RU2018107843A3 - - Google Patents
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- RU2018107843A3 RU2018107843A3 RU2018107843A RU2018107843A RU2018107843A3 RU 2018107843 A3 RU2018107843 A3 RU 2018107843A3 RU 2018107843 A RU2018107843 A RU 2018107843A RU 2018107843 A RU2018107843 A RU 2018107843A RU 2018107843 A3 RU2018107843 A3 RU 2018107843A3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K47/54—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 compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562222059P | 2015-09-22 | 2015-09-22 | |
US62/222,059 | 2015-09-22 | ||
PCT/US2016/052829 WO2017053391A1 (en) | 2015-09-22 | 2016-09-21 | Modified cytotoxins and their therapeutic use |
Publications (3)
Publication Number | Publication Date |
---|---|
RU2018107843A RU2018107843A (ru) | 2019-10-25 |
RU2018107843A3 true RU2018107843A3 (ru) | 2019-11-28 |
RU2721949C2 RU2721949C2 (ru) | 2020-05-25 |
Family
ID=58276138
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
RU2018107843A RU2721949C2 (ru) | 2015-09-22 | 2016-09-21 | Модифицированные цитотоксины и их терапевтическое применение |
Country Status (14)
Country | Link |
---|---|
US (3) | US10023581B2 (ru) |
EP (1) | EP3353159A4 (ru) |
JP (1) | JP2018527360A (ru) |
KR (1) | KR20180045001A (ru) |
CN (1) | CN108368075A (ru) |
AU (1) | AU2016326392B2 (ru) |
CA (1) | CA2998528A1 (ru) |
HK (1) | HK1254461A1 (ru) |
IL (1) | IL257932A (ru) |
MX (1) | MX2018002514A (ru) |
MY (1) | MY193776A (ru) |
RU (1) | RU2721949C2 (ru) |
WO (1) | WO2017053391A1 (ru) |
ZA (1) | ZA201801482B (ru) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2018002514A (es) * | 2015-09-22 | 2018-08-15 | Univ California | Citotoxinas modificadas y su uso terapeutico. |
US10286079B2 (en) | 2015-09-22 | 2019-05-14 | The Regents Of The University Of California | Modified cytotoxins and their therapeutic use |
AU2018237139A1 (en) * | 2017-03-22 | 2019-10-17 | The Regents Of The University Of California | Modified oligonucleotides and therapeutic uses thereof |
WO2021007322A1 (en) * | 2019-07-09 | 2021-01-14 | Northwestern University | Methods of using modified cytotoxins to treat cancer |
IT202100025172A1 (it) | 2021-09-30 | 2023-03-30 | Indena Spa | Processo per la preparazione di derivati tassanici |
Family Cites Families (43)
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US5411984A (en) | 1992-10-16 | 1995-05-02 | Virginia Tech Intellectual Properties, Inc. | Water soluble analogs and prodrugs of taxol |
AU6803494A (en) * | 1993-06-07 | 1995-01-03 | British Technology Group Limited | Anticancer compounds |
US5534499A (en) | 1994-05-19 | 1996-07-09 | The University Of British Columbia | Lipophilic drug derivatives for use in liposomes |
AU735205B2 (en) | 1997-05-16 | 2001-07-05 | Commonwealth Scientific And Industrial Research Organisation | Vaccine and assay |
US5981564A (en) * | 1998-07-01 | 1999-11-09 | Universite Laval | Water-soluble derivatives of paclitaxel, method for producing same and uses thereof |
AU2002953095A0 (en) * | 2002-11-29 | 2002-12-19 | Biota Scientific Management Pty Ltd | Novel chemical compounds and their use |
NO319551B1 (no) | 2003-07-04 | 2005-08-29 | Thia Medica As | Proteinmateriale fra enkeltceller |
GB0321613D0 (en) | 2003-09-15 | 2003-10-15 | Drug Discovery Lab As | Compounds |
KR101241862B1 (ko) | 2003-09-19 | 2013-03-13 | 노보 노르디스크 에이/에스 | 신규 glp-1 유도체 |
RU2340616C2 (ru) * | 2003-10-29 | 2008-12-10 | Сонус Фармасьютикалз, Инк. | Токоферол-модифицированные терапевтические лекарственные соединения |
GB0412181D0 (en) * | 2004-06-01 | 2004-06-30 | Celltech R&D Ltd | Biological products |
US20080103110A1 (en) * | 2004-09-15 | 2008-05-01 | Drug Discovery Laboratory As | Compounds |
US8603972B2 (en) | 2005-03-18 | 2013-12-10 | Novo Nordisk A/S | Extended GLP-1 compounds |
WO2007075825A2 (en) * | 2005-12-20 | 2007-07-05 | Sonus Pharmaceuticals, Inc. | Lipophilic anticancer drug compounds |
JP2011511076A (ja) | 2008-02-08 | 2011-04-07 | エイルロン セラピューティクス,インコーポレイテッド | 治療用ペプチド模倣大環状分子 |
MX2010011165A (es) * | 2008-04-10 | 2011-02-22 | Abraxis Bioscience Llc | Composiciones de derivados de taxano hidrofobos y sus usos. |
US20100240883A1 (en) | 2009-03-18 | 2010-09-23 | Nian Wu | Lipid-drug conjugates for drug delivery |
WO2010112942A1 (en) | 2009-04-02 | 2010-10-07 | Shire Llc | Novel dicarboxylic acid linked amino acid and peptide prodrugs of opioids and uses thereof |
US20130053433A1 (en) * | 2010-01-06 | 2013-02-28 | The University Of North Carolina At Chapel Hill | Fatty acid derivatives and analogs of drugs |
TWI508737B (zh) | 2010-01-22 | 2015-11-21 | 諾佛 儂迪克股份有限公司 | 具有延長的活體內功效的生長激素 |
CA2787895A1 (en) | 2010-01-22 | 2011-07-28 | Novo Nordisk Health Care Ag | Stable growth hormone compounds |
EP2536434B1 (en) | 2010-02-16 | 2016-04-20 | Novo Nordisk A/S | Purification method |
CN103002891B (zh) * | 2010-05-10 | 2016-10-26 | 加利福尼亚大学董事会 | 比例计量型组合药物递送 |
EP2392324A1 (en) * | 2010-06-01 | 2011-12-07 | Societe De Coordination De Recherches Therapeutiques | Rhenium complexes and their pharmaceutical use |
ES2630031T3 (es) | 2010-09-28 | 2017-08-17 | Aegerion Pharmaceuticals, Inc. | Un polipéptido de leptina pinnípedo-humano quimérico con solubilidad aumentada |
JP6121330B2 (ja) | 2010-09-28 | 2017-04-26 | アミリン・ファーマシューティカルズ, リミテッド・ライアビリティ・カンパニーAmylin Pharmaceuticals, Llc | 作用持続時間が増した改変ポリペプチド |
EP2624869A4 (en) * | 2010-10-08 | 2015-11-04 | Univ Virginia Commonwealth | PRODRUGS USING A CONTAINER CONTROLLED ABSORPTION MECHANISM |
CN103857440B (zh) | 2011-06-22 | 2018-09-25 | 维奥姆生物科学有限公司 | 基于缀合物的抗真菌和抗细菌前药 |
ES2732475T3 (es) | 2011-07-08 | 2019-11-22 | Aegerion Pharmaceuticals Inc | Polipéptidos modificados por ingeniería genética que tienen una duración potenciada de la acción y una inmunogenicidad reducida |
EP2729481B1 (en) | 2011-07-08 | 2018-10-17 | Amylin Pharmaceuticals, LLC | Engineered polypeptides having enhanced duration of action with reduced immunogenicity |
KR101435261B1 (ko) * | 2012-07-23 | 2014-09-02 | 아주대학교산학협력단 | 항암제-링커-알부민 결합체, 이의 제조방법 및 상기 결합체를 포함하는 약물 전달용 조성물 |
AU2013350311B2 (en) * | 2012-11-21 | 2018-03-22 | The University Of Sydney | Omega-3 analogues |
WO2014121033A1 (en) * | 2013-02-04 | 2014-08-07 | Fl Therapeutics Llc | Soluble complexes of drug analogs and albumin |
WO2014201026A2 (en) * | 2013-06-10 | 2014-12-18 | Cedars-Sinai Medical Center | Antioxidant, anti-inflammatory and anticancer derivatives of triptolide and nanospheres thereof |
EP3077008B1 (en) | 2013-12-06 | 2023-10-04 | Jie Han | Bioreversable promoieties for nitrogen-containing and hydroxyl-containing drugs |
EP3229810B1 (en) * | 2014-11-17 | 2020-07-22 | Cellectar Biosciences, Inc. | Phospholipid ether analogs as cancer-targeting drug vehicles |
CN104478813A (zh) * | 2014-12-20 | 2015-04-01 | 苏州博源医疗科技有限公司 | 5-氟尿嘧啶衍生物、5-氟尿嘧啶免疫原及其抗体与5-氟尿嘧啶检测试剂盒 |
MX2018002514A (es) * | 2015-09-22 | 2018-08-15 | Univ California | Citotoxinas modificadas y su uso terapeutico. |
US10286079B2 (en) * | 2015-09-22 | 2019-05-14 | The Regents Of The University Of California | Modified cytotoxins and their therapeutic use |
WO2018175601A1 (en) * | 2017-03-22 | 2018-09-27 | The Regents Of The University Of California | Modified platinum compounds and therapeutic uses thereof |
US20210137957A1 (en) * | 2017-03-22 | 2021-05-13 | The Regents Of The University Of California | Modified anthracycline compounds and their therapeutic use |
WO2018175595A1 (en) * | 2017-03-22 | 2018-09-27 | The Regents Of The University Of California | Modified histone deacetylase inhibitors and uses thereof |
US20200046859A1 (en) * | 2017-04-27 | 2020-02-13 | The Regents Of The University Of California | Modified mri contrast agents and uses thereof |
-
2016
- 2016-09-21 MX MX2018002514A patent/MX2018002514A/es unknown
- 2016-09-21 MY MYPI2018000369A patent/MY193776A/en unknown
- 2016-09-21 AU AU2016326392A patent/AU2016326392B2/en not_active Expired - Fee Related
- 2016-09-21 JP JP2018512334A patent/JP2018527360A/ja active Pending
- 2016-09-21 CN CN201680054455.9A patent/CN108368075A/zh active Pending
- 2016-09-21 CA CA2998528A patent/CA2998528A1/en not_active Abandoned
- 2016-09-21 KR KR1020187008860A patent/KR20180045001A/ko not_active Application Discontinuation
- 2016-09-21 US US15/271,822 patent/US10023581B2/en active Active
- 2016-09-21 EP EP16849481.3A patent/EP3353159A4/en not_active Withdrawn
- 2016-09-21 WO PCT/US2016/052829 patent/WO2017053391A1/en active Application Filing
- 2016-09-21 RU RU2018107843A patent/RU2721949C2/ru active
-
2018
- 2018-03-02 ZA ZA2018/01482A patent/ZA201801482B/en unknown
- 2018-03-06 IL IL257932A patent/IL257932A/en unknown
- 2018-04-04 US US15/945,285 patent/US10654864B2/en active Active
- 2018-10-23 HK HK18113547.1A patent/HK1254461A1/zh unknown
-
2020
- 2020-04-09 US US16/844,627 patent/US20210047338A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
CN108368075A (zh) | 2018-08-03 |
AU2016326392B2 (en) | 2021-02-11 |
US20180222915A1 (en) | 2018-08-09 |
IL257932A (en) | 2018-06-03 |
RU2018107843A (ru) | 2019-10-25 |
EP3353159A1 (en) | 2018-08-01 |
US20210047338A1 (en) | 2021-02-18 |
MX2018002514A (es) | 2018-08-15 |
JP2018527360A (ja) | 2018-09-20 |
WO2017053391A1 (en) | 2017-03-30 |
CA2998528A1 (en) | 2017-03-30 |
KR20180045001A (ko) | 2018-05-03 |
US10023581B2 (en) | 2018-07-17 |
MY193776A (en) | 2022-10-27 |
HK1254461A1 (zh) | 2019-07-19 |
ZA201801482B (en) | 2021-07-28 |
AU2016326392A1 (en) | 2018-03-22 |
RU2721949C2 (ru) | 2020-05-25 |
US20170080094A1 (en) | 2017-03-23 |
EP3353159A4 (en) | 2019-03-27 |
US10654864B2 (en) | 2020-05-19 |