BR112019012312A8 - Reagentes para tratamento da distrofia muscular oculofaríngea (opmd) e uso dos mesmos - Google Patents

Reagentes para tratamento da distrofia muscular oculofaríngea (opmd) e uso dos mesmos

Info

Publication number
BR112019012312A8
BR112019012312A8 BR112019012312A BR112019012312A BR112019012312A8 BR 112019012312 A8 BR112019012312 A8 BR 112019012312A8 BR 112019012312 A BR112019012312 A BR 112019012312A BR 112019012312 A BR112019012312 A BR 112019012312A BR 112019012312 A8 BR112019012312 A8 BR 112019012312A8
Authority
BR
Brazil
Prior art keywords
opmd
reagents
treatment
muscular dystrophy
oculopharyngeal muscular
Prior art date
Application number
BR112019012312A
Other languages
English (en)
Portuguese (pt)
Other versions
BR112019012312A2 (pt
Inventor
STRINGS-UFOMBAH Vanessa
Suhy David
Original Assignee
Benitec Biopharma Ltd
Benitec Biopharma Pty Ltd
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 Benitec Biopharma Ltd, Benitec Biopharma Pty Ltd filed Critical Benitec Biopharma Ltd
Publication of BR112019012312A2 publication Critical patent/BR112019012312A2/pt
Publication of BR112019012312A8 publication Critical patent/BR112019012312A8/pt

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088Compounds having three or more nucleosides or nucleotides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86Viral vectors
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86Viral vectors
    • C12N15/861Adenoviral vectors
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86Viral vectors
    • C12N15/864Parvoviral vectors, e.g. parvovirus, densovirus
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86Viral vectors
    • C12N15/867Retroviral vectors
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/10Type of nucleic acid
    • C12N2310/14Type of nucleic acid interfering nucleic acids [NA]
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/10Type of nucleic acid
    • C12N2310/14Type of nucleic acid interfering nucleic acids [NA]
    • C12N2310/141MicroRNAs, miRNAs
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/50Physical structure
    • C12N2310/53Physical structure partially self-complementary or closed
    • C12N2310/531Stem-loop; Hairpin
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2330/00Production
    • C12N2330/50Biochemical production, i.e. in a transformed host cell
    • C12N2330/51Specially adapted vectors
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011Details
    • C12N2710/10011Adenoviridae
    • C12N2710/10041Use of virus, viral particle or viral elements as a vector
    • C12N2710/10043Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00Reverse transcribing RNA viruses
    • C12N2740/00011Details
    • C12N2740/10011Retroviridae
    • C12N2740/10041Use of virus, viral particle or viral elements as a vector
    • C12N2740/10043Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00Reverse transcribing RNA viruses
    • C12N2740/00011Details
    • C12N2740/10011Retroviridae
    • C12N2740/15011Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15041Use of virus, viral particle or viral elements as a vector
    • C12N2740/15043Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011Details
    • C12N2750/14011Parvoviridae
    • C12N2750/14111Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2800/00Nucleic acids vectors
    • C12N2800/22Vectors comprising a coding region that has been codon optimised for expression in a respective host
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2830/00Vector systems having a special element relevant for transcription
    • C12N2830/008Vector systems having a special element relevant for transcription cell type or tissue specific enhancer/promoter combination

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Plant Pathology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Virology (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
BR112019012312A 2016-12-14 2017-12-14 Reagentes para tratamento da distrofia muscular oculofaríngea (opmd) e uso dos mesmos BR112019012312A8 (pt)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201662434312P 2016-12-14 2016-12-14
US62/434,312 2016-12-14
PCT/AU2017/051385 WO2018107228A1 (en) 2016-12-14 2017-12-14 Reagents for treatment of oculopharyngeal muscular dystrophy (opmd) and use thereof

Publications (2)

Publication Number Publication Date
BR112019012312A2 BR112019012312A2 (pt) 2020-02-11
BR112019012312A8 true BR112019012312A8 (pt) 2023-02-28

Family

ID=62557655

Family Applications (1)

Application Number Title Priority Date Filing Date
BR112019012312A BR112019012312A8 (pt) 2016-12-14 2017-12-14 Reagentes para tratamento da distrofia muscular oculofaríngea (opmd) e uso dos mesmos

Country Status (13)

Country Link
US (2) US11142765B2 (enExample)
EP (1) EP3555294A4 (enExample)
JP (2) JP7233149B2 (enExample)
KR (2) KR102495222B1 (enExample)
CN (2) CN118421624A (enExample)
AU (2) AU2017377661B2 (enExample)
BR (1) BR112019012312A8 (enExample)
CA (1) CA3047154A1 (enExample)
IL (2) IL267353B2 (enExample)
MX (2) MX2019007110A (enExample)
RU (1) RU2763319C2 (enExample)
WO (1) WO2018107228A1 (enExample)
ZA (1) ZA202106827B (enExample)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11142765B2 (en) 2016-12-14 2021-10-12 Benitec Ip Holdings, Inc. Reagents for treatment of oculopharyngeal muscular dystrophy (OPMD) and use thereof
MX2021004225A (es) * 2018-10-17 2021-05-27 Benitec Ip Holdings Inc Metodos para tratar distrofia muscular oculofaringea (dmof).
MX2021010412A (es) 2019-02-28 2022-01-24 Benitec Ip Holdings Inc Composiciones y metodos para tratar distrofia muscular oculofaringea (opmd).
PE20230430A1 (es) * 2019-12-23 2023-03-08 Versameb Ag Composiciones y metodos para modular simultaneamente la expresion de genes

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4210737B2 (ja) 2001-07-12 2009-01-21 ユニバーシティー オブ マサチューセッツ 遺伝子サイレンシングを仲介する低分子干渉リボ核酸のインビボにおける製造方法
EP1783645A1 (en) 2005-11-08 2007-05-09 Actigenics Methods for the identification of microRNA and their applications in research and human health
WO2008092935A2 (en) * 2007-01-31 2008-08-07 Basf Plant Science Gmbh Plants having enhanced yield-related traits and/or increased abiotic stress resistance, and a method for making the same
CA2691617C (en) * 2007-05-31 2020-07-21 University Of Iowa Research Foundation Reduction of off-target rna interference toxicity
WO2010105372A1 (en) * 2009-03-20 2010-09-23 Protiva Biotherapeutics, Inc. Compositions and methods for silencing hepatitis c virus expression
DK2814514T3 (en) * 2012-02-16 2017-12-18 Atyr Pharma Inc Histidyl tRNA synthetases for the treatment of autoimmune and inflammatory diseases
WO2014077693A1 (en) * 2012-11-16 2014-05-22 Academisch Ziekenhuis Leiden H.O.D.N. Lumc Means and methods for reducing an effect of aging in a mammalian cell
KR20150103280A (ko) * 2013-01-08 2015-09-09 베니텍 바이오파마 리미티드 연령-관련 황반 변성 치료
EP3443091A4 (en) * 2016-04-14 2019-11-27 Benitec Biopharma Limited REAGENTS FOR THE TREATMENT OF OCULOPHARYNGEAL MUSCLE DYSTROPHY (OPMD) AND USE THEREOF
US11142765B2 (en) 2016-12-14 2021-10-12 Benitec Ip Holdings, Inc. Reagents for treatment of oculopharyngeal muscular dystrophy (OPMD) and use thereof

Also Published As

Publication number Publication date
IL267353A (en) 2019-08-29
JP7233149B2 (ja) 2023-03-06
AU2017377661B2 (en) 2023-07-27
KR102495222B1 (ko) 2023-02-09
EP3555294A4 (en) 2020-08-26
AU2017377661A1 (en) 2019-07-18
EP3555294A1 (en) 2019-10-23
MX2019007110A (es) 2019-12-05
JP2020503014A (ja) 2020-01-30
WO2018107228A1 (en) 2018-06-21
IL267353B1 (en) 2023-08-01
RU2763319C2 (ru) 2021-12-28
IL304674A (en) 2023-09-01
ZA202106827B (en) 2022-07-27
IL304674B2 (en) 2024-11-01
CA3047154A1 (en) 2018-06-21
JP2023062092A (ja) 2023-05-02
US20220056446A1 (en) 2022-02-24
RU2019121950A (ru) 2021-01-18
CN110382698B (zh) 2024-05-10
US20190330629A1 (en) 2019-10-31
US11142765B2 (en) 2021-10-12
AU2023222827B2 (en) 2025-02-27
IL304674B1 (en) 2024-07-01
AU2023222827A1 (en) 2023-09-14
JP7431359B2 (ja) 2024-02-14
CN110382698A (zh) 2019-10-25
MX2024003643A (es) 2024-04-15
CN118421624A (zh) 2024-08-02
KR20230020586A (ko) 2023-02-10
KR20190104151A (ko) 2019-09-06
US11932852B2 (en) 2024-03-19
BR112019012312A2 (pt) 2020-02-11
RU2019121950A3 (enExample) 2021-01-18
KR102667867B1 (ko) 2024-05-29
IL267353B2 (en) 2023-12-01

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B350 Update of information on the portal [chapter 15.35 patent gazette]
B06W Patent application suspended after preliminary examination (for patents with searches from other patent authorities) chapter 6.23 patent gazette]
B25D Requested change of name of applicant approved

Owner name: BENITEC BIOPHARMA PTY LTD (AU)

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Owner name: BENITEC IP HOLDINGS INC. (US)

B07A Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]
B06A Patent application procedure suspended [chapter 6.1 patent gazette]