HRP20201004T1 - Modificirani polipeptidi za skelete bispecifičnog protutijela - Google Patents
Modificirani polipeptidi za skelete bispecifičnog protutijela Download PDFInfo
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- HRP20201004T1 HRP20201004T1 HRP20201004TT HRP20201004T HRP20201004T1 HR P20201004 T1 HRP20201004 T1 HR P20201004T1 HR P20201004T T HRP20201004T T HR P20201004TT HR P20201004 T HRP20201004 T HR P20201004T HR P20201004 T1 HRP20201004 T1 HR P20201004T1
- Authority
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- Croatia
- Prior art keywords
- heavy chain
- domain
- modifications
- amino acid
- cysteine
- Prior art date
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- 229920001184 polypeptide Polymers 0.000 title claims 6
- 102000004196 processed proteins & peptides Human genes 0.000 title claims 6
- 108090000765 processed proteins & peptides Proteins 0.000 title claims 6
- 238000012986 modification Methods 0.000 claims 60
- 230000004048 modification Effects 0.000 claims 60
- 235000001014 amino acid Nutrition 0.000 claims 30
- 235000018417 cysteine Nutrition 0.000 claims 30
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 30
- 125000003275 alpha amino acid group Chemical group 0.000 claims 19
- -1 cysteine amino acid Chemical class 0.000 claims 15
- 238000006467 substitution reaction Methods 0.000 claims 15
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims 12
- 238000002372 labelling Methods 0.000 claims 4
- 239000002773 nucleotide Substances 0.000 claims 4
- 125000003729 nucleotide group Chemical group 0.000 claims 4
- 239000000427 antigen Substances 0.000 claims 2
- 102000036639 antigens Human genes 0.000 claims 2
- 108091007433 antigens Proteins 0.000 claims 2
- 102000039446 nucleic acids Human genes 0.000 claims 2
- 108020004707 nucleic acids Proteins 0.000 claims 2
- 150000007523 nucleic acids Chemical class 0.000 claims 2
- 150000001413 amino acids Chemical class 0.000 claims 1
- 239000000833 heterodimer Substances 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 235000018102 proteins Nutrition 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 239000000126 substance Substances 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
- C07K16/46—Hybrid immunoglobulins
- C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
-
- 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
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
- C07K16/248—IL-6
-
- 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
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- 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
-
- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- 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
- C07K2317/50—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
- C07K2317/70—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]
-
- 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
-
- 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
Claims (12)
1. Ljudsko bispecifično IgG1 protutijelo koje sadrži:
(a) modificirani teški lanac, pri čemu CH1 regija modificiranog teškog lanca sadrži
(i) supstituciju nativnog cisteina ne-cisteinskom aminokiselinom, i
(ii) supstituciju nativne ne-cisteinske aminokiseline s cistein aminokiselinom; i
(b) modificirani odgovarajući laki lanac, pri čemu CL regija modificiranog lakog lanca sadrži
(i) supstituciju nativnog cisteina ne-cisteinskom aminokiselinom, i
(ii) supstituciju nativne ne-cisteinske aminokiseline s cistein aminokiselinom; i
(c) drugi teški lanac i drugi odgovarajući laki lanac, pri čemu drugi teški lanac i drugi odgovarajući laki lanac ne sadrže supstituciju nativne ne-cisteinske aminokiseline s cistein aminokiselinom i ne sadrže supstituciju nativnog cisteina ne-cisteinskom aminokiselinom; i
pri čemu su modificirani teški lanac i modificirani odgovarajući laki lanac odabrani iz skupine koja se sastoji od varijanti koje sadrže
a. CH1 domenu pri čemu je aminokiselina na položaju 141 supstituirana s cisteinom i cistein na položaju 220 je supstituiran s ne-cisteinskom aminokiselinom; i CL domenu pri čemu je aminokiselina na položaju 116 supstituirana s cisteinom i cistein na položaju 214 je supstituiran s ne-cisteinskom aminokiselinom;
b. CH1 domenu pri čemu je aminokiselina na položaju 168 supstituirana s cisteinom i cistein na položaju 220 je supstituiran s ne-cisteinskom aminokiselinom; i CL domenu pri čemu je aminokiselina na položaju 164 supstituirana s cisteinom i cistein na položaju 214 je supstituiran s ne-cisteinskom aminokiselinom;
c. CH1 domenu pri čemu je aminokiselina na položaju 126 supstituirana s cisteinom i cistein na položaju 220 je supstituiran s ne-cisteinskom aminokiselinom; i CL domenu pri čemu je aminokiselina na položaju 121 supstituirana s cisteinom i cistein na položaju 214 je supstituiran s ne-cisteinskom aminokiselinom;
pri čemu je označavanje prema EU indeksu.
2. Protutijelo prema patentnom zahtjevu 1, naznačeno time što,
(a) dva lagana lanca svaki sadrže VL domenu i CL domenu, pri čemu VL domene imaju različite aminokiselinske sekvence, te CL domene imaju različite aminokiselinske sekvence; i/ili
(b) dva teška lanca svaki sadrže VH domenu, CH1 domenu i Fc regiju, pri čemu VH domene imaju različite aminokiselinske sekvence, CH1 domene imaju različite aminokiselinske sekvence, i Fc regije imaju različite aminokiselinske sekvence,
proizvoljno pri čemu je jedan laki lanac kapa laki lanac i jedan laki lanac je lambda laki lanac.
3. Protutijelo prema patentnom zahtjevu 2, naznačeno time što dva teška lanca tvore heterodimer.
4. Protutijelo prema bilo kojem od prethodnih patentnih zahtjeva, naznačeno time što se protutijelo specifično veže na dva neovisna antigena ili na dva neovisna epitopa na istom antigenu.
5. Protutijelo prema patentnim zahtjevima 2 do 4, naznačeno time što Fc regija sadrži prvi teški lanac i drugi teški lanac i modifikacije CH3 domene prvog teškog lanca i drugog teškog lanca su odabrane iz parova koji sadrže
(i) T366Y modifikaciju CH3 domene prvog teškog lanca, i Y407T modifikaciju CH3 domene drugog teškog lanca;
(ii) T366W modifikaciju CH3 domene prvog teškog lanca, i Y407A modifikaciju CH3 domene drugog teškog lanca;
(iii) T394W modifikaciju CH3 domene prvog teškog lanca, i F405A modifikaciju CH3 domene drugog teškog lanca;
(iv) T366Y i F405A modifikacije CH3 domene prvog teškog lanca, i T394W i Y407T modifikacije CH3 domene drugog teškog lanca;
(v) T366W i F405W modifikacije CH3 domene prvog teškog lanca, i T394S i Y407A modifikacije CH3 domene drugog teškog lanca;
(vi) F405W modifikaciju CH3 domene prvog teškog lanca, i T394S modifikaciju CH3 domene drugog teškog lanca;
(vii) D399C modifikaciju CH3 domene prvog teškog lanca, i K392C modifikaciju CH3 domene drugog teškog lanca;
(viii) T366W modifikaciju CH3 domene prvog teškog lanca, i T366S, L368N i Y407V modifikacije CH3 domene drugog teškog lanca;
(ix) T366W i D399C modifikacije CH3 domene prvog teškog lanca, i T366S, L368N, K392C i Y407V modifikacije CH3 domene drugog teškog lanca;
(x) T366W i K392C modifikacije CH3 domene prvog teškog lanca, i T366S, D399C, L368N i Y407V modifikacije CH3 domene drugog teškog lanca;
(xi) S354C i T366W modifikacije CH3 domene prvog teškog lanca, i Y349C, T366S, L368N i Y407V modifikacije CH3 domene drugog teškog lanca;
(xii) Y349C i T366W modifikacije CH3 domene prvog teškog lanca, i S354C, T366S, L368A i Y407V modifikacije CH3 domene drugog teškog lanca;
(xiii) E356C i T366W modifikacije CH3 domene prvog teškog lanca, i Y349C, T366S, L368A i Y407V modifikacije CH3 domene drugog teškog lanca;
(xiv) Y349C i T366W modifikacije CH3 domene prvog teškog lanca, i E356C, T366S, L368N i Y407V modifikacije CH3 domene drugog teškog lanca;
(xv) E357C i T366W modifikacije CH3 domene prvog teškog lanca, i Y349C, T366S, L368N i Y407V modifikacije CH3 domene drugog teškog lanca;
(xvi) Y349C i T366W modifikacije CH3 domene prvog teškog lanca, i E357C, T366S, L368A, Y407V modifikacije CH3 domene drugog teškog lanca;
(xvii) K370E, D399K i K439D modifikacije CH3 domene prvog teškog lanca i D356K, E357K i K409D modifikacije CH3 domene drugog teškog lanca;
(xx) K409D modifikaciju CH3 domene prvog teškog lanca, i D399K modifikaciju CH3 domene drugog teškog lanca;
(xxi) K409E modifikaciju CH3 domene prvog teškog lanca, i D399K modifikaciju CH3 domene drugog teškog lanca;
(xx) K409E modifikaciju CH3 domene prvog teškog lanca, i D399R modifikaciju CH3 domene drugog teškog lanca;
(xxi) K409D modifikaciju CH3 domene prvog teškog lanca, i D399R modifikaciju CH3 domene drugog teškog lanca;
(xxii) D339K modifikaciju CH3 domene prvog teškog lanca, i E356K modifikaciju CH3 domene drugog teškog lanca;
(xxv) D399K i E356K modifikacije CH3 domene prvog teškog lanca i K409D i K392D modifikacije CH3 domene drugog teškog lanca;
(xxiv) D399K i E356K modifikacije CH3 domene prvog teškog lanca i K409D i K439D modifikacije CH3 domene drugog teškog lanca;
(xxv) D399K i E357K modifikacije CH3 domene prvog teškog lanca, i K409D i K370D modifikacije CH3 domene drugog teškog lanca;
(xxvi) D399K, E356K i E357K modifikacije CH3 domene prvog teškog lanca, i K409D, K392D i K370D modifikacije CH3 domene drugog teškog lanca;
(xxvii) D399K i E357K modifikacije CH3 domene prvog teškog lanca, i K409D i K392D modifikacije CH3 domene drugog teškog lanca;
(xxviii) K392D i K409D modifikacije CH3 domene prvog teškog lanca i D399K modifikaciju CH3 domene drugog teškog lanca; i
(xxix) K409D i K360D modifikacije CH3 domene prvog teškog lanca i D399K modifikaciju CH3 domene drugog teškog lanca,
pri čemu je označavanje prema EU indeksu.
6. Protutijelo prema patentnom zahtjevu 5 , naznačeno time što Fc regija bilo kojeg ili oba teška lanca sadrži supstituciju aminokiselina H435R i Y436F koja mijenja vezanje proteina A pri čemu je označavanje prema EU indeksu.
7. Protutijelo prema patentnom zahtjevu 5 ili 6, naznačeno time što:
(a) modificirana Fc regija teškog lanca sadrži supstituciju aminokiseline T366W, i Fc regija drugog teškog lanca sadrži supstituciju aminokiseline Y407V,T366S i L368A; ili
(b) modificirana Fc regija teškog lanca sadrži supstituciju aminokiseline Y407V, T366S i L368A, i Fc regija drugog teškog lanca sadrži supstituciju aminokiseline T366W, i
pri čemu označavanje je prema EU indeksu.
8. Protutijelo prema patentnom zahtjevu 7, naznačeno time što:
(a) modificirana Fc regija teškog lanca nadalje sadrži supstituciju aminokiseline S354C, i Fc regija drugog teškog lanca nadalje sadrži supstituciju aminokiseline Y349C; ili
(b) modificirana Fc regija teškog lanca nadalje sadrži supstituciju aminokiseline Y349C, i Fc regija drugog teškog lanca nadalje sadrži supstituciju aminokiseline S354C, i
pri čemu je označavanje prema EU indeksu.
9. Protutijelo prema bilo kojem od patentnih zahtjeva 5 do 8, naznačeno time što nadalje sadrži M252Y, S254T i T256E modifikacije u Fc regiji.
10. Pripravak naznačen time što sadrži protutijelo prema bilo kojem od prethodnih patentnih zahtjeva i pomoćnu tvar.
11. Stanica naznačena time što sadrži
(a) izoliranu nukleinsku kiselinu koja sadrži nukleotidnu sekvencu koja kodira modificirani odgovarajući polipeptid lakog lanca prema bilo kojem od zahtjeva 1 do 9 i nukleotidnu sekvencu koja kodira drugi odgovarajući polipeptid lakog lanca prema bilo kojem od zahtjeva 1 do 9; i
(b) izoliranu nukleinsku kiselinu koja sadrži nukleotidnu sekvencu koja kodira modificirani polipeptid teškog lanca prema bilo kojem od zahtjeva 1 do 9 i nukleotidnu sekvencu koja kodira drugi polipeptid teškog lanca prema bilo kojem od zahtjeva 1 do 9.
12. Postupak ekspresije protutijela koji obuhvaća dovođenje u kontakt mnoštva stanica u skladu sa zahtjevom 11 pod uvjetima pod kojima su eksprimirani polipeptidi.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161577956P | 2011-12-20 | 2011-12-20 | |
| PCT/US2012/070310 WO2013096291A2 (en) | 2011-12-20 | 2012-12-18 | Modified polypeptides for bispecific antibody scaffolds |
| EP12860127.5A EP2794905B1 (en) | 2011-12-20 | 2012-12-18 | Modified polypeptides for bispecific antibody scaffolds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20201004T1 true HRP20201004T1 (hr) | 2020-10-16 |
Family
ID=48669692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20201004TT HRP20201004T1 (hr) | 2011-12-20 | 2020-06-25 | Modificirani polipeptidi za skelete bispecifičnog protutijela |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US9527927B2 (hr) |
| EP (1) | EP2794905B1 (hr) |
| JP (1) | JP6541974B2 (hr) |
| CN (1) | CN104011221B (hr) |
| AU (1) | AU2012355415B2 (hr) |
| CA (1) | CA2859667C (hr) |
| CY (1) | CY1123079T1 (hr) |
| DK (1) | DK2794905T3 (hr) |
| ES (1) | ES2816078T3 (hr) |
| HK (1) | HK1203560A1 (hr) |
| HR (1) | HRP20201004T1 (hr) |
| HU (1) | HUE049457T2 (hr) |
| LT (1) | LT2794905T (hr) |
| PL (1) | PL2794905T3 (hr) |
| PT (1) | PT2794905T (hr) |
| RS (1) | RS60499B1 (hr) |
| SI (1) | SI2794905T1 (hr) |
| WO (1) | WO2013096291A2 (hr) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090162359A1 (en) | 2007-12-21 | 2009-06-25 | Christian Klein | Bivalent, bispecific antibodies |
| KR101456326B1 (ko) | 2009-04-07 | 2014-11-12 | 로슈 글리카트 아게 | 3가, 이중특이적 항체 |
| US9676845B2 (en) | 2009-06-16 | 2017-06-13 | Hoffmann-La Roche, Inc. | Bispecific antigen binding proteins |
| CN104945509A (zh) | 2009-09-16 | 2015-09-30 | 弗·哈夫曼-拉罗切有限公司 | 包含卷曲螺旋和/或系链的蛋白质复合体及其用途 |
| TW201138821A (en) | 2010-03-26 | 2011-11-16 | Roche Glycart Ag | Bispecific antibodies |
| JP6167040B2 (ja) | 2010-11-05 | 2017-07-19 | ザイムワークス，インコーポレイテッド | Ｆｃドメイン中に突然変異を有する、安定したヘテロ二量体抗体の設計 |
| MY166429A (en) | 2010-11-17 | 2018-06-26 | Chugai Pharmaceutical Co Ltd | Multi-specific antigen-binding molecule having alternative function to function of blood coagulation factor viii |
| EP2681239B8 (en) | 2011-02-28 | 2015-09-09 | F. Hoffmann-La Roche AG | Antigen binding proteins |
| EP2681240B1 (en) | 2011-02-28 | 2017-08-16 | F. Hoffmann-La Roche AG | Monovalent antigen binding proteins |
| RU2605390C2 (ru) | 2011-08-23 | 2016-12-20 | Рош Гликарт Аг | Биспецифические антитела, специфичные к антигенам, активирующим т-клетки, и опухолевому антигену, и способы их применения |
| PL2773671T3 (pl) | 2011-11-04 | 2022-01-24 | Zymeworks Inc. | Projekt stabilnego przeciwciała heterodimerycznego z mutacjami w domenie fc |
| EP3683228A3 (en) | 2012-01-26 | 2020-07-29 | Amgen Inc. | Growth differentiation factor 15 (gdf-15) polypeptides |
| GB201203051D0 (en) * | 2012-02-22 | 2012-04-04 | Ucb Pharma Sa | Biological products |
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| DK2961771T3 (da) | 2013-02-26 | 2020-03-02 | Roche Glycart Ag | Bispecifikke, T-celle-aktiverende, antigenbindende molekyler, der er specifikke for CD3 og CEA |
| EP3444278A1 (en) | 2013-02-26 | 2019-02-20 | Roche Glycart AG | Bispecific t cell activating antigen binding molecules |
| WO2014177461A1 (en) | 2013-04-29 | 2014-11-06 | F. Hoffmann-La Roche Ag | Fcrn-binding abolished anti-igf-1r antibodies and their use in the treatment of vascular eye diseases |
| PE20190920A1 (es) | 2013-04-29 | 2019-06-26 | Hoffmann La Roche | Anticuerpos modificados de union a fcrn humano y metodos de utilizacion |
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- 2012-12-18 HU HUE12860127A patent/HUE049457T2/hu unknown
- 2012-12-18 ES ES12860127T patent/ES2816078T3/es active Active
- 2012-12-18 US US14/366,582 patent/US9527927B2/en active Active
- 2012-12-18 PL PL12860127T patent/PL2794905T3/pl unknown
- 2012-12-18 CA CA2859667A patent/CA2859667C/en active Active
- 2012-12-18 RS RS20200782A patent/RS60499B1/sr unknown
- 2012-12-18 CN CN201280062856.0A patent/CN104011221B/zh active Active
- 2012-12-18 JP JP2014549199A patent/JP6541974B2/ja active Active
- 2012-12-18 SI SI201231794T patent/SI2794905T1/sl unknown
- 2012-12-18 WO PCT/US2012/070310 patent/WO2013096291A2/en active Application Filing
- 2012-12-18 EP EP12860127.5A patent/EP2794905B1/en active Active
- 2012-12-18 AU AU2012355415A patent/AU2012355415B2/en active Active
- 2012-12-18 LT LTEP12860127.5T patent/LT2794905T/lt unknown
-
2015
- 2015-04-28 HK HK15104067.3A patent/HK1203560A1/xx unknown
-
2020
- 2020-06-25 CY CY20201100588T patent/CY1123079T1/el unknown
- 2020-06-25 HR HRP20201004TT patent/HRP20201004T1/hr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US9527927B2 (en) | 2016-12-27 |
| AU2012355415B2 (en) | 2017-07-06 |
| SI2794905T1 (sl) | 2020-08-31 |
| HK1203560A1 (en) | 2015-10-30 |
| WO2013096291A2 (en) | 2013-06-27 |
| PT2794905T (pt) | 2020-06-30 |
| CN104011221A (zh) | 2014-08-27 |
| DK2794905T3 (da) | 2020-07-06 |
| AU2012355415A1 (en) | 2014-07-17 |
| LT2794905T (lt) | 2020-07-10 |
| CA2859667C (en) | 2022-05-24 |
| JP6541974B2 (ja) | 2019-07-10 |
| JP2015502409A (ja) | 2015-01-22 |
| EP2794905A2 (en) | 2014-10-29 |
| HUE049457T2 (hu) | 2020-09-28 |
| RS60499B1 (sr) | 2020-08-31 |
| CA2859667A1 (en) | 2013-06-27 |
| CY1123079T1 (el) | 2021-10-29 |
| WO2013096291A3 (en) | 2013-09-19 |
| US20140348839A1 (en) | 2014-11-27 |
| PL2794905T3 (pl) | 2020-11-02 |
| CN104011221B (zh) | 2019-01-08 |
| EP2794905A4 (en) | 2015-11-18 |
| ES2816078T3 (es) | 2021-03-31 |
| EP2794905B1 (en) | 2020-04-01 |
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