JP2013532176A - 安定化させた第ｖｉｉｉ因子バリアント - Google Patents
安定化させた第ｖｉｉｉ因子バリアント Download PDFInfo
- Publication number
- JP2013532176A JP2013532176A JP2013519027A JP2013519027A JP2013532176A JP 2013532176 A JP2013532176 A JP 2013532176A JP 2013519027 A JP2013519027 A JP 2013519027A JP 2013519027 A JP2013519027 A JP 2013519027A JP 2013532176 A JP2013532176 A JP 2013532176A
- Authority
- JP
- Japan
- Prior art keywords
- fviii
- fviii variant
- variant
- amino acid
- domain
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
Links
- 102000001690 Factor VIII Human genes 0.000 title abstract description 290
- 108010054218 Factor VIII Proteins 0.000 title abstract description 289
- 229960000301 factor viii Drugs 0.000 title abstract description 285
- 150000001413 amino acids Chemical class 0.000 claims description 40
- 230000000694 effects Effects 0.000 claims description 35
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims description 30
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 29
- 238000000338 in vitro Methods 0.000 claims description 27
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 26
- 102100026735 Coagulation factor VIII Human genes 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- 229920001184 polypeptide Polymers 0.000 claims description 22
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 21
- 238000006467 substitution reaction Methods 0.000 claims description 21
- 208000009292 Hemophilia A Diseases 0.000 claims description 15
- 150000004676 glycans Chemical class 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 13
- 208000031220 Hemophilia Diseases 0.000 claims description 11
- 230000002209 hydrophobic effect Effects 0.000 claims description 10
- 125000000539 amino acid group Chemical group 0.000 claims description 9
- 238000003776 cleavage reaction Methods 0.000 claims description 9
- 230000007017 scission Effects 0.000 claims description 9
- 239000012634 fragment Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 4
- 239000000427 antigen Substances 0.000 claims description 4
- 102000036639 antigens Human genes 0.000 claims description 4
- 108091007433 antigens Proteins 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 150000004665 fatty acids Chemical class 0.000 claims description 4
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 4
- 230000009881 electrostatic interaction Effects 0.000 claims description 3
- 230000003993 interaction Effects 0.000 claims description 2
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 claims 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 abstract description 3
- 108010039209 Blood Coagulation Factors Proteins 0.000 abstract description 3
- 239000003114 blood coagulation factor Substances 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 56
- 235000001014 amino acid Nutrition 0.000 description 51
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 45
- 239000000872 buffer Substances 0.000 description 40
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 39
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 36
- 238000000034 method Methods 0.000 description 22
- 239000011780 sodium chloride Substances 0.000 description 22
- 229920001223 polyethylene glycol Polymers 0.000 description 19
- 239000002202 Polyethylene glycol Substances 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 17
- 108090000190 Thrombin Proteins 0.000 description 17
- 230000035772 mutation Effects 0.000 description 17
- 108090000623 proteins and genes Proteins 0.000 description 17
- 229960004072 thrombin Drugs 0.000 description 17
- 235000018102 proteins Nutrition 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 15
- 102100036537 von Willebrand factor Human genes 0.000 description 15
- 125000005647 linker group Chemical group 0.000 description 14
- 239000000523 sample Substances 0.000 description 14
- 208000007536 Thrombosis Diseases 0.000 description 13
- 238000003556 assay Methods 0.000 description 13
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 12
- 230000004087 circulation Effects 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000012925 reference material Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 108010047303 von Willebrand Factor Proteins 0.000 description 11
- 229960001134 von willebrand factor Drugs 0.000 description 11
- 102000009027 Albumins Human genes 0.000 description 10
- 108010088751 Albumins Proteins 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 108020001507 fusion proteins Proteins 0.000 description 10
- 102000037865 fusion proteins Human genes 0.000 description 10
- 229930182830 galactose Natural products 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 9
- 229920000053 polysorbate 80 Polymers 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 8
- 238000012217 deletion Methods 0.000 description 8
- 230000037430 deletion Effects 0.000 description 8
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 8
- 102000003886 Glycoproteins Human genes 0.000 description 7
- 108090000288 Glycoproteins Proteins 0.000 description 7
- 102000003838 Sialyltransferases Human genes 0.000 description 7
- 108090000141 Sialyltransferases Proteins 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000002950 deficient Effects 0.000 description 7
- 230000004927 fusion Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 102220253144 rs1556016638 Human genes 0.000 description 7
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 230000004989 O-glycosylation Effects 0.000 description 6
- 102220466485 Testis-specific H1 histone_D519A_mutation Human genes 0.000 description 6
- 239000007983 Tris buffer Substances 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 230000017531 blood circulation Effects 0.000 description 6
- 239000001110 calcium chloride Substances 0.000 description 6
- 229910001628 calcium chloride Inorganic materials 0.000 description 6
- 238000007398 colorimetric assay Methods 0.000 description 6
- 102000057593 human F8 Human genes 0.000 description 6
- 239000013642 negative control Substances 0.000 description 6
- 150000002482 oligosaccharides Chemical class 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 6
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 102000002110 C2 domains Human genes 0.000 description 4
- 108050009459 C2 domains Proteins 0.000 description 4
- 241000699802 Cricetulus griseus Species 0.000 description 4
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical group CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 4
- 102000005348 Neuraminidase Human genes 0.000 description 4
- 108010006232 Neuraminidase Proteins 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 229920001222 biopolymer Polymers 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 210000001715 carotid artery Anatomy 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000021615 conjugation Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 238000006206 glycosylation reaction Methods 0.000 description 4
- 229940006607 hirudin Drugs 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 229910021645 metal ion Inorganic materials 0.000 description 4
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 4
- 229920001542 oligosaccharide Polymers 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 102220283298 rs754483795 Human genes 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 230000009261 transgenic effect Effects 0.000 description 4
- -1 50 amino acids Chemical class 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 108010048049 Factor IXa Proteins 0.000 description 3
- 201000003542 Factor VIII deficiency Diseases 0.000 description 3
- 108010014173 Factor X Proteins 0.000 description 3
- 108010074860 Factor Xa Proteins 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 102000007625 Hirudins Human genes 0.000 description 3
- 108010007267 Hirudins Proteins 0.000 description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 3
- 229940122388 Thrombin inhibitor Drugs 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 3
- IERHLVCPSMICTF-XVFCMESISA-N cytidine 5'-monophosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1 IERHLVCPSMICTF-XVFCMESISA-N 0.000 description 3
- IERHLVCPSMICTF-UHFFFAOYSA-N cytidine monophosphate Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(COP(O)(O)=O)O1 IERHLVCPSMICTF-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 3
- 229960000900 human factor viii Drugs 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 201000000050 myeloid neoplasm Diseases 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 239000011535 reaction buffer Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 3
- 125000005629 sialic acid group Chemical group 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000003868 thrombin inhibitor Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 2
- 108010089996 B-domain-deleted factor VIII Proteins 0.000 description 2
- 102100029962 CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase Human genes 0.000 description 2
- 102220597411 Cellular tumor antigen p53_E287V_mutation Human genes 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 108010087819 Fc receptors Proteins 0.000 description 2
- 102000009109 Fc receptors Human genes 0.000 description 2
- 108091006020 Fc-tagged proteins Proteins 0.000 description 2
- 239000012739 FreeStyle 293 Expression medium Substances 0.000 description 2
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 2
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 2
- 102220550323 Protein unc-50 homolog_D605E_mutation Human genes 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 102000002262 Thromboplastin Human genes 0.000 description 2
- 102220597969 Thromboxane-A synthase_Q316K_mutation Human genes 0.000 description 2
- 108090000901 Transferrin Proteins 0.000 description 2
- 102000004338 Transferrin Human genes 0.000 description 2
- KBGAYAKRZNYFFG-BOHATCBPSA-N aceneuramic acid Chemical compound OC(=O)C(=O)C[C@H](O)[C@@H](NC(=O)C)[C@@H](O)[C@H](O)[C@H](O)CO KBGAYAKRZNYFFG-BOHATCBPSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 230000001268 conjugating effect Effects 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000002523 gelfiltration Methods 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 125000000311 mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000006320 pegylation Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 102220045488 rs587782150 Human genes 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 238000010257 thawing Methods 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 239000012581 transferrin Substances 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010087765 Antipain Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108010002913 Asialoglycoproteins Proteins 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 101710136075 CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase Proteins 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 102220597395 Cellular tumor antigen p53_E287A_mutation Human genes 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 101100007328 Cocos nucifera COS-1 gene Proteins 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 101100239628 Danio rerio myca gene Proteins 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010021468 Fc gamma receptor IIA Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 108010090444 Innovin Proteins 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 101710149643 Integrin alpha-IIb Proteins 0.000 description 1
- 238000012313 Kruskal-Wallis test Methods 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical group CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 239000012606 POROS 50 HQ resin Substances 0.000 description 1
- 241001524178 Paenarthrobacter ureafaciens Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 102220598720 Reticulon-4 receptor_R279A_mutation Human genes 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102220559400 Transient receptor potential cation channel subfamily A member 1_T646P_mutation Human genes 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 102220476597 Zinc finger CCHC domain-containing protein 8_E676A_mutation Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000002506 anticoagulant protein Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- SDNYTAYICBFYFH-TUFLPTIASA-N antipain Chemical compound NC(N)=NCCC[C@@H](C=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SDNYTAYICBFYFH-TUFLPTIASA-N 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000012223 aqueous fraction Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SXTGIAYWYXVNLT-NRFANRHFSA-N benzyl n-[2-[[2-[[(2s)-5-(diaminomethylideneamino)-1-[(4-methyl-2-oxochromen-7-yl)amino]-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]carbamate Chemical compound N([C@@H](CCCNC(N)=N)C(=O)NC1=CC=2OC(=O)C=C(C=2C=C1)C)C(=O)CNC(=O)CNC(=O)OCC1=CC=CC=C1 SXTGIAYWYXVNLT-NRFANRHFSA-N 0.000 description 1
- 108010079115 benzyloxycarbonyl-glycyl-glycyl-arginine-4-methylcoumaryl-7-amide Proteins 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 230000010405 clearance mechanism Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 238000007819 clotting time assay Methods 0.000 description 1
- 229940105778 coagulation factor viii Drugs 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000006167 equilibration buffer Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- BQINXKOTJQCISL-GRCPKETISA-N keto-neuraminic acid Chemical group OC(=O)C(=O)C[C@H](O)[C@@H](N)[C@@H](O)[C@H](O)[C@H](O)CO BQINXKOTJQCISL-GRCPKETISA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 210000003593 megakaryocyte Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- CERZMXAJYMMUDR-UHFFFAOYSA-N neuraminic acid Natural products NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO CERZMXAJYMMUDR-UHFFFAOYSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000010149 post-hoc-test Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 102220320562 rs116193143 Human genes 0.000 description 1
- 102220265237 rs147975326 Human genes 0.000 description 1
- 102220250980 rs1554832851 Human genes 0.000 description 1
- 102220006188 rs28929473 Human genes 0.000 description 1
- 102200078697 rs371265106 Human genes 0.000 description 1
- 102220013283 rs397516554 Human genes 0.000 description 1
- 102220041483 rs483353026 Human genes 0.000 description 1
- 102220040344 rs587778275 Human genes 0.000 description 1
- 102220307347 rs782485961 Human genes 0.000 description 1
- 102200058194 rs80338676 Human genes 0.000 description 1
- 102220084812 rs863225147 Human genes 0.000 description 1
- 102220117383 rs886041633 Human genes 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000011218 seed culture Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000013169 thromboelastometry Methods 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- PIEPQKCYPFFYMG-UHFFFAOYSA-N tris acetate Chemical compound CC(O)=O.OCC(N)(CO)CO PIEPQKCYPFFYMG-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/96—Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Genetics & Genomics (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Wood Science & Technology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Toxicology (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10169592.2 | 2010-07-15 | ||
| EP10169592 | 2010-07-15 | ||
| US36547810P | 2010-07-19 | 2010-07-19 | |
| US61/365,478 | 2010-07-19 | ||
| PCT/EP2011/061349 WO2012007324A2 (en) | 2010-07-15 | 2011-07-06 | Stabilized factor viii variants |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2013532176A true JP2013532176A (ja) | 2013-08-15 |
| JP2013532176A5 JP2013532176A5 (https=) | 2014-08-21 |
Family
ID=42797590
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2013519027A Ceased JP2013532176A (ja) | 2010-07-15 | 2011-07-06 | 安定化させた第ｖｉｉｉ因子バリアント |
Country Status (5)
| Country | Link |
|---|---|
| US (2) | US20130183280A1 (https=) |
| EP (1) | EP2593130A2 (https=) |
| JP (1) | JP2013532176A (https=) |
| CN (1) | CN102971006A (https=) |
| WO (1) | WO2012007324A2 (https=) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2023542388A (ja) * | 2020-09-23 | 2023-10-06 | アブレヴィア バイオテック ゲーエムベーハー | 第ｖｉｉｉ因子補充療法の有効性を増加させるための化合物 |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7855279B2 (en) | 2005-09-27 | 2010-12-21 | Amunix Operating, Inc. | Unstructured recombinant polymers and uses thereof |
| CA2748314C (en) | 2009-02-03 | 2018-10-02 | Amunix Operating Inc. | Extended recombinant polypeptides and compositions comprising same |
| AU2010290131C1 (en) | 2009-08-24 | 2015-12-03 | Amunix Operating Inc. | Coagulation factor VII compositions and methods of making and using same |
| US20130017997A1 (en) * | 2010-08-19 | 2013-01-17 | Amunix Operating Inc. | Factor VIII Compositions and Methods of Making and Using Same |
| PL2718322T3 (pl) * | 2011-06-06 | 2019-07-31 | Novo Nordisk A/S | Lecznicze przeciwciała |
| CA2864126A1 (en) | 2012-02-15 | 2013-08-22 | Biogen Idec Ma Inc. | Recombinant factor viii proteins |
| BR112014020694A2 (pt) | 2012-02-15 | 2018-05-08 | Amunix Operating Inc. | proteína de fusão do fator viii compreendendo polipeptídeo do fator viii fusionado a polipeptí-deo recombinante estendido (xten) e seu método de fabricação, ácido nucleico, vetores, célula hospedeira, bem como composição farmacêutica e seu uso no tratamento de coagulopatia, episódio de hemorragia e hemofilia a |
| EP2841091A1 (en) * | 2012-04-24 | 2015-03-04 | Novo Nordisk A/S | Pharmaceutical composition suitable for treatment of haemophilia |
| EP2906247A1 (en) | 2012-10-15 | 2015-08-19 | Novo Nordisk Health Care AG | Factor vii conjugates |
| UY35343A (es) * | 2013-02-26 | 2014-09-30 | Bayer Healthcare Llc | Formulaciones y procedimientos para la producción de proteína recombinante aumentada |
| EP3904376B1 (en) | 2013-06-24 | 2024-11-13 | Xiao, Weidong | Mutant factor viii compositions and methods |
| US10548953B2 (en) | 2013-08-14 | 2020-02-04 | Bioverativ Therapeutics Inc. | Factor VIII-XTEN fusions and uses thereof |
| EP3058066A1 (en) | 2013-10-15 | 2016-08-24 | Novo Nordisk Health Care AG | Coagulation factor vii polypeptides |
| US20160252519A1 (en) * | 2013-10-18 | 2016-09-01 | Dr. Reddy's Laboratories Limited | In-vitro method for determining fate of polypeptide variant |
| EP3114138B1 (en) | 2014-03-05 | 2021-11-17 | Pfizer Inc. | Improved muteins of clotting factor viii |
| US10238718B2 (en) | 2014-08-04 | 2019-03-26 | Csl Limited | Factor VIII formulation |
| ES2772933T3 (es) | 2015-03-06 | 2020-07-08 | CSL Behring Lengnau AG | Factor de von Willebrand modificado que tiene una semivida mejorada |
| BR112018002150A2 (pt) | 2015-08-03 | 2018-09-18 | Bioverativ Therapeutics Inc | proteínas de fusão do fator ix e métodos de fabricação e uso das mesmas |
| IL319473A (en) | 2016-12-02 | 2025-05-01 | Bioverativ Therapeutics Inc | Methods for treating hemophilic arthritis using chimeric blood clotting factors |
| BR112020022164A2 (pt) | 2018-05-18 | 2021-02-02 | Bioverativ Therapeutics Inc. | métodos de tratamento de hemofilia a |
| CN114072420B (zh) | 2019-07-04 | 2024-06-11 | 康诺贝林伦瑙有限公司 | 用于增加凝血因子viii的体外稳定性的截短的血管性血友病因子(vwf) |
| EP4051704A2 (en) * | 2019-11-01 | 2022-09-07 | Freeline Therapeutics Limited | Factor viii construct |
| JP7680442B2 (ja) | 2019-11-11 | 2025-05-20 | ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト | 第ｖｉｉｉ因子に対する寛容を誘導するためのポリペプチド |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005500831A (ja) * | 2001-06-14 | 2005-01-13 | ザ スクリプス リサーチ インスティチュート | 操作されたジスルフィド結合を有する安定化蛋白質 |
| JP2008546671A (ja) * | 2005-06-17 | 2008-12-25 | ノボ ノルディスク ヘルス ケア アーゲー | 二量体及び多量体ＦＶＩＩａ化合物 |
| JP2008546670A (ja) * | 2005-06-17 | 2008-12-25 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 少なくとも１つの非天然のシステインを含んでいる操作されたタンパク質の選択的な還元および誘導体化 |
| WO2009108806A1 (en) * | 2008-02-27 | 2009-09-03 | Novo Nordisk A/S | Conjugated factor viii molecules |
| JP2009532351A (ja) * | 2006-03-31 | 2009-09-10 | バクスター・インターナショナル・インコーポレイテッド | ペグ化第ｖｉｉｉ因子 |
| WO2010045568A1 (en) * | 2008-10-17 | 2010-04-22 | Baxter International Inc. | Modified blood factors comprising a low degree of water soluble polymer |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2645588A (en) | 1987-12-04 | 1989-06-15 | Scripps Clinic And Research Foundation | The von willebrand factor binding domain of factor viii |
| US5824784A (en) | 1994-10-12 | 1998-10-20 | Amgen Inc. | N-terminally chemically modified protein compositions and methods |
| WO1999055377A2 (en) | 1998-04-28 | 1999-11-04 | Applied Research Systems Ars Holding N.V. | Polyol-ifn-beta conjugates |
| EP2042196B1 (en) | 2001-10-10 | 2016-07-13 | ratiopharm GmbH | Remodelling and glycoconjugation of Granulocyte Colony Stimulating Factor (G-CSF) |
| US20100143969A1 (en) | 2005-03-24 | 2010-06-10 | Neose Technologies, Inc. | Expression of soluble, active eukaryotic glycosyltransferases in prokaryotic organisms |
| JP2008534559A (ja) * | 2005-04-01 | 2008-08-28 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 血液凝固ｆｖｉｉｉ類似体 |
| WO2007056191A2 (en) | 2005-11-03 | 2007-05-18 | Neose Technologies, Inc. | Nucleotide sugar purification using membranes |
| ES2516694T3 (es) * | 2006-07-21 | 2014-10-31 | Ratiopharm Gmbh | Glicosilación de péptidos a través de secuencias de glicosilación con unión en O |
-
2011
- 2011-07-06 JP JP2013519027A patent/JP2013532176A/ja not_active Ceased
- 2011-07-06 EP EP11735405.0A patent/EP2593130A2/en not_active Withdrawn
- 2011-07-06 US US13/808,204 patent/US20130183280A1/en not_active Abandoned
- 2011-07-06 WO PCT/EP2011/061349 patent/WO2012007324A2/en not_active Ceased
- 2011-07-06 CN CN2011800348298A patent/CN102971006A/zh not_active Withdrawn
-
2016
- 2016-06-01 US US15/170,502 patent/US20160264645A1/en not_active Abandoned
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005500831A (ja) * | 2001-06-14 | 2005-01-13 | ザ スクリプス リサーチ インスティチュート | 操作されたジスルフィド結合を有する安定化蛋白質 |
| JP2008546671A (ja) * | 2005-06-17 | 2008-12-25 | ノボ ノルディスク ヘルス ケア アーゲー | 二量体及び多量体ＦＶＩＩａ化合物 |
| JP2008546670A (ja) * | 2005-06-17 | 2008-12-25 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 少なくとも１つの非天然のシステインを含んでいる操作されたタンパク質の選択的な還元および誘導体化 |
| JP2009532351A (ja) * | 2006-03-31 | 2009-09-10 | バクスター・インターナショナル・インコーポレイテッド | ペグ化第ｖｉｉｉ因子 |
| WO2009108806A1 (en) * | 2008-02-27 | 2009-09-03 | Novo Nordisk A/S | Conjugated factor viii molecules |
| WO2010045568A1 (en) * | 2008-10-17 | 2010-04-22 | Baxter International Inc. | Modified blood factors comprising a low degree of water soluble polymer |
Non-Patent Citations (4)
| Title |
|---|
| JPN6015028291; Ａ． Ｊ． ＧＡＬＥ: 'Ｉｎｔｒｉｎｓｉｃ ｓｔａｂｉｌｉｔｙ ａｎｄ ｆｕｎｃｔｉｏｎａｌ ｐｒｏｐｅｒｔｉｅｓ ｏｆ ｄｉｓｕｌｆｉｄｅ ｂｏｎｄ-ｓｔａｂｉｌｉｚｅｄ ｃｏａｇｕｌａｔｉｏｎ ｆａｃｔｏｒ ＶＩＩＩａ' Ｊｏｕｒｎａｌ ｏｆ Ｔｈｒｏｍｂｏｓｉｓ ａｎｄ Ｈａｅｍｏｓｔａｓｉｓ Ｖｏｌ．４, 2006, Ｐａｇｅｓ １３１５-１３２２ * |
| JPN6015028292; Ａ． Ｊ． ＧＡＬＥ: 'Ａｎ ｅｎｇｉｎｅｅｒｅｄ ｉｎｔｅｒｄｏｍａｉｎ ｄｉｓｕｌｆｉｄｅ ｂｏｎｄ ｓｔａｂｉｌｉｚｅｓ ｈｕｍａｎ ｂｌｏｏｄ ｃｏａｇｕｌａｔｉｏｎ ｆａｃｔｏｒ ＶＩＩＩａ' Ｊｏｕｒｎａｌ ｏｆ Ｔｈｒｏｍｂｏｓｉｓ ａｎｄ Ｈａｅｍｏｓｔａｓｉｓ Ｖｏｌ．１, 2003, Ｐａｇｅｓ １９６６-１９７１ * |
| JPN6015028294; Ｋ． Ｐ． ＲＡＤＴＫＥ: 'Ｄｉｓｕｌｆｉｄｅ ｂｏｎｄ-ｓｔａｂｉｌｉｚｅｄ ｆａｃｔｏｒ ＶＩＩＩ ｈａｓ ｐｒｏｌｏｎｇｅｄ ｆａｃｔｏｒ ＶＩＩＩａ ａｃｔｉｖｉｔｙ ａｎｄ ｉｍｐｒｏｖｅｄ ｐｏｔｅｎｃｙ ｉｎ ｗｈ' Ｊｏｕｒｎａｌ ｏｆ Ｔｈｒｏｍｂｏｓｉｓ ａｎｄ Ｈａｅｍｏｓｔａｓｉｓ Ｖｏｌ．５, 2007, Ｐａｇｅｓ １０２-１０８ * |
| JPN6015028295; Ｈ． ＷＡＫＡＢＡＹＡＳＨＩ: 'Ｃｏｍｂｉｎｉｎｇ ｍｕｔａｔｉｏｎｓ ｏｆ ｃｈａｒｇｅｄ ｒｅｓｉｄｕｅｓ ａｔ ｔｈｅ Ａ２ ｄｏｍａｉｎ ｉｎｔｅｒｆａｃｅ ｅｎｈａｎｃｅｓ ｆａｃｔｏｒ ＶＩＩＩ ｓｔａｂｉｌｉｔｙ ｏｖ' Ｊｏｕｒｎａｌ ｏｆ Ｔｈｒｏｍｂｏｓｉｓ ａｎｄ Ｈａｅｍｏｓｔａｓｉｓ Ｖｏｌ．７, 2009, Ｐａｇｅｓ ４３８-４４４ * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2023542388A (ja) * | 2020-09-23 | 2023-10-06 | アブレヴィア バイオテック ゲーエムベーハー | 第ｖｉｉｉ因子補充療法の有効性を増加させるための化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012007324A2 (en) | 2012-01-19 |
| EP2593130A2 (en) | 2013-05-22 |
| US20130183280A1 (en) | 2013-07-18 |
| CN102971006A (zh) | 2013-03-13 |
| US20160264645A1 (en) | 2016-09-15 |
| WO2012007324A3 (en) | 2012-03-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2013532176A (ja) | 安定化させた第ｖｉｉｉ因子バリアント | |
| JP5914363B2 (ja) | 低減されたｖｗｆ結合を有する因子ｖｉｉｉ分子 | |
| JP6185097B2 (ja) | 因子ｖｉｉｉ融合タンパク質 | |
| EP2097096B1 (en) | Modified coagulation factors with prolonged in vivo half-life | |
| US8536126B2 (en) | Conjugated factor VIII molecules | |
| RU2722374C1 (ru) | Высокогликозилированный слитый белок на основе фактора свертывания крови человека viii, способ его получения и его применение | |
| JP5826772B2 (ja) | コンジュゲートタンパク質 | |
| JP6336522B2 (ja) | 細胞取込みが低下した第ｖｉｉｉ因子変異体 | |
| CN112673026B (zh) | 突变型单链人凝血因子viii融合蛋白及其制备方法与用途 | |
| WO2017117630A9 (en) | Mutated von willebrand factor | |
| AU2017358861B2 (en) | Truncated von Willebrand Factor polypeptides for treating hemophilia | |
| HK40051475A (en) | Fusion protein of mutated single-chain human coagulation factor viii, preparation method therefor, and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140703 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20140703 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150713 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20151007 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160113 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20160620 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20161014 |
|
| A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20161021 |
|
| A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20161228 |
|
| A045 | Written measure of dismissal of application [lapsed due to lack of payment] |
Free format text: JAPANESE INTERMEDIATE CODE: A045 Effective date: 20180528 |