JP4809977B2 - 貧血の予防および治療用の方法および組成物 - Google Patents
貧血の予防および治療用の方法および組成物 Download PDFInfo
- Publication number
- JP4809977B2 JP4809977B2 JP2000578445A JP2000578445A JP4809977B2 JP 4809977 B2 JP4809977 B2 JP 4809977B2 JP 2000578445 A JP2000578445 A JP 2000578445A JP 2000578445 A JP2000578445 A JP 2000578445A JP 4809977 B2 JP4809977 B2 JP 4809977B2
- Authority
- JP
- Japan
- Prior art keywords
- epo
- analog
- rhuepo
- analogs
- week
- 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.)
- Expired - Fee Related
Links
- 239000000203 mixture Substances 0.000 title claims description 13
- 238000000034 method Methods 0.000 title description 27
- 208000007502 anemia Diseases 0.000 title description 26
- 238000011282 treatment Methods 0.000 title description 16
- 230000002265 prevention Effects 0.000 title 1
- 125000000837 carbohydrate group Chemical group 0.000 claims description 53
- 230000013595 glycosylation Effects 0.000 claims description 20
- 238000006206 glycosylation reaction Methods 0.000 claims description 20
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 claims description 16
- 101000920686 Homo sapiens Erythropoietin Proteins 0.000 claims description 15
- 102000044890 human EPO Human genes 0.000 claims description 15
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical group [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 13
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
- 108091029865 Exogenous DNA Proteins 0.000 claims 1
- 238000005534 hematocrit Methods 0.000 description 66
- 210000004027 cell Anatomy 0.000 description 28
- 238000001990 intravenous administration Methods 0.000 description 28
- 241000699670 Mus sp. Species 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 210000002966 serum Anatomy 0.000 description 24
- 238000003752 polymerase chain reaction Methods 0.000 description 23
- 230000000694 effects Effects 0.000 description 20
- 108090000765 processed proteins & peptides Proteins 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 238000002474 experimental method Methods 0.000 description 18
- 241000699666 Mus <mouse, genus> Species 0.000 description 17
- 235000001014 amino acid Nutrition 0.000 description 17
- 229940024606 amino acid Drugs 0.000 description 16
- 150000001413 amino acids Chemical class 0.000 description 16
- 230000004071 biological effect Effects 0.000 description 15
- 108020004414 DNA Proteins 0.000 description 14
- 230000008859 change Effects 0.000 description 14
- 238000001727 in vivo Methods 0.000 description 14
- 241000700159 Rattus Species 0.000 description 13
- 238000007912 intraperitoneal administration Methods 0.000 description 13
- 230000003442 weekly effect Effects 0.000 description 13
- 241000282472 Canis lupus familiaris Species 0.000 description 12
- 102000003951 Erythropoietin Human genes 0.000 description 12
- 108090000394 Erythropoietin Proteins 0.000 description 12
- 102000001708 Protein Isoforms Human genes 0.000 description 12
- 108010029485 Protein Isoforms Proteins 0.000 description 12
- 238000007792 addition Methods 0.000 description 12
- 238000002703 mutagenesis Methods 0.000 description 12
- 231100000350 mutagenesis Toxicity 0.000 description 12
- 230000004044 response Effects 0.000 description 12
- 230000002441 reversible effect Effects 0.000 description 12
- 150000001720 carbohydrates Chemical group 0.000 description 11
- 235000014633 carbohydrates Nutrition 0.000 description 11
- 238000010253 intravenous injection Methods 0.000 description 11
- 238000006467 substitution reaction Methods 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 208000020832 chronic kidney disease Diseases 0.000 description 10
- 231100000673 dose–response relationship Toxicity 0.000 description 10
- 229940105423 erythropoietin Drugs 0.000 description 10
- 230000003389 potentiating effect Effects 0.000 description 10
- 239000007989 BIS-Tris Propane buffer Substances 0.000 description 9
- HHKZCCWKTZRCCL-UHFFFAOYSA-N bis-tris propane Chemical compound OCC(CO)(CO)NCCCNC(CO)(CO)CO HHKZCCWKTZRCCL-UHFFFAOYSA-N 0.000 description 9
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- 230000007423 decrease Effects 0.000 description 8
- 238000012217 deletion Methods 0.000 description 8
- 230000037430 deletion Effects 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 210000003743 erythrocyte Anatomy 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 239000007928 intraperitoneal injection Substances 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 125000000539 amino acid group Chemical group 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 6
- 239000000872 buffer Substances 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
- 230000010437 erythropoiesis Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 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 6
- 125000005629 sialic acid group Chemical group 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 239000013598 vector Substances 0.000 description 6
- 230000004988 N-glycosylation Effects 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 125000003275 alpha amino acid group Chemical group 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000004166 bioassay Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 101100519158 Arabidopsis thaliana PCR2 gene Proteins 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 241000699802 Cricetulus griseus Species 0.000 description 3
- 108010074604 Epoetin Alfa Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 101150102573 PCR1 gene Proteins 0.000 description 3
- 208000008601 Polycythemia Diseases 0.000 description 3
- 108010071390 Serum Albumin Proteins 0.000 description 3
- 102000007562 Serum Albumin Human genes 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000012911 assay medium Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000003636 conditioned culture medium Substances 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940089118 epogen Drugs 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000003907 kidney function Effects 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 210000004962 mammalian cell Anatomy 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 150000002482 oligosaccharides Polymers 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010242 retro-orbital bleeding Methods 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 3
- 229960002555 zidovudine Drugs 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 2
- 230000004989 O-glycosylation Effects 0.000 description 2
- 239000012614 Q-Sepharose Substances 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 108091081024 Start codon Proteins 0.000 description 2
- 108020005038 Terminator Codon Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 238000000246 agarose gel electrophoresis Methods 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000001143 conditioned effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 108020001096 dihydrofolate reductase Proteins 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 230000001146 hypoxic effect Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003039 myelosuppressive effect Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 238000003156 radioimmunoprecipitation Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 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 2
- 239000002904 solvent Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 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
- NKDFYOWSKOHCCO-YPVLXUMRSA-N 20-hydroxyecdysone Chemical compound C1[C@@H](O)[C@@H](O)C[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@@](C)(O)[C@H](O)CCC(C)(O)C)CC[C@]33O)C)C3=CC(=O)[C@@H]21 NKDFYOWSKOHCCO-YPVLXUMRSA-N 0.000 description 1
- 238000010600 3H thymidine incorporation assay Methods 0.000 description 1
- 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 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 101100273566 Humulus lupulus CCL10 gene Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 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
- 241001460678 Napo <wasp> Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 239000012564 Q sepharose fast flow resin Substances 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 108010001244 Tli polymerase Proteins 0.000 description 1
- 239000007997 Tricine buffer Substances 0.000 description 1
- 108010018161 UlTma DNA polymerase Proteins 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 238000012867 alanine scanning Methods 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000007630 basic procedure Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 201000006491 bone marrow cancer Diseases 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- -1 carrier Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000012219 cassette mutagenesis Methods 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 description 1
- SUYVUBYJARFZHO-UHFFFAOYSA-N dATP Natural products C1=NC=2C(N)=NC=NC=2N1C1CC(O)C(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-UHFFFAOYSA-N 0.000 description 1
- RGWHQCVHVJXOKC-SHYZEUOFSA-J dCTP(4-) Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)C1 RGWHQCVHVJXOKC-SHYZEUOFSA-J 0.000 description 1
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 description 1
- NHVNXKFIZYSCEB-XLPZGREQSA-N dTTP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C1 NHVNXKFIZYSCEB-XLPZGREQSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 210000003013 erythroid precursor cell Anatomy 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000001605 fetal effect Effects 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
- 239000003365 glass fiber Substances 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000001155 isoelectric focusing Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
- A61K38/22—Hormones
-
- 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
- C07K14/475—Growth factors; Growth regulators
- C07K14/505—Erythropoietin [EPO]
-
- 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
- A61K38/18—Growth factors; Growth regulators
- A61K38/1816—Erythropoietin [EPO]
-
- 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
-
- 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
- A61P7/06—Antianaemics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US17829298A | 1998-10-23 | 1998-10-23 | |
| US09/178,292 | 1998-10-23 | ||
| PCT/US1999/024435 WO2000024893A2 (en) | 1998-10-23 | 1999-10-18 | Methods and compositions for the prevention and treatment of anemia |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2010130046A Division JP5558213B2 (ja) | 1998-10-23 | 2010-06-07 | 貧血の予防および治療用の方法および組成物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002528465A JP2002528465A (ja) | 2002-09-03 |
| JP4809977B2 true JP4809977B2 (ja) | 2011-11-09 |
Family
ID=22651968
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000578445A Expired - Fee Related JP4809977B2 (ja) | 1998-10-23 | 1999-10-18 | 貧血の予防および治療用の方法および組成物 |
| JP2010130046A Expired - Fee Related JP5558213B2 (ja) | 1998-10-23 | 2010-06-07 | 貧血の予防および治療用の方法および組成物 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2010130046A Expired - Fee Related JP5558213B2 (ja) | 1998-10-23 | 2010-06-07 | 貧血の予防および治療用の方法および組成物 |
Country Status (19)
| Country | Link |
|---|---|
| EP (2) | EP1123313B2 (enExample) |
| JP (2) | JP4809977B2 (enExample) |
| KR (1) | KR20010075661A (enExample) |
| CN (2) | CN101703760A (enExample) |
| AR (1) | AR020848A1 (enExample) |
| AT (2) | ATE477270T1 (enExample) |
| AU (1) | AU774989B2 (enExample) |
| CA (1) | CA2345882C (enExample) |
| CY (2) | CY1107584T1 (enExample) |
| DE (2) | DE69935345T3 (enExample) |
| DK (2) | DK1813624T3 (enExample) |
| ES (2) | ES2283139T5 (enExample) |
| HK (1) | HK1040944B (enExample) |
| HU (1) | HU228492B1 (enExample) |
| IL (2) | IL142334A (enExample) |
| PT (2) | PT1123313E (enExample) |
| SI (2) | SI1813624T1 (enExample) |
| TW (1) | TWI234583B (enExample) |
| WO (1) | WO2000024893A2 (enExample) |
Families Citing this family (130)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7217689B1 (en) | 1989-10-13 | 2007-05-15 | Amgen Inc. | Glycosylation analogs of erythropoietin |
| FR2686899B1 (fr) | 1992-01-31 | 1995-09-01 | Rhone Poulenc Rorer Sa | Nouveaux polypeptides biologiquement actifs, leur preparation et compositions pharmaceutiques les contenant. |
| ES2206695T3 (es) | 1996-03-14 | 2004-05-16 | Genentech, Inc. | Receptor de gdnf y utiolizacion del mismo. |
| ATE267215T1 (de) | 1997-12-08 | 2004-06-15 | Lexigen Pharm Corp | Heterodimäre fusionsproteine zur verwendung für gezielte immuntherapie und allgemeine immunerregung |
| US7304150B1 (en) | 1998-10-23 | 2007-12-04 | Amgen Inc. | Methods and compositions for the prevention and treatment of anemia |
| US6831060B2 (en) | 1999-05-07 | 2004-12-14 | Genentech, Inc. | Chimpanzee erythropoietin (CHEPO) polypeptides and nucleic acids encoding the same |
| AU766507B2 (en) * | 1999-05-07 | 2003-10-16 | Genentech Inc. | Novel chimpanzee erythropoietin (CHEPO) polypeptides and nucleic acids encoding the same |
| US6555343B1 (en) | 1999-05-07 | 2003-04-29 | Genentech Inc. | Chimpanzee erythropoietin (CHEPO) polypeptides and nucleic acids encoding the same |
| US7067110B1 (en) | 1999-07-21 | 2006-06-27 | Emd Lexigen Research Center Corp. | Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens |
| PL202058B1 (pl) | 1999-08-09 | 2009-05-29 | Merck Patent Gmbh | Wielofunkcyjne białko fuzyjne cytokin i przeciwciała |
| EP1228214A2 (en) | 1999-11-12 | 2002-08-07 | MERCK PATENT GmbH | Erythropoietin forms with improved properties |
| AU4314801A (en) | 2000-02-11 | 2001-08-20 | Lexigen Pharm Corp | Enhancing the circulating half-life of antibody-based fusion proteins |
| ES2529300T3 (es) | 2000-04-12 | 2015-02-18 | Novozymes Biopharma Dk A/S | Proteínas de fusión de albúmina |
| CA2406807C (en) * | 2000-04-21 | 2010-04-06 | Amgen Inc. | Methods and compositions for the prevention and treatment of anemia |
| SI1311285T1 (enExample) | 2000-05-15 | 2005-08-31 | Hoffmann La Roche | |
| SK982003A3 (en) | 2000-06-29 | 2004-05-04 | Merck Patent Gmbh | Enhancement of antibody-cytokine fusion protein mediated immune responses by combined treatment with immunocytokine uptake enhancing agents |
| US7078376B1 (en) * | 2000-08-11 | 2006-07-18 | Baxter Healthcare S.A. | Therapeutic methods for treating subjects with a recombinant erythropoietin having high activity and reduced side effects |
| US7087224B2 (en) | 2000-10-31 | 2006-08-08 | Amgen Inc. | Method of treating anemia by administering IL-1ra |
| US7148321B2 (en) | 2001-03-07 | 2006-12-12 | Emd Lexigen Research Center Corp. | Expression technology for proteins containing a hybrid isotype antibody moiety |
| US6992174B2 (en) | 2001-03-30 | 2006-01-31 | Emd Lexigen Research Center Corp. | Reducing the immunogenicity of fusion proteins |
| US6969517B2 (en) | 2001-05-03 | 2005-11-29 | Emd Lexigen Research Center Corp. | Recombinant tumor specific antibody and use thereof |
| ATE542137T1 (de) | 2001-12-04 | 2012-02-15 | Merck Patent Gmbh | Immunocytokine mit modulierter selektivität |
| WO2005003296A2 (en) | 2003-01-22 | 2005-01-13 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| WO2003060071A2 (en) | 2001-12-21 | 2003-07-24 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| WO2004003176A2 (en) * | 2002-07-01 | 2004-01-08 | The Kenneth S. Warren Institute, Inc. | Recombinant tissue protective cytokines and encoding nucleic acids thereof for protection, restoration, and enhancement of responsive cells, tissues, and organs |
| AU2003246486A1 (en) * | 2002-07-19 | 2004-02-09 | Cangene Corporation | Pegylated erythropoietic compounds |
| KR101086660B1 (ko) | 2002-12-17 | 2011-11-24 | 메르크 파텐트 게엠베하 | Ｇｄ2 에 결합하는 마우스 14.18 항체의 인간화 항체(ｈ14.18) 및 그것의 ｉｌ-2 와의 융합 |
| PL1644363T3 (pl) | 2003-05-30 | 2012-07-31 | Gemin X Pharmaceuticals Canada Inc | Związki triheterocykliczne, kompozycje i metody leczenia raka |
| RU2370276C2 (ru) | 2003-12-31 | 2009-10-20 | Мерк Патент Гмбх | Fc-ЭРИТРОПОЭТИН СЛИТЫЙ БЕЛОК С УЛУЧШЕННОЙ ФАРМАКОКИНЕТИКОЙ |
| TWI376234B (en) | 2005-02-01 | 2012-11-11 | Msd Oss Bv | Conjugates of a polypeptide and an oligosaccharide |
| CA2609473A1 (en) * | 2005-05-24 | 2006-11-30 | Avestha Gengraine Technologies Pvt Ltd. | A recombinant method for production of an erythropoiesis stimulating protein |
| EP1957637B1 (en) | 2005-12-08 | 2013-08-14 | Amgen, Inc. | Improved host cells and culture methods |
| EP3026109B1 (en) | 2005-12-08 | 2022-03-09 | Amgen Inc. | Improved production of glycoproteins using manganese |
| JP5410971B2 (ja) | 2006-07-21 | 2014-02-05 | アムジエン・インコーポレーテツド | サンプル中のヘプシジンを検出および／または測定する方法 |
| AU2008304111B2 (en) | 2007-09-27 | 2014-04-24 | Amgen Inc. | Pharmaceutical formulations |
| US8796206B2 (en) | 2007-11-15 | 2014-08-05 | Amgen Inc. | Aqueous formulation of erythropoiesis stimulating protein stabilised by antioxidants for parenteral administration |
| EP2247618B1 (en) | 2008-01-25 | 2014-06-11 | Amgen, Inc | Ferroportin antibodies and methods of use |
| CA2722600C (en) | 2008-05-01 | 2014-01-21 | Amgen Inc. | Anti-hepcidin antibodies and methods of use |
| CN101323630B (zh) * | 2008-07-25 | 2013-06-05 | 中国科学院上海有机化学研究所 | 一种过渡金属络合物、合成方法及其用途 |
| ES2766257T3 (es) | 2008-11-13 | 2020-06-12 | Massachusetts Gen Hospital | Métodos y composiciones para regular la homeostasis del hierro mediante la modulación de bmp-6 |
| EP3009447B1 (en) | 2009-07-24 | 2018-06-06 | Dr. Reddy's Laboratories, Ltd. | Production of erythropoiesis stimulating protein using metal ions |
| EP2488553B1 (en) | 2009-10-12 | 2015-06-17 | Pfizer Inc. | Cancer treatment |
| MX344382B (es) | 2009-10-23 | 2016-12-14 | Amgen Inc * | Adaptador de vial y sistema. |
| DK2575935T4 (da) | 2010-06-07 | 2023-11-27 | Amgen Inc | Anordning til indgivelse af lægemiddel |
| US9480624B2 (en) | 2011-03-31 | 2016-11-01 | Amgen Inc. | Vial adapter and system |
| CA3019531A1 (en) | 2011-04-19 | 2012-10-26 | Pfizer Inc. | Combinations of anti-4-1bb antibodies and adcc-inducing antibodies for the treatment of cancer |
| EP2699293B8 (en) | 2011-04-20 | 2022-07-20 | Amgen Inc. | Autoinjector apparatus |
| EP3045188B1 (en) | 2011-10-14 | 2020-12-23 | Amgen Inc. | Injector and method of assembly |
| EP2922590B1 (en) | 2012-11-21 | 2020-02-05 | Amgen Inc. | Drug delivery device |
| EP2968775B1 (en) | 2013-03-15 | 2019-12-18 | Amgen Inc. | Drug cassette, autoinjector, and autoinjector system |
| EP2968760B1 (en) | 2013-03-15 | 2024-01-03 | Amgen Inc. | Drug cassette, autoinjector, and autoinjector system |
| CA2904357C (en) | 2013-03-15 | 2020-09-22 | Intrinsic Lifesciences Llc | Anti-hepcidin antibodies and uses thereof |
| CN111617347B (zh) | 2013-03-15 | 2023-09-29 | 安进公司 | 身体轮廓可调适的自动注射器装置 |
| BR112015024282B1 (pt) | 2013-03-22 | 2022-05-17 | Amgen Inc | Injetor e método de montagem do injetor |
| MX2016005315A (es) | 2013-10-24 | 2016-08-11 | Amgen Inc | Sistema de administracion de farmacos con control sensible a la temperatura. |
| EP3421066B1 (en) | 2013-10-24 | 2021-03-03 | Amgen Inc. | Injector and method of assembly |
| US10994112B2 (en) | 2014-02-05 | 2021-05-04 | Amgen Inc. | Drug delivery system with electromagnetic field generator |
| KR102496507B1 (ko) | 2014-05-07 | 2023-02-03 | 암겐 인코포레이티드 | 충격 감소 요소들을 가진 자동 주사기 |
| KR102710533B1 (ko) | 2014-06-03 | 2024-09-26 | 암겐 인코포레이티드 | 제어 가능한 약물 전달 시스템 및 사용 방법 |
| US10323088B2 (en) | 2014-09-22 | 2019-06-18 | Intrinsic Lifesciences Llc | Humanized anti-hepcidin antibodies and uses thereof |
| EP3206739B1 (en) | 2014-10-14 | 2021-12-01 | Amgen Inc. | Drug injection device with visual and audio indicators |
| ES2785311T3 (es) | 2014-12-19 | 2020-10-06 | Amgen Inc | Dispositivo de administración de fármacos con botón móvil o campo de interfaz de usuario |
| EP3848072A1 (en) | 2014-12-19 | 2021-07-14 | Amgen Inc. | Drug delivery device with proximity sensor |
| CN113813386A (zh) | 2014-12-31 | 2021-12-21 | 查克美特制药公司 | 组合肿瘤免疫疗法 |
| US10583245B2 (en) | 2015-02-17 | 2020-03-10 | Amgen Inc. | Drug delivery device with vacuum assisted securement and/or feedback |
| ES2905870T3 (es) | 2015-02-27 | 2022-04-12 | Amgen Inc | Dispositivo de suministro de fármacos que tiene un mecanismo de protección de aguja con un umbral de resistencia ajustable al movimiento de la protección de aguja |
| WO2017039786A1 (en) | 2015-09-02 | 2017-03-09 | Amgen Inc. | Syringe assembly adapter for a syringe |
| ES2755717T3 (es) | 2015-12-09 | 2020-04-23 | Amgen Inc | Autoinyector con tapa de señalización |
| WO2017120178A1 (en) | 2016-01-06 | 2017-07-13 | Amgen Inc. | Auto-injector with signaling electronics |
| ES2814287T3 (es) | 2016-03-15 | 2021-03-26 | Amgen Inc | Reducir la probabilidad de rotura de cristal en dispositivos de administración de fármaco |
| US11541168B2 (en) | 2016-04-29 | 2023-01-03 | Amgen Inc. | Drug delivery device with messaging label |
| US11389588B2 (en) | 2016-05-02 | 2022-07-19 | Amgen Inc. | Syringe adapter and guide for filling an on-body injector |
| ES2959783T3 (es) | 2016-05-13 | 2024-02-28 | Amgen Inc | Conjunto de cubierta protectora de vial |
| WO2017200989A1 (en) | 2016-05-16 | 2017-11-23 | Amgen Inc. | Data encryption in medical devices with limited computational capability |
| US11541176B2 (en) | 2016-06-03 | 2023-01-03 | Amgen Inc. | Impact testing apparatuses and methods for drug delivery devices |
| WO2018004842A1 (en) | 2016-07-01 | 2018-01-04 | Amgen Inc. | Drug delivery device having minimized risk of component fracture upon impact events |
| WO2018034784A1 (en) | 2016-08-17 | 2018-02-22 | Amgen Inc. | Drug delivery device with placement detection |
| US11202818B2 (en) | 2016-09-14 | 2021-12-21 | President And Fellows Of Harvard College | Methods and compositions for modulating erythropoiesis |
| EP3532127A1 (en) | 2016-10-25 | 2019-09-04 | Amgen Inc. | On-body injector |
| CA3049780A1 (en) | 2017-01-17 | 2018-07-26 | Amgen Inc. | Injection devices and related methods of use and assembly |
| JP7064501B2 (ja) | 2017-02-17 | 2022-05-10 | アムジエン・インコーポレーテツド | 無菌流体流路を備える薬物送達デバイスおよび関連する組立方法 |
| MX2019009755A (es) | 2017-02-17 | 2019-10-07 | Amgen Inc | Mecanismo de insercion para dispositivo de suministro de farmacos. |
| EP3592403B1 (en) | 2017-03-06 | 2025-08-20 | Amgen Inc. | Drug delivery device with activation prevention feature |
| CA3052482A1 (en) | 2017-03-07 | 2018-09-13 | Amgen Inc. | Needle insertion by overpressure |
| US11986624B2 (en) | 2017-03-09 | 2024-05-21 | Amgen Inc. | Insertion mechanism for drug delivery device |
| WO2018172219A1 (en) | 2017-03-20 | 2018-09-27 | F. Hoffmann-La Roche Ag | Method for in vitro glycoengineering of an erythropoiesis stimulating protein |
| CN114588404B (zh) | 2017-03-28 | 2024-07-09 | 美国安进公司 | 柱塞杆和注射器组件系统以及方法 |
| US11590294B2 (en) | 2017-06-08 | 2023-02-28 | Amgen Inc. | Syringe assembly for a drug delivery device and method of assembly |
| AU2018282077B2 (en) | 2017-06-08 | 2023-11-23 | Amgen Inc. | Torque driven drug delivery device |
| AU2018288604B2 (en) | 2017-06-22 | 2023-12-21 | Amgen Inc. | Device activation impact/shock reduction |
| AU2018290302B2 (en) | 2017-06-23 | 2024-02-29 | Amgen Inc. | Electronic drug delivery device comprising a cap activated by a switch assembly |
| ES2972207T3 (es) | 2017-07-14 | 2024-06-11 | Amgen Inc | Sistema de inserción-retracción de agujas con sistema de resorte de torsión doble |
| JP7649105B2 (ja) | 2017-07-21 | 2025-03-19 | アムジエン・インコーポレーテツド | 薬物容器のためのガス透過性シーリング部材及び組立方法 |
| WO2019022951A1 (en) | 2017-07-25 | 2019-01-31 | Amgen Inc. | DRUG DELIVERY DEVICE WITH GEAR MODULE AND ASSEMBLY METHOD THEREOF |
| MA49676A (fr) | 2017-07-25 | 2020-06-03 | Amgen Inc | Dispositif d'administration de médicament doté d'un système d'accès à un récipient et procédé d'assemblage associé |
| US12318593B2 (en) | 2017-08-09 | 2025-06-03 | Amgen Inc. | Hydraulic-pneumatic pressurized chamber drug delivery system |
| EP3668567A1 (en) | 2017-08-18 | 2020-06-24 | Amgen Inc. | Wearable injector with sterile adhesive patch |
| US11103636B2 (en) | 2017-08-22 | 2021-08-31 | Amgen Inc. | Needle insertion mechanism for drug delivery device |
| WO2019070472A1 (en) | 2017-10-04 | 2019-04-11 | Amgen Inc. | FLOW ADAPTER FOR MEDICATION DELIVERY DEVICE |
| CN111132711B (zh) | 2017-10-06 | 2022-07-01 | 安进公司 | 带有联锁组件的药物递送装置及相关组装方法 |
| EP3694578B1 (en) | 2017-10-09 | 2025-09-24 | Amgen Inc. | Drug delivery device with drive assembly and related method of assembly |
| EP3703779A1 (en) | 2017-11-03 | 2020-09-09 | Amgen Inc. | Systems and approaches for sterilizing a drug delivery device |
| MA50553A (fr) | 2017-11-06 | 2020-09-16 | Amgen Inc | Dispositif d'administration de médicament avec détection de positionnement et de débit |
| WO2019090303A1 (en) | 2017-11-06 | 2019-05-09 | Amgen Inc. | Fill-finish assemblies and related methods |
| SG11202002966QA (en) | 2017-11-10 | 2020-05-28 | Amgen Inc | Plungers for drug delivery devices |
| CA3079540A1 (en) | 2017-11-16 | 2019-05-23 | Amgen Inc. | Door latch mechanism for drug delivery device |
| WO2019099322A1 (en) | 2017-11-16 | 2019-05-23 | Amgen Inc. | Autoinjector with stall and end point detection |
| EP3752194A4 (en) | 2018-02-13 | 2022-03-16 | Checkmate Pharmaceuticals, Inc. | COMPOSITIONS AND METHODS FOR TUMOR IMMUNOTHERAPY |
| EP3775218A1 (en) | 2018-04-09 | 2021-02-17 | Checkmate Pharmaceuticals | Packaging oligonucleotides into virus-like particles |
| US10835685B2 (en) | 2018-05-30 | 2020-11-17 | Amgen Inc. | Thermal spring release mechanism for a drug delivery device |
| US11083840B2 (en) | 2018-06-01 | 2021-08-10 | Amgen Inc. | Modular fluid path assemblies for drug delivery devices |
| US12303677B2 (en) | 2018-07-24 | 2025-05-20 | Amgen Inc. | Hybrid drug delivery devices with optional grip portion and related method of preparation |
| WO2020023336A1 (en) | 2018-07-24 | 2020-01-30 | Amgen Inc. | Hybrid drug delivery devices with grip portion |
| WO2020023444A1 (en) | 2018-07-24 | 2020-01-30 | Amgen Inc. | Delivery devices for administering drugs |
| WO2020023451A1 (en) | 2018-07-24 | 2020-01-30 | Amgen Inc. | Delivery devices for administering drugs |
| MA53320A (fr) | 2018-07-31 | 2021-11-03 | Amgen Inc | Ensemble de trajet de fluide pour dispositif d'administration de médicament |
| WO2020068623A1 (en) | 2018-09-24 | 2020-04-02 | Amgen Inc. | Interventional dosing systems and methods |
| IL281469B2 (en) | 2018-09-28 | 2024-08-01 | Amgen Inc | Muscle wire escapement activation assembly for a drug delivery device |
| SG11202103236YA (en) | 2018-10-02 | 2021-04-29 | Amgen Inc | Injection systems for drug delivery with internal force transmission |
| WO2020072846A1 (en) | 2018-10-05 | 2020-04-09 | Amgen Inc. | Drug delivery device having dose indicator |
| EP3866889A1 (en) | 2018-10-15 | 2021-08-25 | Amgen Inc. | Platform assembly process for drug delivery device |
| AU2019361919B2 (en) | 2018-10-15 | 2024-09-26 | Amgen Inc. | Drug delivery device having damping mechanism |
| IL281908B2 (en) | 2018-11-01 | 2025-06-01 | Amgen Inc | Drug delivery devices with partial drug delivery member retraction |
| US11213620B2 (en) | 2018-11-01 | 2022-01-04 | Amgen Inc. | Drug delivery devices with partial drug delivery member retraction |
| TWI831847B (zh) | 2018-11-01 | 2024-02-11 | 美商安進公司 | 部分針頭縮回之藥物遞送裝置及其操作方法 |
| ES3032751T3 (en) | 2019-04-24 | 2025-07-24 | Amgen Inc | Syringe sterilization verification assemblies and methods |
| MX2022002149A (es) | 2019-08-23 | 2022-03-17 | Amgen Inc | Dispositivo de suministro de farmacos con componentes de acoplamiento de capuchon de aguja configurable y metodos relacionados. |
| CA3217207A1 (en) | 2021-05-21 | 2022-11-24 | Amgen Inc. | Method of optimizing a filling recipe for a drug container |
| WO2023209074A1 (en) | 2022-04-28 | 2023-11-02 | Institut National de la Santé et de la Recherche Médicale | Methods of restoring erythropoiesis in patients suffering from a sf3b1 mutant myelodysplastic syndrome by correcting coasy mis-splicing |
| JP2025536587A (ja) | 2022-11-02 | 2025-11-07 | エフ． ホフマン－ラ ロシュ アーゲー | 糖タンパク質組成物を生産するための方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08506023A (ja) * | 1993-08-17 | 1996-07-02 | アムジエン・インコーポレーテツド | エリトロポエチン類似体 |
| WO1997009996A1 (de) * | 1995-09-14 | 1997-03-20 | Boehringer Mannheim Gmbh | Pharmazeutische kombinationspräparate enthaltend erythropoietin und eisenpräparate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4954437A (en) * | 1986-09-15 | 1990-09-04 | Integrated Genetics, Inc. | Cell encoding recombinant human erythropoietin |
| AU646822B2 (en) * | 1989-10-13 | 1994-03-10 | Kirin-Amgen Inc. | Erythropoietin isoforms |
| US5716644A (en) * | 1992-06-11 | 1998-02-10 | Alkermes, Inc. | Composition for sustained release of non-aggregated erythropoietin |
| US5541458A (en) * | 1994-11-14 | 1996-07-30 | Hewlett-Packard Company | Power supply for timed residual power after turn off |
| DE69726571T2 (de) * | 1997-09-01 | 2004-11-04 | Aventis Pharma Deutschland Gmbh | Rekombinantes humanes Erythropoietin mit vorteilhaftem Glykosylierungsmuster |
-
1999
- 1999-10-18 WO PCT/US1999/024435 patent/WO2000024893A2/en not_active Ceased
- 1999-10-18 CN CN200910151885A patent/CN101703760A/zh active Pending
- 1999-10-18 DE DE69935345.9T patent/DE69935345T3/de not_active Expired - Lifetime
- 1999-10-18 CN CN998146978A patent/CN1346369B/zh not_active Expired - Fee Related
- 1999-10-18 EP EP99955046.0A patent/EP1123313B2/en not_active Expired - Lifetime
- 1999-10-18 DE DE69942680T patent/DE69942680D1/de not_active Expired - Lifetime
- 1999-10-18 HK HK02101019.3A patent/HK1040944B/en not_active IP Right Cessation
- 1999-10-18 PT PT99955046T patent/PT1123313E/pt unknown
- 1999-10-18 ES ES99955046.0T patent/ES2283139T5/es not_active Expired - Lifetime
- 1999-10-18 SI SI9931049T patent/SI1813624T1/sl unknown
- 1999-10-18 KR KR1020017005047A patent/KR20010075661A/ko not_active Ceased
- 1999-10-18 ES ES07004087T patent/ES2347884T3/es not_active Expired - Lifetime
- 1999-10-18 CA CA2345882A patent/CA2345882C/en not_active Expired - Fee Related
- 1999-10-18 JP JP2000578445A patent/JP4809977B2/ja not_active Expired - Fee Related
- 1999-10-18 AU AU11241/00A patent/AU774989B2/en not_active Ceased
- 1999-10-18 DK DK07004087.8T patent/DK1813624T3/da active
- 1999-10-18 AT AT07004087T patent/ATE477270T1/de active
- 1999-10-18 DK DK99955046T patent/DK1123313T3/da active
- 1999-10-18 HU HU0103920A patent/HU228492B1/hu not_active IP Right Cessation
- 1999-10-18 AR ARP990105261A patent/AR020848A1/es unknown
- 1999-10-18 AT AT99955046T patent/ATE355303T1/de active
- 1999-10-18 SI SI9930955T patent/SI1123313T1/sl unknown
- 1999-10-18 PT PT07004087T patent/PT1813624E/pt unknown
- 1999-10-18 EP EP07004087A patent/EP1813624B1/en not_active Expired - Lifetime
- 1999-10-22 TW TW088118320A patent/TWI234583B/zh not_active IP Right Cessation
-
2001
- 2001-03-29 IL IL142334A patent/IL142334A/en not_active IP Right Cessation
-
2007
- 2007-03-07 CY CY20071100322T patent/CY1107584T1/el unknown
-
2009
- 2009-01-21 IL IL196645A patent/IL196645A/en not_active IP Right Cessation
-
2010
- 2010-06-07 JP JP2010130046A patent/JP5558213B2/ja not_active Expired - Fee Related
- 2010-09-27 CY CY20101100863T patent/CY1110801T1/el unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08506023A (ja) * | 1993-08-17 | 1996-07-02 | アムジエン・インコーポレーテツド | エリトロポエチン類似体 |
| WO1997009996A1 (de) * | 1995-09-14 | 1997-03-20 | Boehringer Mannheim Gmbh | Pharmazeutische kombinationspräparate enthaltend erythropoietin und eisenpräparate |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4809977B2 (ja) | 貧血の予防および治療用の方法および組成物 | |
| JP5022551B2 (ja) | 貧血の予防及び治療用の方法及び組成物 | |
| US8268588B2 (en) | Methods and compositions for the prevention and treatment of anemia | |
| AU2001255516A1 (en) | Methods and compositions for the prevention and treatment of anemia | |
| MXPA01003867A (en) | Methods and compositions for the prevention and treatment of anemia | |
| HK1127275A (en) | Methods and compositions for the prevention and treatment of anemia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20060906 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20091208 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20100301 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20100308 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100607 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20101214 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110413 |
|
| A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20110616 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20110809 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20110822 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140826 Year of fee payment: 3 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |