PL3495495T3 - Markery diagnostyczne do leczenia zaburzeń proliferacyjnych komórek za pomocą inhibitorów telomerazy - Google Patents

Markery diagnostyczne do leczenia zaburzeń proliferacyjnych komórek za pomocą inhibitorów telomerazy

Info

Publication number
PL3495495T3
PL3495495T3 PL18192236T PL18192236T PL3495495T3 PL 3495495 T3 PL3495495 T3 PL 3495495T3 PL 18192236 T PL18192236 T PL 18192236T PL 18192236 T PL18192236 T PL 18192236T PL 3495495 T3 PL3495495 T3 PL 3495495T3
Authority
PL
Poland
Prior art keywords
treatment
cell proliferation
diagnostic markers
proliferation disorders
telomerase inhibitors
Prior art date
Application number
PL18192236T
Other languages
English (en)
Polish (pl)
Inventor
Ekaterina Bassett
Bart Burington
Hui Wang
Kevin Eng
Original Assignee
Geron Corporation
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
Priority claimed from US13/802,035 external-priority patent/US9200327B2/en
Application filed by Geron Corporation filed Critical Geron Corporation
Publication of PL3495495T3 publication Critical patent/PL3495495T3/pl

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Classifications

    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088Compounds having three or more nucleosides or nucleotides
    • A61K31/7125Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/10Drugs for disorders of the urinary system of the bladder
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531Production of immunochemical test materials
    • G01N33/532Production of labelled immunochemicals
    • G01N33/533Production of labelled immunochemicals with fluorescent label
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/106Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/156Polymorphic or mutational markers
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90Enzymes; Proenzymes
    • G01N2333/91Transferases (2.)
    • G01N2333/912Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • G01N2333/91205Phosphotransferases in general
    • G01N2333/91245Nucleotidyltransferases (2.7.7)
    • G01N2333/9125Nucleotidyltransferases (2.7.7) with a definite EC number (2.7.7.-)
    • G01N2333/9128RNA-directed DNA polymerases, e.g. RT (2.7.7.49)

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • General Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Neurology (AREA)
  • Biophysics (AREA)
  • Hospice & Palliative Care (AREA)
  • General Engineering & Computer Science (AREA)
  • Reproductive Health (AREA)
PL18192236T 2012-11-30 2013-11-27 Markery diagnostyczne do leczenia zaburzeń proliferacyjnych komórek za pomocą inhibitorów telomerazy PL3495495T3 (pl)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US201261732263P 2012-11-30 2012-11-30
US201361780851P 2013-03-13 2013-03-13
US13/802,035 US9200327B2 (en) 2012-11-30 2013-03-13 Diagnostic markers for treating cell proliferative disorders with telomerase inhibitors
US201361798478P 2013-03-15 2013-03-15
US201361809228P 2013-04-05 2013-04-05
PCT/US2013/072302 WO2014085632A1 (en) 2012-11-30 2013-11-27 Diagnostic markers for treating cell proliferative disorders with telomerase inhibitors
EP13858528.6A EP2925889B1 (en) 2012-11-30 2013-11-27 Diagnostic markers for treating cell proliferative disorders with telomerase inhibitors
EP18192236.0A EP3495495B1 (en) 2012-11-30 2013-11-27 Diagnostic markers for treating cell proliferative disorders with telomerase inhibitors

Publications (1)

Publication Number Publication Date
PL3495495T3 true PL3495495T3 (pl) 2021-08-30

Family

ID=50828470

Family Applications (2)

Application Number Title Priority Date Filing Date
PL18192236T PL3495495T3 (pl) 2012-11-30 2013-11-27 Markery diagnostyczne do leczenia zaburzeń proliferacyjnych komórek za pomocą inhibitorów telomerazy
PL13858528T PL2925889T3 (pl) 2012-11-30 2013-11-27 Markery diagnostyczne do leczenia zaburzeń proliferacyjnych komórek za pomocą inhibitorów telomerazy

Family Applications After (1)

Application Number Title Priority Date Filing Date
PL13858528T PL2925889T3 (pl) 2012-11-30 2013-11-27 Markery diagnostyczne do leczenia zaburzeń proliferacyjnych komórek za pomocą inhibitorów telomerazy

Country Status (24)

Country Link
EP (4) EP3882355B1 (https=)
JP (2) JP6359028B2 (https=)
KR (3) KR102174763B1 (https=)
CN (2) CN104937110A (https=)
AU (4) AU2013352105B2 (https=)
BR (1) BR112015012507B1 (https=)
CA (1) CA2892445C (https=)
CY (1) CY1124140T1 (https=)
DK (2) DK3495495T3 (https=)
ES (3) ES2865446T3 (https=)
HR (2) HRP20181991T1 (https=)
HU (1) HUE054053T2 (https=)
IL (3) IL282112B (https=)
LT (2) LT2925889T (https=)
MX (1) MX362094B (https=)
NZ (2) NZ708654A (https=)
PL (2) PL3495495T3 (https=)
PT (2) PT3495495T (https=)
RS (1) RS61513B1 (https=)
SG (1) SG11201504209YA (https=)
SI (2) SI3495495T1 (https=)
SM (1) SMT202100142T1 (https=)
WO (1) WO2014085632A1 (https=)
ZA (2) ZA201900759B (https=)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT3029154T (lt) 2008-10-17 2017-12-27 Geron Corporation Paciento jautrumo telomerazės slopinimo terapijai nustatymo būdas
US9375485B2 (en) 2012-12-07 2016-06-28 Geron Corporation Use of telomerase inhibitors for the treatment of myeloproliferative disorders and myeloproliferative neoplasms
EP3318276A1 (en) 2016-11-04 2018-05-09 Janssen Biotech, Inc. Combinations of a telomerase inhibitor and a bcl-2 inhibitor for the treatment of hematological cancers
JPWO2018207952A1 (ja) * 2017-05-12 2020-04-16 国立大学法人九州大学 発毛及び/又は育毛用組成物
KR102867725B1 (ko) 2017-07-28 2025-10-13 제론 코포레이션 골수형성이상 증후군의 치료 방법
US20200063214A1 (en) * 2018-07-31 2020-02-27 Geron Corporation Methods of identifying patients likely to benefit from treatment with a telomerase inhibitor
GB201818792D0 (en) * 2018-11-19 2019-01-02 Telonostix Ltd Compounds for telomere length-related treatment of cancer
UA130012C2 (uk) 2018-11-29 2025-10-15 Джерон Корпорейшн Спосіб лікування мієлодиспластичного синдрому
EP3674418A1 (en) * 2018-12-26 2020-07-01 Life Length S.L. Method for measuring telomere associated variables and uses thereof for the diagnosis and/or prognosis of telomeric-associated diseases
CN114306602B (zh) * 2020-09-28 2024-06-11 中国科学院上海营养与健康研究所 靶向tert在调节皮肤及毛发色素中的应用
CN115463122B (zh) * 2022-08-16 2025-03-25 吕梁学院 一种增强盐霉素抗癌活性的方法及应用

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5489508A (en) 1992-05-13 1996-02-06 University Of Texas System Board Of Regents Therapy and diagnosis of conditions related to telomere length and/or telomerase activity
US5958680A (en) 1994-07-07 1999-09-28 Geron Corporation Mammalian telomerase
US5583016A (en) 1994-07-07 1996-12-10 Geron Corporation Mammalian telomerase
US5863936A (en) 1995-04-18 1999-01-26 Geron Corporation Telomerase inhibitors
US5760062A (en) 1995-04-18 1998-06-02 Geron Corporation Telomerase inhibitors
US5656638A (en) 1995-04-18 1997-08-12 Geron Corporation Telomerase inhibitors
US5770613A (en) 1995-09-29 1998-06-23 Geron Corporation Telomerase inhibitors
US5767278A (en) 1995-10-06 1998-06-16 Geron Corporation Telomerase inhibitors
US6444650B1 (en) 1996-10-01 2002-09-03 Geron Corporation Antisense compositions for detecting and inhibiting telomerase reverse transcriptase
US6261836B1 (en) 1996-10-01 2001-07-17 Geron Corporation Telomerase
AU733610B2 (en) 1996-12-20 2001-05-17 Geron Corporation Methods for detecting and inhibiting the RNA component of telomerase
JPH11276182A (ja) * 1997-12-26 1999-10-12 Chugai Pharmaceut Co Ltd 逆転写酵素モチーフを有する新規遺伝子
US6331399B1 (en) 2000-05-16 2001-12-18 Isis Pharmaceuticals, Inc. Antisense inhibition of tert expression
CA2474468C (en) 2002-01-31 2014-03-25 University Of Utah Amplifying repetitive nucleic acid sequences
US20040234961A1 (en) * 2002-04-22 2004-11-25 Fordyce Colleen A. Telomere length determination and applications
WO2004068110A2 (en) 2003-01-24 2004-08-12 University Of Utah Methods of predicting mortality risk by determining telomere length
CN100393209C (zh) 2003-09-09 2008-06-11 杰龙公司 用于端粒酶抑制的改性寡核苷酸
ME02933B (me) 2004-07-02 2018-04-20 Geron Corp Sinteza zaštićenih 3'-amino nukleozionih monomera
CA2602562C (en) * 2005-03-25 2015-07-07 Alt Solutions, Inc. Modulation of telomere length in telomerase positive cells and cancer therapy
EP1876893B1 (en) * 2005-04-15 2012-04-11 Geron Corporation Cancer treatment by combined inhibition of proteasome and telomerase activities
LT3029154T (lt) * 2008-10-17 2017-12-27 Geron Corporation Paciento jautrumo telomerazės slopinimo terapijai nustatymo būdas
US9689028B2 (en) 2008-12-22 2017-06-27 University Of Utah Foundation Monochrome multiplex quantitative PCR
US20110207128A1 (en) 2010-02-16 2011-08-25 Cawthon Richard M Methods and kits for determining biological age and longevity based on gene expression profiles
ES2656958T3 (es) * 2011-03-28 2018-03-01 Geron Corporation Medición de la longitud de telómeros en muestras fijadas en formalina, embebidas en parafina (FFPE) por PCR cuantitativa

Also Published As

Publication number Publication date
CY1124140T1 (el) 2022-05-27
BR112015012507A8 (pt) 2019-10-08
HK1215874A1 (en) 2016-09-23
KR102348240B1 (ko) 2022-01-10
CN111494629A (zh) 2020-08-07
SG11201504209YA (en) 2015-06-29
KR20150091491A (ko) 2015-08-11
EP3882355C0 (en) 2023-12-20
NZ748624A (en) 2020-08-28
EP3495495A1 (en) 2019-06-12
SI2925889T1 (sl) 2019-01-31
EP2925889A4 (en) 2016-06-15
EP2925889A1 (en) 2015-10-07
IL239035B (en) 2020-09-30
EP4497441A2 (en) 2025-01-29
AU2025201333B2 (en) 2025-10-16
ZA202101317B (en) 2023-03-29
AU2013352105B2 (en) 2019-09-19
DK2925889T3 (da) 2019-01-02
KR102174763B1 (ko) 2020-11-06
BR112015012507A2 (pt) 2017-07-11
EP2925889B1 (en) 2018-09-05
PT3495495T (pt) 2021-03-22
AU2022202808B2 (en) 2024-11-28
AU2019283840A1 (en) 2020-01-23
EP3495495B1 (en) 2020-12-23
IL270636B (en) 2021-04-29
ES2972330T3 (es) 2024-06-12
IL282112A (en) 2021-05-31
ES2703914T3 (es) 2019-03-13
SMT202100142T1 (it) 2021-05-07
LT2925889T (lt) 2018-12-27
ES2865446T3 (es) 2021-10-15
IL282112B (en) 2022-09-01
MX362094B (es) 2019-01-07
WO2014085632A1 (en) 2014-06-05
CA2892445C (en) 2022-06-28
ZA201900759B (en) 2020-10-28
KR20210112394A (ko) 2021-09-14
PT2925889T (pt) 2018-12-12
JP2016501523A (ja) 2016-01-21
KR20200128446A (ko) 2020-11-12
IL239035A0 (en) 2015-07-30
CN104937110A (zh) 2015-09-23
EP3882355A1 (en) 2021-09-22
JP2018099127A (ja) 2018-06-28
HUE054053T2 (hu) 2021-08-30
JP6359028B2 (ja) 2018-07-18
NZ708654A (en) 2020-04-24
AU2025201333A1 (en) 2025-03-20
AU2013352105A1 (en) 2015-06-18
RS61513B1 (sr) 2021-03-31
MX2015006538A (es) 2015-09-23
EP3882355B1 (en) 2023-12-20
PL2925889T3 (pl) 2019-02-28
LT3495495T (lt) 2021-02-25
CA2892445A1 (en) 2014-06-05
BR112015012507B1 (pt) 2023-03-07
SI3495495T1 (sl) 2021-07-30
HRP20210451T1 (hr) 2021-05-14
AU2022202808A1 (en) 2022-05-19
HRP20181991T1 (hr) 2019-03-08
DK3495495T3 (da) 2021-03-22

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