DK2776567T3 - Sammensætninger og fremgangsmåder til behandling af cytomegalovirus. - Google Patents
Sammensætninger og fremgangsmåder til behandling af cytomegalovirus. Download PDFInfo
- Publication number
- DK2776567T3 DK2776567T3 DK12847559.7T DK12847559T DK2776567T3 DK 2776567 T3 DK2776567 T3 DK 2776567T3 DK 12847559 T DK12847559 T DK 12847559T DK 2776567 T3 DK2776567 T3 DK 2776567T3
- Authority
- DK
- Denmark
- Prior art keywords
- cytomegalovirus
- compositions
- treatment
- methods
- Prior art date
Links
- 241000701022 Cytomegalovirus Species 0.000 title 1
- 239000000203 mixture Substances 0.000 title 1
Classifications
-
- 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
-
- 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
- A61K39/12—Viral antigens
-
- 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
- A61K39/12—Viral antigens
- A61K39/245—Herpetoviridae, e.g. herpes simplex virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5258—Virus-like particles
-
- 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
- A61K2039/70—Multivalent vaccine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16111—Cytomegalovirus, e.g. human herpesvirus 5
- C12N2710/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- 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
- C12N2740/13011—Gammaretrovirus, e.g. murine leukeamia virus
- C12N2740/13023—Virus like particles [VLP]
-
- 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
- C12N2760/20011—Rhabdoviridae
- C12N2760/20211—Vesiculovirus, e.g. vesicular stomatitis Indiana virus
- C12N2760/20234—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- 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
- C12N2760/20011—Rhabdoviridae
- C12N2760/20211—Vesiculovirus, e.g. vesicular stomatitis Indiana virus
- C12N2760/20241—Use of virus, viral particle or viral elements as a vector
- C12N2760/20245—Special targeting system for viral vectors
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Lubricants (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161558800P | 2011-11-11 | 2011-11-11 | |
| US201261654157P | 2012-06-01 | 2012-06-01 | |
| PCT/IB2012/002854 WO2013068847A2 (en) | 2011-11-11 | 2012-11-09 | Compositions and methods for treatment of cytomegalovirus |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2776567T3 true DK2776567T3 (da) | 2021-04-26 |
Family
ID=48290708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK12847559.7T DK2776567T3 (da) | 2011-11-11 | 2012-11-09 | Sammensætninger og fremgangsmåder til behandling af cytomegalovirus. |
Country Status (14)
| Country | Link |
|---|---|
| US (3) | US9777043B2 (enExample) |
| EP (2) | EP2776567B1 (enExample) |
| JP (2) | JP6232544B2 (enExample) |
| KR (2) | KR102301463B1 (enExample) |
| CN (3) | CN111995664B (enExample) |
| AU (3) | AU2012335277B2 (enExample) |
| BR (2) | BR112014011229B1 (enExample) |
| CA (2) | CA3166278A1 (enExample) |
| DK (1) | DK2776567T3 (enExample) |
| ES (1) | ES2874233T3 (enExample) |
| MX (2) | MX353189B (enExample) |
| PT (1) | PT2776567T (enExample) |
| RU (2) | RU2737530C1 (enExample) |
| WO (1) | WO2013068847A2 (enExample) |
Families Citing this family (46)
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| US9575055B2 (en) | 2009-06-18 | 2017-02-21 | Kiyatec Inc. | Co-culture bioreactor system |
| US8822663B2 (en) | 2010-08-06 | 2014-09-02 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
| DK4108671T3 (da) | 2010-10-01 | 2025-01-06 | Modernatx Inc | Modificerede nukleosider, nukleotider og nukleinsyrer samt anvendelser deraf |
| JP2014511687A (ja) | 2011-03-31 | 2014-05-19 | モデルナ セラピューティクス インコーポレイテッド | 工学操作された核酸の送達および製剤 |
| US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
| JP6113737B2 (ja) | 2011-10-03 | 2017-04-12 | モデルナティエックス インコーポレイテッドＭｏｄｅｒｎａＴＸ，Ｉｎｃ． | 修飾型のヌクレオシド、ヌクレオチドおよび核酸、ならびにそれらの使用方法 |
| AU2012335277B2 (en) * | 2011-11-11 | 2018-06-14 | Variation Biotechnologies Inc. | Compositions and methods for treatment of cytomegalovirus |
| KR20140102759A (ko) | 2011-12-16 | 2014-08-22 | 모더나 세라퓨틱스, 인코포레이티드 | 변형된 뉴클레오사이드, 뉴클레오타이드 및 핵산 조성물 |
| WO2013144722A2 (en) * | 2012-03-27 | 2013-10-03 | Variation Biotechnologies, Inc. | Methods for detection of anti-cytomegalovirus neutralizing antibodies |
| US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
| US9254311B2 (en) | 2012-04-02 | 2016-02-09 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins |
| EP2834259A4 (en) | 2012-04-02 | 2016-08-24 | Moderna Therapeutics Inc | MODIFIED POLYNUCLEOTIDES |
| US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
| SG11201501623PA (en) * | 2012-10-30 | 2015-05-28 | Redvax Gmbh | Recombinant particle based vaccines against human cytomegalovirus infection |
| US9597380B2 (en) | 2012-11-26 | 2017-03-21 | Modernatx, Inc. | Terminally modified RNA |
| US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
| US9340800B2 (en) | 2013-09-06 | 2016-05-17 | President And Fellows Of Harvard College | Extended DNA-sensing GRNAS |
| US10023626B2 (en) | 2013-09-30 | 2018-07-17 | Modernatx, Inc. | Polynucleotides encoding immune modulating polypeptides |
| EP3052521A1 (en) | 2013-10-03 | 2016-08-10 | Moderna Therapeutics, Inc. | Polynucleotides encoding low density lipoprotein receptor |
| US10273285B2 (en) | 2014-06-18 | 2019-04-30 | Morphosys Ag | Fusion proteins and uses thereof |
| KR101678740B1 (ko) * | 2014-10-24 | 2016-11-23 | 단국대학교 천안캠퍼스 산학협력단 | 세포 부착활성 및 골분화 촉진활성을 나타내는 피브로넥틴 융합단백질 |
| WO2016149426A1 (en) * | 2015-03-16 | 2016-09-22 | The Broad Institute, Inc. | Constructs for continuous monitoring of live cells |
| WO2017068077A1 (en) * | 2015-10-20 | 2017-04-27 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Methods and products for genetic engineering |
| CA3002922A1 (en) * | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Human cytomegalovirus vaccine |
| US10611800B2 (en) | 2016-03-11 | 2020-04-07 | Pfizer Inc. | Human cytomegalovirus gB polypeptide |
| WO2017162265A1 (en) * | 2016-03-21 | 2017-09-28 | Biontech Rna Pharmaceuticals Gmbh | Trans-replicating rna |
| CA3041307A1 (en) | 2016-10-21 | 2018-04-26 | Giuseppe Ciaramella | Human cytomegalovirus vaccine |
| US11898179B2 (en) | 2017-03-09 | 2024-02-13 | President And Fellows Of Harvard College | Suppression of pain by gene editing |
| CN110662556A (zh) | 2017-03-09 | 2020-01-07 | 哈佛大学的校长及成员们 | 癌症疫苗 |
| US11732274B2 (en) | 2017-07-28 | 2023-08-22 | President And Fellows Of Harvard College | Methods and compositions for evolving base editors using phage-assisted continuous evolution (PACE) |
| EP3784276A4 (en) * | 2018-04-24 | 2022-03-16 | Merck Sharp & Dohme Corp. | SCALABLE CHROMATOGRAPHY PROCEDURE FOR PURIFICATION OF HUMAN CYTOMEGALOVIRUS |
| JP7575096B2 (ja) | 2018-05-04 | 2024-10-29 | スパイバイオテック・リミテッド | ワクチン組成物 |
| US12522807B2 (en) | 2018-07-09 | 2026-01-13 | The Broad Institute, Inc. | RNA programmable epigenetic RNA modifiers and uses thereof |
| US11629172B2 (en) | 2018-12-21 | 2023-04-18 | Pfizer Inc. | Human cytomegalovirus gB polypeptide |
| WO2020154500A1 (en) | 2019-01-23 | 2020-07-30 | The Broad Institute, Inc. | Supernegatively charged proteins and uses thereof |
| MX2021011426A (es) | 2019-03-19 | 2022-03-11 | Broad Inst Inc | Metodos y composiciones para editar secuencias de nucleótidos. |
| WO2020214842A1 (en) | 2019-04-17 | 2020-10-22 | The Broad Institute, Inc. | Adenine base editors with reduced off-target effects |
| KR20220038608A (ko) * | 2019-05-31 | 2022-03-29 | 배리에이션 바이오테크놀로지스 아이엔씨. | 다형성 교모세포종의 치료를 위한 면역치료 조성물 |
| CN114258398A (zh) | 2019-06-13 | 2022-03-29 | 总医院公司 | 工程化的人内源性病毒样颗粒及使用其递送至细胞的方法 |
| GB201910651D0 (en) * | 2019-07-25 | 2019-09-11 | Autolus Ltd | Virus-like particle |
| WO2021048081A1 (en) | 2019-09-09 | 2021-03-18 | Glaxosmithkline Biologicals Sa | Immunotherapeutic compositions |
| US11857622B2 (en) * | 2020-06-21 | 2024-01-02 | Pfizer Inc. | Human cytomegalovirus GB polypeptide |
| BR112023001272A2 (pt) | 2020-07-24 | 2023-04-04 | Massachusetts Gen Hospital | Partículas semelhantes a vírus aprimoradas e métodos de uso das mesmas para entrega às células |
| US11406703B2 (en) | 2020-08-25 | 2022-08-09 | Modernatx, Inc. | Human cytomegalovirus vaccine |
| CN115948468A (zh) * | 2022-09-09 | 2023-04-11 | 青岛大学 | 一种人巨细胞病毒重组载体及其制备方法和应用 |
| WO2024243675A1 (en) * | 2023-06-02 | 2024-12-05 | Variation Biotechnologies Inc. | Compositions of mrna-encoded virus-like particles, compositions of mrna-lipid nanoparticles, and methods for use thereof |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6267965B1 (en) | 1981-12-24 | 2001-07-31 | Virogenetics Corporation | Recombinant poxvirus—cytomegalovirus compositions and uses |
| JPS61103895A (ja) * | 1984-10-26 | 1986-05-22 | Green Cross Corp:The | ＨＢｓＡｇの精製方法 |
| JP2607712B2 (ja) * | 1988-01-29 | 1997-05-07 | カイロン コーポレイション | 組換えｃｍｖ中和タンパク |
| US5500161A (en) | 1993-09-21 | 1996-03-19 | Massachusetts Institute Of Technology And Virus Research Institute | Method for making hydrophobic polymeric microparticles |
| DE19856463B4 (de) * | 1998-11-26 | 2006-02-02 | Heinrich-Pette-Institut | Retrovirale, mit LCMV pseudotypisierte Hybrid-Vektoren |
| DE19910044A1 (de) | 1999-03-08 | 2000-09-14 | Bodo Plachter | Virale Partikel, die nach Infektion durch humanes Cytomegalovirus freigesetzt werden und ihre Verwendung als Impfstoff |
| US6413518B1 (en) | 1999-09-30 | 2002-07-02 | University Of Washington | Immunologically significant herpes simplex virus antigens and methods for identifying and using same |
| EP1201750A1 (en) * | 2000-10-26 | 2002-05-02 | Genopoietic | Synthetic viruses and uses thereof |
| US9045727B2 (en) * | 2002-05-17 | 2015-06-02 | Emory University | Virus-like particles, methods of preparation, and immunogenic compositions |
| PT2311848E (pt) | 2002-12-23 | 2013-10-03 | Vical Inc | Vacinas à base de polinucleótido optimizadas por codão contra a infecção do citomegalovírus humano |
| PT1651666E (pt) | 2003-07-11 | 2009-08-28 | Alphavax Inc | Vacinas de citomegalovírus à base de alfavírus |
| RU2290204C1 (ru) * | 2005-07-27 | 2006-12-27 | Общество с ограниченной ответственностью "Аванген" | Рекомбинантный гибридный белок, препарат для иммунотерапии на его основе и способ иммунотерапии рецидивирующего папилломатоза гортани |
| EP2044224A4 (en) * | 2006-07-27 | 2011-04-13 | Ligocyte Pharmaceuticals Inc | CHIMERIC VIRUS TYPE PARTICLES |
| US20090123494A1 (en) * | 2007-07-31 | 2009-05-14 | William Staplin | Momlv-based pseudovirion packaging cell line |
| WO2009120883A2 (en) * | 2008-03-26 | 2009-10-01 | Life Technologies Corporation | Virus-like particle mediated cellular delivery |
| GB0907935D0 (en) | 2009-05-08 | 2009-06-24 | Henderson Morley Plc | Vaccines |
| AU2012335277B2 (en) | 2011-11-11 | 2018-06-14 | Variation Biotechnologies Inc. | Compositions and methods for treatment of cytomegalovirus |
| WO2015089340A1 (en) | 2013-12-11 | 2015-06-18 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Human herpesvirus trimeric glycoprotein b, protein complexes comprising trimeric gb and their use as vaccines |
-
2012
- 2012-11-09 AU AU2012335277A patent/AU2012335277B2/en active Active
- 2012-11-09 CA CA3166278A patent/CA3166278A1/en active Pending
- 2012-11-09 WO PCT/IB2012/002854 patent/WO2013068847A2/en not_active Ceased
- 2012-11-09 CN CN202010272504.4A patent/CN111995664B/zh active Active
- 2012-11-09 EP EP12847559.7A patent/EP2776567B1/en active Active
- 2012-11-09 DK DK12847559.7T patent/DK2776567T3/da active
- 2012-11-09 CN CN201711042348.7A patent/CN107875382B/zh active Active
- 2012-11-09 CN CN201280066355.XA patent/CN104271745A/zh active Pending
- 2012-11-09 KR KR1020147015909A patent/KR102301463B1/ko active Active
- 2012-11-09 KR KR1020197025818A patent/KR102340558B1/ko active Active
- 2012-11-09 BR BR112014011229-0A patent/BR112014011229B1/pt active IP Right Grant
- 2012-11-09 MX MX2014005653A patent/MX353189B/es active IP Right Grant
- 2012-11-09 PT PT128475597T patent/PT2776567T/pt unknown
- 2012-11-09 JP JP2014540570A patent/JP6232544B2/ja active Active
- 2012-11-09 BR BR122019027913-6A patent/BR122019027913B1/pt active IP Right Grant
- 2012-11-09 EP EP21152309.7A patent/EP3854416A1/en active Pending
- 2012-11-09 CA CA2889659A patent/CA2889659C/en active Active
- 2012-11-09 RU RU2014123465A patent/RU2737530C1/ru active
- 2012-11-09 ES ES12847559T patent/ES2874233T3/es active Active
- 2012-11-09 MX MX2017017128A patent/MX387666B/es unknown
- 2012-11-09 RU RU2019139064A patent/RU2019139064A/ru unknown
- 2012-11-09 US US14/357,423 patent/US9777043B2/en active Active
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2017
- 2017-08-04 JP JP2017151540A patent/JP6657150B2/ja active Active
- 2017-08-22 US US15/683,355 patent/US11248026B2/en active Active
-
2018
- 2018-05-18 AU AU2018203538A patent/AU2018203538A1/en not_active Abandoned
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2020
- 2020-11-03 AU AU2020264275A patent/AU2020264275B2/en active Active
-
2022
- 2022-02-11 US US17/670,052 patent/US12421283B2/en active Active
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