CA3064897A1 - Novel oncolytic viruses for sensitizing tumor cells to killing by natural killer cells - Google Patents
Novel oncolytic viruses for sensitizing tumor cells to killing by natural killer cells Download PDFInfo
- Publication number
- CA3064897A1 CA3064897A1 CA3064897A CA3064897A CA3064897A1 CA 3064897 A1 CA3064897 A1 CA 3064897A1 CA 3064897 A CA3064897 A CA 3064897A CA 3064897 A CA3064897 A CA 3064897A CA 3064897 A1 CA3064897 A1 CA 3064897A1
- Authority
- CA
- Canada
- Prior art keywords
- virus
- cell
- cells
- domain
- oncolytic virus
- 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.)
- Pending
Links
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/761—Adenovirus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K40/00—Cellular immunotherapy
- A61K40/10—Cellular immunotherapy characterised by the cell type used
- A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K40/00—Cellular immunotherapy
- A61K40/10—Cellular immunotherapy characterised by the cell type used
- A61K40/15—Natural-killer [NK] cells; Natural-killer T [NKT] cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K40/00—Cellular immunotherapy
- A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
- A61K40/31—Chimeric antigen receptors [CAR]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K40/00—Cellular immunotherapy
- A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
- A61K40/41—Vertebrate antigens
- A61K40/42—Cancer antigens
- A61K40/4202—Receptors, cell surface antigens or cell surface determinants
- A61K40/421—Immunoglobulin superfamily
- A61K40/4211—CD19 or B4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K40/00—Cellular immunotherapy
- A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
- A61K40/41—Vertebrate antigens
- A61K40/42—Cancer antigens
- A61K40/4202—Receptors, cell surface antigens or cell surface determinants
- A61K40/4221—CD20
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- 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
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
- A61K2239/59—Reproductive system, e.g. uterus, ovaries, cervix or testes
-
- 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
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/18011—Paramyxoviridae
- C12N2760/18711—Rubulavirus, e.g. mumps virus, parainfluenza 2,4
- C12N2760/18721—Viruses as such, e.g. new isolates, mutants or their genomic sequences
-
- 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
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/18011—Paramyxoviridae
- C12N2760/18711—Rubulavirus, e.g. mumps virus, parainfluenza 2,4
- C12N2760/18732—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
-
- 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
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/18011—Paramyxoviridae
- C12N2760/18711—Rubulavirus, e.g. mumps virus, parainfluenza 2,4
- C12N2760/18741—Use of virus, viral particle or viral elements as a vector
- C12N2760/18743—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- 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
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/18011—Paramyxoviridae
- C12N2760/18711—Rubulavirus, e.g. mumps virus, parainfluenza 2,4
- C12N2760/18741—Use of virus, viral particle or viral elements as a vector
- C12N2760/18745—Special targeting system for viral vectors
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Microbiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Gastroenterology & Hepatology (AREA)
- Cell Biology (AREA)
- Mycology (AREA)
- Toxicology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762511010P | 2017-05-25 | 2017-05-25 | |
| US62/511,010 | 2017-05-25 | ||
| PCT/US2018/034655 WO2018218151A1 (en) | 2017-05-25 | 2018-05-25 | Novel oncolytic viruses for sensitizing tumor cells to killing by natural killer cells |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3064897A1 true CA3064897A1 (en) | 2018-11-29 |
Family
ID=64397136
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3064897A Pending CA3064897A1 (en) | 2017-05-25 | 2018-05-25 | Novel oncolytic viruses for sensitizing tumor cells to killing by natural killer cells |
Country Status (10)
| Country | Link |
|---|---|
| US (2) | US11684637B2 (OSRAM) |
| EP (1) | EP3630144A4 (OSRAM) |
| JP (2) | JP7522426B2 (OSRAM) |
| KR (2) | KR102700175B1 (OSRAM) |
| CN (1) | CN110891584B (OSRAM) |
| AU (1) | AU2018273963B2 (OSRAM) |
| BR (1) | BR112019024656A2 (OSRAM) |
| CA (1) | CA3064897A1 (OSRAM) |
| IL (1) | IL270876B2 (OSRAM) |
| WO (1) | WO2018218151A1 (OSRAM) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111676245A (zh) * | 2020-06-24 | 2020-09-18 | 武汉波睿达生物科技有限公司 | 一种含有HSV-1型溶瘤病毒的NFAT-Cre-CAR-T细胞及其应用 |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JOP20190256A1 (ar) | 2017-05-12 | 2019-10-28 | Icahn School Med Mount Sinai | فيروسات داء نيوكاسل واستخداماتها |
| JP2020530454A (ja) | 2017-08-07 | 2020-10-22 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 安全な細胞治療薬を生成するためのプラットフォーム |
| US12391957B2 (en) | 2018-08-17 | 2025-08-19 | Icahn School Of Medicine At Mount Sinai | Recombinant Newcastle disease viruses and uses thereof for the prevention of RSV disease or human metapneumovirus disease |
| AU2020211456A1 (en) * | 2019-01-24 | 2021-08-26 | University Of Central Florida Research Foundation, Inc. | Compositions and methods for stimulating natural killer cells |
| KR20220151601A (ko) * | 2019-11-25 | 2022-11-15 | 안선 바이오파르마, 아이엔씨. | 암세포, 면역세포 및 종양 미세환경으로의 시알리다제의 면역세포 전달 |
| CN112852757A (zh) * | 2021-02-01 | 2021-05-28 | 南京大学 | 一种制备新型溶瘤病毒EM/VSV-G Ad5sPVRCD137L的方法 |
| US20240191252A1 (en) * | 2021-04-08 | 2024-06-13 | Immvira Biopharmaceuticals Co., Limited | Genetically modified oncolytic herpes simplex virus delivering chemokine and tumor associated/specific antigen |
| CN115678854A (zh) * | 2021-07-29 | 2023-02-03 | 上海中医药大学 | 一种基因工程细胞及其制备方法和应用 |
| CN116875547A (zh) * | 2023-09-04 | 2023-10-13 | 山东德升细胞治疗工程技术有限公司 | 一种利用细胞外泌体激活nk细胞的体外扩增培养方法 |
Family Cites Families (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1601438A (OSRAM) | 1968-10-17 | 1970-08-24 | ||
| WO2002080983A1 (en) * | 2001-04-05 | 2002-10-17 | The Uab Research Foundation | Enhanced dispersion of adenoviral vectors by fusogenic membrane glycoproteins |
| US20090214590A1 (en) * | 2005-07-08 | 2009-08-27 | Wayne State University | Virus Vaccines Comprising Envelope-Bound Immunomodulatory Proteins and Methods of Use Thereof |
| JP2009513608A (ja) | 2005-10-28 | 2009-04-02 | ノボ・ノルデイスク・エー/エス | エフェクターリンパ球と標的細胞とを結合する融合タンパク質 |
| WO2008067305A2 (en) | 2006-11-28 | 2008-06-05 | Giic Research Development Corporation | Polypeptides comprising intracytoplasmic death domain and nkg2d ligand domain |
| WO2008140603A2 (en) | 2006-12-08 | 2008-11-20 | Macrogenics, Inc. | METHODS FOR THE TREATMENT OF DISEASE USING IMMUNOGLOBULINS HAVING FC REGIONS WITH ALTERED AFFINITIES FOR FCγR ACTIVATING AND FCγR INHIBITING |
| US20100178684A1 (en) | 2006-12-21 | 2010-07-15 | Woo Savio L C | Transgenic oncolytic viruses and uses thereof |
| FR2938840B1 (fr) * | 2008-11-21 | 2010-12-17 | Centre Nat Rech Scient | Proteines mutantes de la proteine f de piv-5 et de piv-2 |
| SI2379586T1 (sl) | 2008-12-22 | 2017-02-28 | Targovax Oy | Onkolitični adenovirusni vektorji in z njimi povezani postopki in uporabe |
| WO2011044158A1 (en) * | 2009-10-09 | 2011-04-14 | New York Blood Center, Inc. | Immunopotentiator-linked oligomeric influenza immunogenic compositions |
| CN108130345A (zh) | 2012-01-24 | 2018-06-08 | 乔治亚大学研究基金公司 | 基于副流感病毒5的疫苗 |
| PT3578201T (pt) * | 2012-06-28 | 2023-05-10 | Univ Of Central Florida Research Foundation Incorporated | Métodos e composições para células assassinas naturais |
| WO2014037124A1 (en) * | 2012-09-04 | 2014-03-13 | Bavarian Nordic A/S | Methods and compositions for enhancing vaccine immune responses |
| WO2014041119A1 (en) * | 2012-09-14 | 2014-03-20 | Deutsches Krebsforschungszentrum | Oncolytic viruses expressing immuno-nucleases |
| WO2014158811A1 (en) | 2013-03-14 | 2014-10-02 | Icahn School Of Medicine At Mount Sinai | Newcastle disease viruses and uses thereof |
| US20170007685A1 (en) | 2013-11-05 | 2017-01-12 | The Board Of Regents Of The University Of Texas System | TUMORS EXPRESSING IgG1 Fc INDUCE ROBUST CD8 T CELL RESPONSES |
| US10238700B2 (en) * | 2014-01-02 | 2019-03-26 | Genelux Corporation | Oncolytic virus adjunct therapy with agents that increase virus infectivity |
| US10512684B2 (en) * | 2014-09-26 | 2019-12-24 | Bavarian Nordic A/S | Methods and compositions for intra-nasal immunization with recombinant MVA encoding flagellin |
| BR112017008696A2 (pt) | 2014-10-27 | 2017-12-26 | Univ Central Florida Res Found Inc | métodos e composições para células exterminadoras naturais |
| WO2016109668A1 (en) * | 2014-12-31 | 2016-07-07 | Anthrogenesis Corporation | Methods of treating hematological disorders, solid tumors, or infectious diseases using natural killer cells |
| PT3280729T (pt) * | 2015-04-08 | 2022-08-01 | Novartis Ag | Terapias para cd20, terapias para cd22 e terapias de combinação com uma célula que expressa o recetor de antigénio quimérico (car) para cd19 |
| HRP20200439T1 (hr) | 2015-04-30 | 2020-06-12 | Psioxus Therapeutics Limited | Onkolitički adenovirus koji kodira protein b7 |
| WO2018083259A1 (en) * | 2016-11-03 | 2018-05-11 | Psioxus Therapeutics Limited | Oncolytic adenovirus encoding transgenes |
-
2018
- 2018-05-25 BR BR112019024656A patent/BR112019024656A2/pt unknown
- 2018-05-25 IL IL270876A patent/IL270876B2/en unknown
- 2018-05-25 CN CN201880047292.0A patent/CN110891584B/zh active Active
- 2018-05-25 US US16/616,671 patent/US11684637B2/en active Active
- 2018-05-25 EP EP18806947.0A patent/EP3630144A4/en active Pending
- 2018-05-25 KR KR1020197037594A patent/KR102700175B1/ko active Active
- 2018-05-25 CA CA3064897A patent/CA3064897A1/en active Pending
- 2018-05-25 KR KR1020247028510A patent/KR20240132124A/ko active Pending
- 2018-05-25 WO PCT/US2018/034655 patent/WO2018218151A1/en not_active Ceased
- 2018-05-25 JP JP2019564782A patent/JP7522426B2/ja active Active
- 2018-05-25 AU AU2018273963A patent/AU2018273963B2/en active Active
-
2023
- 2023-05-15 US US18/317,616 patent/US12312393B2/en active Active
-
2024
- 2024-07-05 JP JP2024109160A patent/JP2024133640A/ja active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111676245A (zh) * | 2020-06-24 | 2020-09-18 | 武汉波睿达生物科技有限公司 | 一种含有HSV-1型溶瘤病毒的NFAT-Cre-CAR-T细胞及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP7522426B2 (ja) | 2024-07-25 |
| US20210145876A1 (en) | 2021-05-20 |
| US20240000842A1 (en) | 2024-01-04 |
| EP3630144A4 (en) | 2021-03-31 |
| AU2018273963B2 (en) | 2023-07-20 |
| CN110891584B (zh) | 2024-02-13 |
| CN110891584A (zh) | 2020-03-17 |
| KR20200010405A (ko) | 2020-01-30 |
| BR112019024656A2 (pt) | 2020-06-09 |
| IL270876B2 (en) | 2024-06-01 |
| AU2018273963A1 (en) | 2020-01-23 |
| JP2020521447A (ja) | 2020-07-27 |
| US11684637B2 (en) | 2023-06-27 |
| IL270876B1 (en) | 2024-02-01 |
| KR20240132124A (ko) | 2024-09-02 |
| WO2018218151A1 (en) | 2018-11-29 |
| IL270876A (en) | 2020-01-30 |
| JP2024133640A (ja) | 2024-10-02 |
| KR102700175B1 (ko) | 2024-08-30 |
| EP3630144A1 (en) | 2020-04-08 |
| US12312393B2 (en) | 2025-05-27 |
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