AU2019219201B2 - EDB targeting IL-12 compositions - Google Patents

EDB targeting IL-12 compositions Download PDF

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Publication number
AU2019219201B2
AU2019219201B2 AU2019219201A AU2019219201A AU2019219201B2 AU 2019219201 B2 AU2019219201 B2 AU 2019219201B2 AU 2019219201 A AU2019219201 A AU 2019219201A AU 2019219201 A AU2019219201 A AU 2019219201A AU 2019219201 B2 AU2019219201 B2 AU 2019219201B2
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Australia
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gly
leu
thr
ala
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AU2019219201A
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AU2019219201A1 (en
Inventor
Mattia MATASCI
Tiziano ONGARO
Alessandra Villa
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Philogen SpA
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Philogen SpA
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19Cytokines; Lymphokines; Interferons
    • A61K38/20Interleukins [IL]
    • A61K38/208IL-12
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52Cytokines; Lymphokines; Interferons
    • C07K14/54Interleukins [IL]
    • C07K14/5434IL-12
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/62Medicinal 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
    • A61K47/65Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6813Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6835Medicinal 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
    • A61K47/6843Medicinal 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 material from animals or humans
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6835Medicinal 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
    • A61K47/6851Medicinal 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 determinant of a tumour cell
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6889Conjugates 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/60Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622Single chain antibody (scFv)
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/60Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/626Diabody or triabody
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/33Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/70Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/74Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
    • C07K2319/75Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cell Biology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
AU2019219201A 2018-02-09 2019-02-08 EDB targeting IL-12 compositions Active AU2019219201B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2021203986A AU2021203986A1 (en) 2018-02-09 2021-06-16 EDB Targeting IL-12 Compositions

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP18156141 2018-02-09
EP18156141.6 2018-02-09
EP18179313 2018-06-22
EP18179313.4 2018-06-22
PCT/EP2019/053136 WO2019154986A1 (en) 2018-02-09 2019-02-08 Edb targeting il-12 compositions

Related Child Applications (1)

Application Number Title Priority Date Filing Date
AU2021203986A Division AU2021203986A1 (en) 2018-02-09 2021-06-16 EDB Targeting IL-12 Compositions

Publications (2)

Publication Number Publication Date
AU2019219201A1 AU2019219201A1 (en) 2020-07-23
AU2019219201B2 true AU2019219201B2 (en) 2021-07-08

Family

ID=65268973

Family Applications (2)

Application Number Title Priority Date Filing Date
AU2019219201A Active AU2019219201B2 (en) 2018-02-09 2019-02-08 EDB targeting IL-12 compositions
AU2021203986A Abandoned AU2021203986A1 (en) 2018-02-09 2021-06-16 EDB Targeting IL-12 Compositions

Family Applications After (1)

Application Number Title Priority Date Filing Date
AU2021203986A Abandoned AU2021203986A1 (en) 2018-02-09 2021-06-16 EDB Targeting IL-12 Compositions

Country Status (25)

Country Link
US (1) US12173044B2 (https=)
EP (1) EP3749372B1 (https=)
JP (2) JP7279054B2 (https=)
KR (2) KR102259085B1 (https=)
CN (1) CN111683687B (https=)
AU (2) AU2019219201B2 (https=)
BR (1) BR112020012888A2 (https=)
CA (1) CA3087488C (https=)
CL (1) CL2020002052A1 (https=)
CO (1) CO2020009737A2 (https=)
CR (1) CR20200342A (https=)
CU (1) CU20200054A7 (https=)
EC (1) ECSP20047171A (https=)
ES (1) ES3035714T3 (https=)
IL (1) IL275713A (https=)
JO (1) JOP20200193A1 (https=)
MX (1) MX2020008231A (https=)
MY (1) MY200700A (https=)
PE (1) PE20210122A1 (https=)
PH (1) PH12020551230A1 (https=)
RU (2) RU2758143C1 (https=)
SG (1) SG11202006334XA (https=)
TW (1) TWI844524B (https=)
UY (1) UY38074A (https=)
WO (1) WO2019154986A1 (https=)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI844524B (zh) * 2018-02-09 2024-06-11 義大利商費洛根公司 靶向edb之il-12組合物
EP3856763A1 (en) 2018-09-28 2021-08-04 Massachusetts Institute of Technology Collagen-localized immunomodulatory molecules and methods thereof
KR102524247B1 (ko) * 2018-12-21 2023-04-21 가톨릭대학교 산학협력단 p40-EBI3의 복합체 및 이의 용도
CA3150224A1 (en) 2019-09-10 2021-03-18 Obsidian Therapeutics, Inc. Ca2 compositions and methods for tunable regulation
US20230312726A1 (en) * 2020-04-14 2023-10-05 Philogen S.P.A. Dosage units and regimen, uses, methods or formulations of compositions comprising a recombinant protein comprising interleukin-12 and an antibody binding the extra-domain b of fibronectin
KR102649794B1 (ko) * 2020-10-19 2024-03-22 고려대학교 산학협력단 암 및/또는 뇌질환 바이오마커인 엑스트라-도메인 b 파이브로넥틴 및 이를 이용한 진단 방법
AU2023206004B2 (en) * 2022-01-04 2025-04-17 Philogen S.P.A. Combination of an immunocytokine comprising il-12 and a kinase inhibitor
CN118359730A (zh) * 2023-01-17 2024-07-19 上海君赛生物科技有限公司 包含细胞因子的靶向型融合蛋白
WO2025061801A1 (en) 2023-09-19 2025-03-27 Philochem Ag Therapeutic combination of an anti-edb fibronectin domain antibody il2 or il12 fusion protein and a lutetium-177 radioconjugate
WO2025251110A1 (en) * 2024-06-03 2025-12-11 Selvax Pty Ltd Anti-cd40 antibody il-2 fusion proteins
WO2026003203A1 (en) 2024-06-27 2026-01-02 Philogen S.P.A. Combination of an immunocytokine comprising targeted il2 and a jak inhibitor
WO2026013184A1 (en) 2024-07-10 2026-01-15 Ac Immune Sa Fusion protein peptide linkers and uses thereof

Citations (1)

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WO2013014149A1 (en) * 2011-07-27 2013-01-31 Philogen S.P.A. Il-12 immunoconjugate

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US5994104A (en) * 1996-11-08 1999-11-30 Royal Free Hospital School Of Medicine Interleukin-12 fusion protein
JP2003524018A (ja) 2000-02-24 2003-08-12 アイトゲネーシシェ テクニシェ ホッホシューレ チューリッヒ フィブロネクチンのed‐bドメインに特異的な抗体、前記抗体を含む複合体、および血管形成を検出および治療するためのその使用
ATE333900T1 (de) * 2000-02-24 2006-08-15 Philogen Spa Zusamensetzungen und verfahren zur behandlung von angiogenese in pathologischen schädigungen
CN100535013C (zh) 2002-03-11 2009-09-02 菲洛根股份公司 应用抗体分子对肿瘤血管进行选择性定向
AU2005203962C1 (en) * 2004-01-05 2012-11-08 Antisoma Research Limited Interleukin-12 targeted to oncofoetal fibronectin
ATE459648T1 (de) 2005-05-11 2010-03-15 Philogen Spa Fusionsprotein von antikörper l19 gegen fibronectin ed-b und interleukin 12
US8580267B2 (en) * 2008-12-19 2013-11-12 Philogen S.P.A. Immunocytokines for tumour therapy with chemotherapeutic agents
ES2534085T3 (es) 2009-08-17 2015-04-17 Roche Glycart Ag Inmunoconjugados dirigidos
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SG11201802912PA (en) * 2015-10-10 2018-05-30 Intrexon Corp Improved therapeutic control of proteolytically sensitive, destabilized forms of interleukin-12
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WO2018224550A1 (en) * 2017-06-07 2018-12-13 Philogen S.P.A Vascular endothelial growth factor/anti-fibronectin antibody fusion proteins
TWI844524B (zh) * 2018-02-09 2024-06-11 義大利商費洛根公司 靶向edb之il-12組合物

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Also Published As

Publication number Publication date
TW201934136A (zh) 2019-09-01
ES3035714T3 (en) 2025-09-08
JP2023113648A (ja) 2023-08-16
EP3749372C0 (en) 2025-04-16
EP3749372B1 (en) 2025-04-16
KR20200109380A (ko) 2020-09-22
CL2020002052A1 (es) 2021-01-04
PE20210122A1 (es) 2021-01-19
IL275713A (en) 2020-08-31
CO2020009737A2 (es) 2020-08-21
AU2019219201A1 (en) 2020-07-23
RU2021130306A (ru) 2021-11-10
MY200700A (en) 2024-01-11
AU2021203986A1 (en) 2021-07-08
CA3087488C (en) 2021-11-02
CR20200342A (es) 2020-10-19
US20200397915A1 (en) 2020-12-24
JOP20200193A1 (ar) 2020-08-06
CN111683687B (zh) 2024-08-02
MX2020008231A (es) 2020-09-25
RU2758143C1 (ru) 2021-10-26
CU20200054A7 (es) 2021-05-12
NZ766787A (en) 2024-05-31
UY38074A (es) 2019-10-01
US12173044B2 (en) 2024-12-24
TWI844524B (zh) 2024-06-11
CA3087488A1 (en) 2019-08-15
ECSP20047171A (es) 2020-09-30
PH12020551230A1 (en) 2021-05-17
KR20210063467A (ko) 2021-06-01
JP7279054B2 (ja) 2023-05-22
CN111683687A (zh) 2020-09-18
WO2019154986A1 (en) 2019-08-15
JP2021513536A (ja) 2021-05-27
KR102259085B1 (ko) 2021-06-03
BR112020012888A2 (pt) 2020-12-08
KR102488801B1 (ko) 2023-01-13
SG11202006334XA (en) 2020-08-28
EP3749372A1 (en) 2020-12-16

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