SG11201609911YA - Chloride salt of tat-nr2b9c - Google Patents

Chloride salt of tat-nr2b9c

Info

Publication number
SG11201609911YA
SG11201609911YA SG11201609911YA SG11201609911YA SG11201609911YA SG 11201609911Y A SG11201609911Y A SG 11201609911YA SG 11201609911Y A SG11201609911Y A SG 11201609911YA SG 11201609911Y A SG11201609911Y A SG 11201609911YA SG 11201609911Y A SG11201609911Y A SG 11201609911YA
Authority
SG
Singapore
Prior art keywords
nr2b9c
tat
chloride salt
chloride
salt
Prior art date
Application number
SG11201609911YA
Other languages
English (en)
Inventor
Jonathan David Garman
Original Assignee
Nono Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nono Inc filed Critical Nono Inc
Publication of SG11201609911YA publication Critical patent/SG11201609911YA/en

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Classifications

    • 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
    • A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/08—RNA viruses
    • C07K14/15—Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus human T-cell leukaemia-lymphoma virus
    • C07K14/155—Lentiviridae, e.g. human immunodeficiency virus [HIV], visna-maedi virus or equine infectious anaemia virus
    • C07K14/16—HIV-1 ; HIV-2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/08—RNA viruses
    • C07K14/15—Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus human T-cell leukaemia-lymphoma virus
    • C07K14/155—Lentiviridae, e.g. human immunodeficiency virus [HIV], visna-maedi virus or equine infectious anaemia virus
    • C07K14/16—HIV-1 ; HIV-2
    • C07K14/163—Regulatory proteins, e.g. tat, nef, rev, vif, vpu, vpr, vpt, vpx
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70571—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16311—Human Immunodeficiency Virus, HIV concerning HIV regulatory proteins
    • C12N2740/16322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Virology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • AIDS & HIV (AREA)
  • Toxicology (AREA)
  • Cell Biology (AREA)
  • Zoology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Neurosurgery (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
SG11201609911YA 2014-05-28 2015-05-28 Chloride salt of tat-nr2b9c SG11201609911YA (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462004142P 2014-05-28 2014-05-28
PCT/IB2015/053995 WO2015181756A1 (en) 2014-05-28 2015-05-28 Chloride salt of tat-nr2b9c

Publications (1)

Publication Number Publication Date
SG11201609911YA true SG11201609911YA (en) 2016-12-29

Family

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Family Applications (2)

Application Number Title Priority Date Filing Date
SG11201609911YA SG11201609911YA (en) 2014-05-28 2015-05-28 Chloride salt of tat-nr2b9c
SG10202001285XA SG10202001285XA (en) 2014-05-28 2015-05-28 Chloride salt of tat-nr2b9c

Family Applications After (1)

Application Number Title Priority Date Filing Date
SG10202001285XA SG10202001285XA (en) 2014-05-28 2015-05-28 Chloride salt of tat-nr2b9c

Country Status (26)

Country Link
US (4) US10206973B2 (da)
EP (2) EP3757134B1 (da)
JP (4) JP6622222B2 (da)
KR (3) KR102605540B1 (da)
CN (2) CN114057895A (da)
AU (2) AU2015265487B2 (da)
BR (1) BR112016027814A2 (da)
CA (1) CA2950395C (da)
CY (1) CY1122793T1 (da)
DK (1) DK3149048T3 (da)
ES (1) ES2784500T3 (da)
HR (1) HRP20200462T1 (da)
HU (1) HUE049074T2 (da)
IL (1) IL249252B (da)
LT (1) LT3149048T (da)
ME (1) ME03790B (da)
MX (2) MX2016015457A (da)
PL (1) PL3149048T3 (da)
PT (1) PT3149048T (da)
RS (1) RS60625B1 (da)
RU (2) RU2707885C2 (da)
SG (2) SG11201609911YA (da)
SI (1) SI3149048T1 (da)
UA (1) UA123820C2 (da)
WO (1) WO2015181756A1 (da)
ZA (1) ZA201608843B (da)

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US10251935B2 (en) * 2012-11-28 2019-04-09 Nono Inc. Lyophilized formulation comprising tat-NR2B9C, histidine and trehalose
GB201319446D0 (en) 2013-11-04 2013-12-18 Immatics Biotechnologies Gmbh Personalized immunotherapy against several neuronal and brain tumors
EP3148568A4 (en) 2014-05-28 2018-01-17 Nono Inc. Lyophilized formulation of tat-nr2b9c with acetylation scavenger
SG11201609911YA (en) 2014-05-28 2016-12-29 Nono Inc Chloride salt of tat-nr2b9c
EP3919507A3 (en) 2015-07-01 2022-01-12 Immatics Biotechnologies GmbH Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers
GB201511546D0 (en) * 2015-07-01 2015-08-12 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers
GB201620611D0 (en) * 2016-12-05 2017-01-18 Univ Of Lancaster Treatment of neurological diseases
US11767344B2 (en) 2017-07-05 2023-09-26 Biocells (Beijing) Biotech Co., Ltd. Pharmaceutically acceptable salts of polypeptides and methods of inhibiting the interaction between psd-95 and n-methyl-d-aspartic acid receptor (nmdar)
CN110627877A (zh) * 2019-09-25 2019-12-31 成都奥达生物科技有限公司 一种psd-95抑制剂
CN111560050A (zh) * 2020-05-25 2020-08-21 成都圣诺生物制药有限公司 一种Nerinetide的制备方法

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CN102241745A (zh) * 2011-05-19 2011-11-16 南京医科大学 多肽类似物Tat-HA-NR2B9C及其制备方法和应用
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HUE043820T2 (hu) 2012-11-28 2019-09-30 Nono Inc Liofilizált TAT-NR2B9c készítmény
US10251935B2 (en) 2012-11-28 2019-04-09 Nono Inc. Lyophilized formulation comprising tat-NR2B9C, histidine and trehalose
EP3148568A4 (en) 2014-05-28 2018-01-17 Nono Inc. Lyophilized formulation of tat-nr2b9c with acetylation scavenger
SG11201609911YA (en) 2014-05-28 2016-12-29 Nono Inc Chloride salt of tat-nr2b9c

Also Published As

Publication number Publication date
ZA201608843B (en) 2019-04-24
CY1122793T1 (el) 2021-05-05
KR20210125109A (ko) 2021-10-15
US20220175880A1 (en) 2022-06-09
RU2707885C2 (ru) 2019-12-02
KR102605540B1 (ko) 2023-11-22
AU2020267304C1 (en) 2024-03-14
EP3757134C0 (en) 2024-03-06
RU2016150678A (ru) 2018-07-02
EP3149048A1 (en) 2017-04-05
ME03790B (me) 2021-04-20
US20200384071A1 (en) 2020-12-10
RS60625B1 (sr) 2020-09-30
HUE049074T2 (hu) 2020-08-28
SI3149048T1 (sl) 2020-08-31
JP2022023122A (ja) 2022-02-07
EP3149048B1 (en) 2020-01-29
JP6622222B2 (ja) 2019-12-18
MX2020009633A (es) 2020-10-08
AU2015265487B2 (en) 2020-08-13
KR20170020820A (ko) 2017-02-24
MX2016015457A (es) 2017-06-30
EP3757134B1 (en) 2024-03-06
PL3149048T3 (pl) 2020-06-29
DK3149048T3 (en) 2020-04-14
AU2015265487A1 (en) 2017-01-12
UA123820C2 (uk) 2021-06-09
CN106661126B (zh) 2021-12-10
US10758589B2 (en) 2020-09-01
KR102311038B1 (ko) 2021-10-07
CA2950395C (en) 2023-03-21
BR112016027814A2 (pt) 2017-10-24
SG10202001285XA (en) 2020-04-29
AU2020267304A1 (en) 2020-12-10
JP2017517517A (ja) 2017-06-29
EP3149048A4 (en) 2018-01-03
CN106661126A (zh) 2017-05-10
RU2019138024A (ru) 2019-12-05
AU2020267304B2 (en) 2023-10-05
HRP20200462T1 (hr) 2020-10-16
JP2020045352A (ja) 2020-03-26
EP3757134A1 (en) 2020-12-30
IL249252B (en) 2021-06-30
US20170119845A1 (en) 2017-05-04
KR102407856B1 (ko) 2022-06-10
CN114057895A (zh) 2022-02-18
PT3149048T (pt) 2020-04-21
IL249252A0 (en) 2017-02-28
LT3149048T (lt) 2020-05-11
JP7338890B2 (ja) 2023-09-05
US20190175689A1 (en) 2019-06-13
JP6961661B2 (ja) 2021-11-05
US11266714B2 (en) 2022-03-08
ES2784500T3 (es) 2020-09-28
KR20220082113A (ko) 2022-06-16
RU2016150678A3 (da) 2018-12-25
US10206973B2 (en) 2019-02-19
WO2015181756A1 (en) 2015-12-03
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JP2023113751A (ja) 2023-08-16
CA2950395A1 (en) 2015-12-03

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