 2023-03-07 | 思看科技(杭州)股份有限公司 | 一种三维扫描系统及方法 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1267935A2 (en) * | 2000-01-12 | 2003-01-02 | Light Sciences Corporation | Novel treatment for eye disease |
| EA201390722A1 (ru) | 2010-11-15 | 2013-11-29 | Файв Прайм Терапьютикс, Инк. | Лечение рака повышенными дозами растворимых белков слияния fgfr1 |
| CN103458930B (zh) * | 2011-02-01 | 2019-10-15 | 健玛保 | 针对cd74的人抗体和抗体-药物缀合物 |
| US9504756B2 (en) * | 2012-05-15 | 2016-11-29 | Seattle Genetics, Inc. | Self-stabilizing linker conjugates |
| CA2874412A1 (en) | 2012-06-01 | 2013-12-05 | Ophthotech Corporation | Compositions comprising an anti-pdgf aptamer and a vegf antagonist |
| HK1214128A1 (zh) | 2012-10-05 | 2016-07-22 | Bluelink Pharmaceuticals, Inc. | 癌症的治療 |
| CN110893188A (zh) * | 2012-11-08 | 2020-03-20 | 克莱尔塞德生物医学股份有限公司 | 用于在人类受试者中治疗眼部疾病的方法和装置 |
| WO2014161004A2 (en) | 2013-03-29 | 2014-10-02 | Mackay John Andrew | Compositions and methods for the delivery of drugs to the ocular surface by contact lenses |
| KR20220025946A (ko) * | 2014-03-21 | 2022-03-03 | 애브비 인코포레이티드 | 항-egfr 항체 및 항체 약물 접합체 |
| JP7100425B2 (ja) | 2014-06-28 | 2022-07-13 | コディアック サイエンシーズ インコーポレイテッド | デュアルpdgf/vegfアンタゴニスト |
| US9840553B2 (en) | 2014-06-28 | 2017-12-12 | Kodiak Sciences Inc. | Dual PDGF/VEGF antagonists |
| US10550170B2 (en) | 2015-11-23 | 2020-02-04 | Acceleron Pharma Inc. | Methods for treating vascular eye disorders with actrii antagonists |
| TWI844571B (zh) | 2018-10-30 | 2024-06-11 | 丹麥商珍美寶股份有限公司 | 使用抗血管內皮生長因子(vegf)抗體與抗組織因子(tf)抗體-藥物共軛體之組合以治療癌症之方法 |
| KR20230104188A (ko) | 2020-11-03 | 2023-07-07 | 에이디에스 테라퓨틱스 엘엘씨 | 안구용 항체-약물 접합체 |
-
2017
- 2017-02-02 JP JP2018541214A patent/JP7081818B2/ja active Active
- 2017-02-02 BR BR112018014467-3A patent/BR112018014467A2/en unknown
- 2017-02-02 CA CA3010623A patent/CA3010623A1/en active Pending
- 2017-02-02 MX MX2018008078A patent/MX394623B/es unknown
- 2017-02-02 US US16/072,415 patent/US10835617B2/en active Active
- 2017-02-02 AU AU2017214475A patent/AU2017214475B2/en active Active
- 2017-02-02 WO PCT/US2017/016107 patent/WO2017136486A1/en not_active Ceased
- 2017-02-02 EP EP17748105.8A patent/EP3411399A4/en active Pending
- 2017-02-02 KR KR1020187025582A patent/KR20180105235A/ko not_active Ceased
- 2017-02-02 CN CN201780009541.2A patent/CN108602879A/zh active Pending
-
2020
- 2020-10-08 US US17/065,901 patent/US12214049B2/en active Active
-
2024
- 2024-03-06 AU AU2024201466A patent/AU2024201466A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU2017214475A1 (en) | 2018-08-23 |
| CA3010623A1 (en) | 2017-08-10 |
| JP7081818B2 (ja) | 2022-06-07 |
| US20190030179A1 (en) | 2019-01-31 |
| US12214049B2 (en) | 2025-02-04 |
| AU2017214475B2 (en) | 2024-03-28 |
| EP3411399A4 (en) | 2019-10-16 |
| KR20180105235A (ko) | 2018-09-27 |
| US10835617B2 (en) | 2020-11-17 |
| WO2017136486A1 (en) | 2017-08-10 |
| BR112018014467A2 (en) | 2018-12-11 |
| US20210030889A1 (en) | 2021-02-04 |
| MX394623B (es) | 2025-03-24 |
| AU2024201466A1 (en) | 2024-03-28 |
| EP3411399A1 (en) | 2018-12-12 |
| JP2019504849A (ja) | 2019-02-21 |
| CN108602879A (zh) | 2018-09-28 |
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