HRP20200306T1 - Bispecifične molekule vezane na antigene koji aktiviraju t stanice specifične za cd3 i cea - Google Patents
Bispecifične molekule vezane na antigene koji aktiviraju t stanice specifične za cd3 i cea Download PDFInfo
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- HRP20200306T1 HRP20200306T1 HRP20200306TT HRP20200306T HRP20200306T1 HR P20200306 T1 HRP20200306 T1 HR P20200306T1 HR P20200306T T HRP20200306T T HR P20200306TT HR P20200306 T HRP20200306 T HR P20200306T HR P20200306 T1 HRP20200306 T1 HR P20200306T1
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- 239000000427 antigen Substances 0.000 title claims 36
- 102000036639 antigens Human genes 0.000 title claims 36
- 108091007433 antigens Proteins 0.000 title claims 36
- 230000027455 binding Effects 0.000 title claims 15
- 230000003213 activating effect Effects 0.000 title 1
- 210000001744 T-lymphocyte Anatomy 0.000 claims 22
- 125000003275 alpha amino acid group Chemical group 0.000 claims 15
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims 14
- 108090000765 processed proteins & peptides Proteins 0.000 claims 5
- 125000000539 amino acid group Chemical group 0.000 claims 4
- 229920001184 polypeptide Polymers 0.000 claims 4
- 102000004196 processed proteins & peptides Human genes 0.000 claims 4
- 102000012406 Carcinoembryonic Antigen Human genes 0.000 claims 3
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 claims 3
- 235000001014 amino acid Nutrition 0.000 claims 3
- 201000010099 disease Diseases 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims 3
- 102000040430 polynucleotide Human genes 0.000 claims 3
- 108091033319 polynucleotide Proteins 0.000 claims 3
- 239000002157 polynucleotide Substances 0.000 claims 3
- 238000006467 substitution reaction Methods 0.000 claims 3
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 claims 2
- 210000004027 cell Anatomy 0.000 claims 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims 2
- 238000000034 method Methods 0.000 claims 2
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 claims 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims 2
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims 2
- 102000009109 Fc receptors Human genes 0.000 claims 1
- 108010087819 Fc receptors Proteins 0.000 claims 1
- 102000009490 IgG Receptors Human genes 0.000 claims 1
- 108010073807 IgG Receptors Proteins 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 238000012258 culturing Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000012636 effector Substances 0.000 claims 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 238000012986 modification Methods 0.000 claims 1
- 230000004048 modification Effects 0.000 claims 1
- 230000009870 specific binding Effects 0.000 claims 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 claims 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3007—Carcino-embryonic Antigens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3053—Skin, nerves, brain
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/526—CH3 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/66—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/71—Decreased effector function due to an Fc-modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Claims (22)
1. Bispecifična molekula vezana na antigen koji aktivira T stanicu, naznačena time, da sadrži
(i) prvu skupinu vezanu na antigen koja je Fab molekula sa sposobnošću vezivanja na CD3, koja sadrži područje koje određuje komplementarnost teškog lanca (CDR) 1 identifikacijskog broja sekvence: 4, teškog lanca CDR 2 identifikacijskog broja sekvence: 5, teškog lanca CDR 3 identifikacijskog broja sekvence: 6, lakog lanca CDR 1 identifikacijskog broja sekvence: 8, lakog lanca CDR 2 identifikacijskog broja sekvence: 9 i lakog lanca CDR 3 identifikacijskog broja sekvence: 10, pri čemu je prva skupina vezana na antigen unakrsna Fab molekula u kojoj se izmjenjuju konstantna područja Fab lakog lanca i Fab teškog lanca;
(ii) drugu i treću skupinu vezanu na antigen od kojih je svaka Fab molekula koja ima sposobnost vezivanja na karcinoembrionalni antigen (CEA) koja sadrži područje koje određuje komplementarnost teškog lanca (CDR) 1 identifikacijskog broja sekvence: 24, teškog lanca CDR 2 identifikacijskog broja sekvence: 25, teškog lanca CDR 3 identifikacijskog broja sekvence: 26, lakog lanca CDR 1 identifikacijskog broja sekvence: 28, lakog lanca CDR 2 identifikacijskog broja sekvence: 29 i lakog lanca CDR 3 identifikacijskog broja sekvence: 30;
(iii) Fc domenu koja se sastoji od prve i druge podjedinice sposobne za stabilno udruživanje,
pri čemu se druga skupina vezana na antigen spaja na C-kraju Fab teškog lanca s N-krajem Fab teškog lanca prve skupine vezane na antigen, a prva skupina vezana na antigen se spaja na C-kraju Fab teškog lanca s N-krajem prve podjedinice Fc domene, te pri čemu se treća skupina vezana na antigen spaja na C-kraju Fab teškog lanca s N-krajem druge podjedinice Fc domene.
2. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema patentnom zahtjevu 1, naznačena time, da prva skupina vezana na antigen sadrži varijabilnu regiju teškog lanca koja sadrži aminokiselinsku sekvencu koja je najmanje 95 %, 96 %, 97 %, 98 %, 99 % ili 100 % identična aminokiselinskoj sekvenci identifikacijskog broja: 3 te varijabilno područje lakog lanca koje sadrži aminokiselinsku sekvencu koja je najmanje 95 %, 96 %, 97 %, 98 %, 99 % ili 100 % identična aminokiselinskoj sekvenci identifikacijskog broja: 7.
3. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema patentnom zahtjevu 1 ili 2, naznačena time, da i prva i druga skupina vezana na antigen sadrži varijabilnu regiju teškog lanca koja sadrži aminokiselinsku sekvencu koja je najmanje 95 %, 96 %, 97 %, 98 %, 99 % ili 100 % identična aminokiselinskoj sekvenci identifikacijskog broja: 23 te varijabilno područje lakog lanca koje sadrži aminokiselinsku sekvencu koja je najmanje 95 %, 96 %, 97 %, 98 %, 99 % ili 100 % identična aminokiselinskoj sekvenci identifikacijskog broja: 27.
4. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 3, naznačena time, da je prva skupina vezana na antigen unakrsna Fab molekula u kojoj se izmjenjuju konstantna područja Fab lakog lanca i Fab teškog lanca i koja sadrži varijabilno područje teškog lanca koje sadrži aminokiselinsku sekvencu identifikacijskog broja: 3 i varijabilno područje lakog lanca koje sadrži aminokiselinsku sekvencu identifikacijskog boja: 7, i pri čemu je svaka od druge i treće skupine vezane na antigen uobičajena Fab molekula koja sadrži varijabilno područje teškog lanca koje sadrži aminokiselinsku sekvencu identifikacijskog broja: 23 i varijabilno područje lakog lanca koje sadrži aminokiselinsku sekvencu identifikacijskog broja: 27.
5. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 4, naznačena time, da je Fc domena jedna IgG, osobito IgG1, Fc domena.
6. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 5, naznačena time, da je Fc domena ljudska Fc domena.
7. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 6, naznačena time, da Fc domena sadrži modifikaciju koja pokreće udruživanje prve i druge podjedinice Fc domene.
8. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema patentnom zahtjevu 7, naznačena time, da se u domeni CH3 prve podjedinice Fc domene aminokiselinski ostatak zamjenjuje ostatkom aminokiseline koji ima veći volumen bočnog lanca, čime se generira izbočenje unutar domene CH3 prve podjedinice, koje se može pozicionirati u šupljini unutar CH3 domene druge podjedinice, a u CH3 domeni druge podjedinice Fc domene aminokiselinski ostatak se zamjenjuje s aminokiselinskim ostatkom koji ima manji volumen bočnog lanca, čime se generira šupljina unutar CH3 domene druge podjedinice unutar koje se može pozicionirati izbočina koja je unutar CH3 domene prve podjedinice.
9. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 8, naznačena time, da je u CH3 domeni prve podjedinice Fc domene, ostatak treonina na položaju 366 zamijenjen ostatkom triptofana (T366W), a u CH3 domeni druge podjedinice Fc domene, ostatak tirozina na položaju 407 zamijenjen ostatkom valina (Y407V); i pri čemu je neobvezno
(a) u drugoj podjedinici Fc domene ostatak treonina na položaju 366 dodatno zamijenjen ostatkom serina (T366S) i ostatak leukina na položaju 368 zamijenjen ostatkom alanina (L368A); i/ili
(b) u prvoj podjedinici Fc domene serinski ostatak na položaju 354 dodatno zamijenjen ostatkom cisteina (S354C), a u drugoj podjedinici Fc domene ostatak tirozina na položaju 349 dodatno zamijenjen ostatkom cisteina (Y349C) (numeriranje u skladu s EU indeksom Kabat).
10. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 9, naznačena time, da Fc domena sadrži jednu ili više aminokiselinskih supstitucija koje smanjuju vezanje na Fc receptor, osobito Fcγ receptor, i/ili efektorsku funkciju, osobito stanično posredovanu citotoksičnost ovisnu o protutijelima (ADCC).
11. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema patentnom zahtjevu 10, naznačena time, da je navedena jedna ili više aminokiselinskih supstitucija na jednom ili više položaja odabrana iz skupine od L234, L235 i P329 (numeriranje u skladu s EU indeksom Kabat).
12. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 11, naznačena time, da svaka podjedinica Fc domene sadrži aminokiselinske supstitucije L234A, L235A i P329G (numeriranje u skladu s EU indeksom Kabat).
13. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 12, naznačena time, da se sastoji od prve, druge i treće skupine vezane na antigen, Fc domene i, po izboru, jednog ili više peptidnih povezivača.
14. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 13, naznačena time, da sadrži polipeptidnu sekvencu koja je najmanje 95 %, 96 %, 97 %, 98 %, 99 % ili 100 % identična identifikacijskom broju sekvence: 22, polipeptidnu sekvencu koja je najmanje 95 %, 96 %, 97 %, 98 %, 99 % ili 100 % identična identifikacijskom broju sekvence: 56, polipeptidnu sekvencu koja je najmanje 95 %, 96 %, 97 %, 98 %, 99 % ili 100 % identična identifikacijskom broju sekvence: 57, i polipeptidnu sekvencu koja je najmanje 95 %, 96 %, 97 %, 98 %, 99 % ili 100 % identična identifikacijskom broju sekvence: 58.
15. Jedan ili više izoliranih polinukleotida, naznačen/i time, da kodira/ju bispecifičnu molekulu koja se veže na antigen koji aktivira T stanicu, prema bilo kojem od patentnih zahtjeva 1 do 14.
16. Stanica domaćina, naznačena time, da sadrži polinukleotid ili više polinukleotida prema patentnom zahtjevu 15.
17. Postupak proizvodnje bispecifične molekule vezane na antigen koji aktivira T stanicu koja je sposobna za specifično vezanje na CD3 i CEA, naznačen time, da sadrži korake a) kultiviranja stanice domaćina prema patentnom zahtjevu 16 u uvjetima prikladnima za ekspresiju bispecifične molekule vezane na antigen koji aktivira T stanicu i b) dobivanja bispecifične molekule vezane na antigen koji aktivira T stanicu.
18. Bispecifična molekula vezana na antigen koji aktivira T stanicu, naznačena time, da se dobiva izvođenjem postupka prema patentnom zahtjevu 17.
19. Farmaceutski pripravak, naznačen time, da sadrži bispecifičnu molekulu vezenu na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 14 ili 18 te farmaceutski prihvatljivi nosač.
20. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 14 ili 18, ili farmaceutski pripravak prema patentnom zahtjevu 19, naznačen/a time, da se upotrebljava kao medikament.
21. Bispecifična molekula vezana na antigen koji aktivira T stanicu prema bilo kojem od patentnih zahtjeva 1 do 14 ili 18, ili farmaceutski pripravak prema patentnom zahtjevu 19, naznačen/a time, da je za uporabu u liječenju bolesti kod pojedinaca kojima je takvo liječenje potrebno.
22. Bispecifična molekula vezana na antigen koji aktivira T stanicu, koja se upotrebljava u liječenju bolesti prema patentnom zahtjevu 21, naznačena time, da je spomenuta bolest rak.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13156686 | 2013-02-26 | ||
EP14708507.0A EP2961771B1 (en) | 2013-02-26 | 2014-02-24 | Bispecific t cell activating antigen binding molecules specific to cd3 and cea |
PCT/EP2014/053490 WO2014131712A1 (en) | 2013-02-26 | 2014-02-24 | Bispecific t cell activating antigen binding molecules |
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HRP20200306T1 true HRP20200306T1 (hr) | 2020-06-12 |
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HRP20200306TT HRP20200306T1 (hr) | 2013-02-26 | 2020-02-24 | Bispecifične molekule vezane na antigene koji aktiviraju t stanice specifične za cd3 i cea |
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Country | Link |
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US (11) | US10155815B2 (hr) |
EP (2) | EP2961771B1 (hr) |
JP (4) | JP6133444B2 (hr) |
KR (5) | KR20180023035A (hr) |
CN (2) | CN104936986B (hr) |
AR (1) | AR094896A1 (hr) |
AU (3) | AU2014222779B2 (hr) |
BR (1) | BR112015015824B1 (hr) |
CA (1) | CA2891493C (hr) |
CL (1) | CL2015001988A1 (hr) |
CR (1) | CR20150393A (hr) |
DK (1) | DK2961771T3 (hr) |
EA (2) | EA201891502A1 (hr) |
ES (1) | ES2775207T3 (hr) |
HK (1) | HK1211300A1 (hr) |
HR (1) | HRP20200306T1 (hr) |
HU (1) | HUE047925T2 (hr) |
IL (2) | IL240045B (hr) |
LT (1) | LT2961771T (hr) |
MA (1) | MA38308B1 (hr) |
MX (2) | MX2015008920A (hr) |
MY (1) | MY192312A (hr) |
NZ (1) | NZ708182A (hr) |
PE (1) | PE20151410A1 (hr) |
PH (1) | PH12015501340A1 (hr) |
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