WO1995025170B1 - NOVEL MUTEINS OF IFN-$g(b) - Google Patents
NOVEL MUTEINS OF IFN-$g(b)Info
- Publication number
- WO1995025170B1 WO1995025170B1 PCT/US1995/003206 US9503206W WO9525170B1 WO 1995025170 B1 WO1995025170 B1 WO 1995025170B1 US 9503206 W US9503206 W US 9503206W WO 9525170 B1 WO9525170 B1 WO 9525170B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- leu
- phe
- glu
- tyr
- asn
- Prior art date
Links
- 229920001850 Nucleic acid sequence Polymers 0.000 claims abstract 13
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims abstract 10
- 230000002519 immonomodulatory Effects 0.000 claims abstract 9
- 102100015720 IFNB1 Human genes 0.000 claims abstract 8
- 101700011451 IFNB1 Proteins 0.000 claims abstract 8
- 201000011510 cancer Diseases 0.000 claims abstract 8
- 206010047461 Viral infection Diseases 0.000 claims abstract 7
- 208000001756 Virus Disease Diseases 0.000 claims abstract 7
- 230000017613 viral reproduction Effects 0.000 claims abstract 7
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 claims abstract 6
- 206010028980 Neoplasm Diseases 0.000 claims abstract 6
- 229920003013 deoxyribonucleic acid Polymers 0.000 claims abstract 6
- 108020004511 Recombinant DNA Proteins 0.000 claims abstract 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- 125000002068 L-phenylalanino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 13
- 230000000840 anti-viral Effects 0.000 claims 8
- 210000004027 cells Anatomy 0.000 claims 6
- 210000001519 tissues Anatomy 0.000 claims 6
- 125000003275 alpha amino acid group Chemical group 0.000 claims 5
- 102000004965 antibodies Human genes 0.000 claims 5
- 108090001123 antibodies Proteins 0.000 claims 5
- 230000004663 cell proliferation Effects 0.000 claims 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-M tryptophanate Chemical compound C1=CC=C2C(CC(N)C([O-])=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-M 0.000 claims 4
- 230000001093 anti-cancer Effects 0.000 claims 3
- 230000000259 anti-tumor Effects 0.000 claims 3
- 238000001415 gene therapy Methods 0.000 claims 3
- 230000001131 transforming Effects 0.000 claims 3
- 108020004705 Codon Proteins 0.000 claims 2
- 208000006454 Hepatitis Diseases 0.000 claims 2
- 231100000283 hepatitis Toxicity 0.000 claims 2
- 239000002773 nucleotide Substances 0.000 claims 2
- 125000003729 nucleotide group Chemical group 0.000 claims 2
- 206010018338 Glioma Diseases 0.000 claims 1
- 206010025650 Malignant melanoma Diseases 0.000 claims 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N Methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 210000004102 animal cell Anatomy 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 200000000008 restenosis Diseases 0.000 claims 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 abstract 1
- 230000001939 inductive effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
Abstract
A IFN-β mutein in which phe (F), tyr (Y), trp (W) or his (H) is substituted for val (V) at position 101, when numbered in accordance with wild type IFN-β, DNA sequences encoding these IFN-β muteins, recombinant DNA molecules containing those DNA sequences operatively linked to expression control sequences and capable of inducing expression of an IFN-β mutein, hosts transformed with those recombinant DNA molecules, pharmaceutical compositions containing IFN-β muteins and methods of using those compositions to treat viral infections, cancer or tumors or for immunomodulation.
Claims
1. An IFN-/8 mutein wherein the val (V) at position 101 in wild type IFN-/3, numbered in accordance with wild type IFN-/3, is substituted with phe (F) , tyr (Y) , trp ( ) , or his (H) , said mutein displaying an antiviral activity that is at least partially neutralized by antibodies to wild type IFN-3.
2. An IFN-3 mutein having an a ino acid sequence identical to wild type IFN-p" except that the val (V) at position 101 in wild type IFN-p*. numbered in accordance with wild type IFN-/3, is substituted with phe (F) , tyr (Y) , trp ( ) or his (H) .
3. The IFN-3 mutein according to claim 2, wherein the val (V) is substituted with phe (F) .
4. The IFN-3 mutein according to claim 2 having the formula:
Met-Ser-Tyr-Asn-Leu-Leu-Gly-Phe-Leu-Gln-Arg-Ser-Ser- Asn-Phe-Gln-Cys-Gln-Lys-Leu-Leu-Trp-Gln-Leu-Asn-Gly- Arg-Leu-Glu-Tyr-Cys-Leu-Lys-Asp-Arg-Met-Asn-Phe-Asp- Ile-Pro-Glu-Glu-Ile-Lys-Gln-Leu-Gln-Gln-Phe-Gln-Lys- Glu-Asp-Ala-Ala-Leu-Thr-Ile-Tyr-Glu-Met-Leu-Gln-Asn- Ile-Phe-Ala-Ile-Phe-Arg-Gln-Asp-Ser-Ser-Ser-Thr-Gly- Trp-Asn-Glu-Thr-Ile-Val-Glu-Asn- eu- eu-Ala-Asn-Val- Tyr-His-Gln-Ile-Asn-His- eu-Lys-Thr-Phe-Leu-Glu-Glu- Lys-Leu-Glu-Lys-Glu-Asp-Phe-Thr-Arg-Gly-Lys-Leu-Met- Ser-Ser-Leu-His-Leu-Lys-Arg-Tyr-Tyr-Gly-Arg-Ile-Leu- His-Tyr-Leu-Lys-Ala-Lys-Glu-Tyr-Ser-His-Cys-Ala-Trp- Thr-Ile-Val-Arg-Val-Glu-Ile-Leu-Arg-Asn-Phe-Tyr-Phe- Ile-Asn-Arg-Leu-Thr-Gly-Tyr-Leu-Arg-Asn (SEQ ID NO:l). 4 1
5. A DNA sequence encoding an IFN-3 mutein where in the val (V) at position 101 in wild type IFN-/S numbered in accordance with wild type IFN-3, is substituted with phe (F) , tyr (Y) , trp ( ) , or his (H) , said mutein displaying an antiviral activity that is at least partially neutralized by antibodies to wild type IFN-/3.
6. A DNA sequence encoding an IFN-/3 mutein having an amino acid sequence identical to wild type IFN-/3 except that the val (V) at position 101 in wild type IFN-3, numbered in accordance with wild type IFN-S, is substituted with phe (F) , tyr (Y) , trp (W) or his (H) .
7. The DNA sequence according to claim 6, wherein the val (V) is substituted with phe (F) .
8. The DNA sequence according to claim 7 encoding an IFN-/3 mutein of the formula: Met-Ser-Tyr-Asn-Leu-Leu-Gly-Phe- eu-Gln-Arg-Ser-Ser- Asn-Phe-Gln-Cys-Gln-Lys-Leu-Leu-Trp-Gln-Leu-Asn-Gly- Arg-Leu-Glu-Tyr-Cys-Leu-Lys-Asp-Arg-Met-Asn-Phe-Asp- Ile-Pro-Glu-Glu-Ile-Lys-Gln-Leu-Gln-Gln-Phe-Gln-Lys- Glu-Asp-Ala-Ala-Leu-Thr-Ile-Tyr-Glu-Met-Leu-Gln-Asn- Ile-Phe-Ala-Ile-Phe-Arg-Gln-Asp-Ser-Ser-Ser-Thr-Gly- Trp-Asn-Glu-Thr-Ile-Val-Glu-Asn-Leu-Leu-Ala-Asn-Val- Tyr-His-Gln-Ile-Asn-His-Leu-Lys-Thr-Phe-Leu-Glu-Glu- Lys-Leu-Glu-Lys-Glu-Asp-Phe-Thr-Arg-Gly-Lys-Leu-Met- Ser-Ser-Leu-His-Leu-Lys-Arg-Tyr-Tyr-Gly-Arg-Ile-Leu- His-Tyr-Leu-Lys-Ala-Lys-Glu-Tyr-Ser-His-Cys-Ala-Trp- Thr-Ile-Val-Arg-Val-Glu-Ile-Leu-Arg-Asn-Phe-Tyr-Phe- Ile-Asn-Arg-Leu-Thr-Gly-Tyr-Leu-Arg-Asn (SEQ ID NO:l). 42
9. The DNA sequence according to claim 8 wherein the codon encoding the amino acid at position 101 is TTC.
10. A DNA having the formula of SEQ ID NO:2.
11. A recombinant DNA molecule characterized by the DNA sequence of any of claims 5 to 10, the sequence being operatively linked to an expression control sequence in the recombinant DNA molecule.
12. A host transformed with a recombinant DNA molecule of claim 11.
13. A method of producing an IFN-/3 mutein wherein the val (V) at position 101 in wild type IFN-jS, numbered in accordance with wild type IFN-/3, is substituted with Phe (F) , tyr (Y) , trp (W) , or His (H) , said mutein displaying an antiviral activity that is at least partially neutralized by antibodies to wild type IFN-S, the method comprising the steps of culturing a host according to claim 12 and collecting the IFN-/3 mutein.
14. The method according to Claim 13, wherein the IFN-/3 mutein is encoded by a DNA sequence comprised by the formula of Sequence Id No:2 and the host is an animal cell in culture.
15. A pharmaceutical composition comprising an antiviral, anticancer, antitumor or immunomodulation effective amount of the IFN-" mutein of any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
16. A method for treating viral infections, cancer or tumors, or for immunomodulation comprising administration of an antiviral, anticancer, antitumor or immunomodulation effective amount of an IFN-β mutein, the IFN-β mutein characterized in that the val (V) at position 101 in wild type IFN-/3, numbered in accordance with wild type IFN-p", is substituted with phe (F) , tyr (Y) , trp ( ) , or his (H) , said mutein displaying an antiviral activity that is at least partially neutralized by antibodies to wild type IFN-p*.
17. A method for treating viral infections, cancer or tumors, or for immunomodulation comprising administration of an antiviral, anticancer, antitumor or immunomodulation effective amount of an IFN-β mutein, the IFN-S mutein having an amino acid sequence identical to wild type IFN-3 except that the val (V) at position 101 in wild type IFN-p", numbered in accordance with wild type IFN-", is substituted with phe (F) , tyr (Y) , trp (W) or his (H) .
18. The method according to claim 16 or 17, wherein the val (V) is substituted with phe (F) .
19. The method according to claim 16 or 17, the mutein having the formula:
Met-Ser-Tyr-Asn-Leu-Leu-Gly-Phe-Leu-Gln-Arg-Ser-Ser- Asn-Phe-Gln-Cys-Gln-Lys-Leu-Leu-Trp-Gln-Leu-Asn-Gly- Arg-Leu-Glu-Tyr-Cys-Leu-Lys-Asp-Arg-Met-Asn-Phe-Asp- Ile-Pro-Glu-Glu-Ile-Lys-Gln-Leu-Gln-Gln-Phe-Gln-Lys- Glu-Asp-Ala-Ala-Leu-Thr-Ile-Tyr-Glu-Met-Leu-Gln-Asn- Ile-Phe-Ala-Ile-Phe-Arg-Gln-Asp-Ser-Ser-Ser-Thr-Gly- Trp-Asn-Glu-Thr-Ile-Val-Glu-Asn-Leu-Leu-Ala-Asn-Val- Tyr-His-Gln-Ile-Asn-His-Leu-Lys-Thr-Phe-Leu-Glu-Glu- 44
Lys-Leu-Glu-Lys-Glu-Asp-Phe-Thr-Arg-Gly-Lys-Leu-Met- Ser-Ser-Leu-His-Leu-Lys-Arg-Tyr-Tyr-Gly-Arg-Ile-Leu- His-Tyr-Leu-Lys-Ala-Lys-Glu-Tyr-Ser-His-Cys-Ala-Trp- Thr-Ile-Val-Arg-Val-Glu-Ile-Leu-Arg-Asn-Phe-Tyr-Phe- Ile-Asn-Arg-Leu-Thr-Gly-Tyr-Leu-Arg-Asn (SEQ ID NO: l) .
20. A method of gene therapy for treating viral infections, cancers, tumors, undesired cell proliferation, or for immunomodulation in a defined cell population or tissue in a patient comprising transforming the cell population or tissue with a DNA sequence encoding an IFN-p" mutein wherein the val (V) at position 101 in wild type IFN-" numbered in accordance with wild type IFN-p", is substituted with phe (F) , tyr (Y) , trp (W) , or his (H) , said mutein displaying an antiviral activity that is at least partially neutralized by antibodies to wild type IFN-p".
21. A method of gene therapy for treating viral infections, cancers, tumors, undesired cell proliferation, or for immunomodulation in a defined cell population or tissue in a patient comprising transforming the cell population or tissue with a DNA sequence encoding an IFN-p" mutein having an amino acid sequence identical to wild type IFN-p" except that the val (V) at position 101 in wild type IFN-/3, numbered in accordance with wild type IFN-p", is substituted with phe (F) , tyr (Y) , trp (W) or his (H) .
22. The method according to claim 20 or 21, wherein the val (V) is substituted with phe (F) .
23. The method according to claim 22, wherein the DNA sequence encodes an IFN-p" mutein of the formula:
HEET ARTICLE D 45
Met-Ser-Tyr-Asn-Leu-Leu-Gly-Phe-Leu-Gln-Arg-Ser-Ser- Asn-Phe-Gln-Cys-Gln-Lys-Leu-Leu-Trp-Gln-Leu-Asn-Gly- Arg-Leu-Glu-Tyr-Cys-Leu-Lys-Asp-Arg-Met-Asn-Phe-Asp- Ile-Pro-Glu-Glu-Ile-Lys-Gln-Leu-Gln-Gln-Phe-Gln-Lys- Glu-Asp-Ala-Ala-Leu-Thr-Ile-Tyr-Glu-Met-Leu-Gln-Asn- Ile-Phe-Ala-Ile-Phe-Arg-Gln-Asp-Ser-Ser-Ser-Thr-Gly- Trp-Asn-Glu-Thr-Ile-Val-Glu-Asn-Leu-Leu-Ala-Asn-Val- Tyr-His-Gln-Ile-Asn-His-Leu-Lys-Thr-Phe-Leu-Glu-Glu- Lys-Leu-Glu-Lys-Glu-Asp-Phe-Thr-Arg-Gly-Lys-Leu-Met- Ser-Ser-Leu-His-Leu-Lys-Arg-Tyr-Tyr-Gly-Arg-Ile-Leu- His-Tyr-Leu-Lys-Ala-Lys-Glu-Tyr-Ser-His-Cys-Ala-Trp- Thr-Ile-Val-Arg-Val-Glu-Ile-Leu-Arg-Asn-Phe-Tyr-Phe- Ile-Asn-Arg-Leu-Thr-Gly-Tyr-Leu-Arg-Asn (SEQ ID NO: l) .
24. The method according to claim 23 wherein the codon encoding the amino acid at position 101 is TTC.
25. A method of gene therapy for treating viral infections, cancers, tumors, undesired cell proliferation, or for immunomodulation in a defined cell population or tissue in a patient comprising transforming the cell population or tissue with a DNA sequence having the sequence of nucleotides 1-561 of SEQ ID NO:2 or nucleotides 64-561 of SEQ ID NO:2.
26. The method of any one of claims 20-25 wherein the viral infection is hepatitis.
27. The method according to ciaim 26 wherein the hepatitis is HBV.
28. The method of any one of claims 20-25 wherein the undesired cell proliferation is restenosis. 46
29. The method of any one of claims 20-25 wherein the cancer is glioma.
30. The method of any one of claims 20-25 wherein the cancer is melanoma.
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK95914045T DK0750668T3 (en) | 1994-03-15 | 1995-03-13 | New muteins of IFN-beta |
| JP52414595A JP3822903B2 (en) | 1994-03-15 | 1995-03-13 | Novel mutant protein of IFN-β |
| AU21202/95A AU695208B2 (en) | 1994-03-15 | 1995-03-13 | Novel muteins of IFN-beta |
| CA002185352A CA2185352C (en) | 1994-03-15 | 1995-03-13 | Novel muteins of ifn-.beta. |
| EP95914045A EP0750668B1 (en) | 1994-03-15 | 1995-03-13 | Novel muteins of ifn-beta |
| DE69535883T DE69535883D1 (en) | 1994-03-15 | 1995-03-13 | MUTINS OF IFN-BETA |
| NZ283217A NZ283217A (en) | 1994-03-15 | 1995-03-13 | Ifn-beta muteins and medicaments |
| MXPA/A/1996/004073A MXPA96004073A (en) | 1994-03-15 | 1996-09-13 | Novel muteins of ifn-'beta' |
| FI963630A FI120356B (en) | 1994-03-15 | 1996-09-13 | New muteins in IFN-beta |
| NO19963837A NO318989B1 (en) | 1994-03-15 | 1996-09-13 | New muteins of IFN-beta |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/213,448 US5545723A (en) | 1994-03-15 | 1994-03-15 | Muteins of IFN-β |
| US08/213,448 | 1994-03-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1995025170A1 WO1995025170A1 (en) | 1995-09-21 |
| WO1995025170B1 true WO1995025170B1 (en) | 1995-10-05 |
Family
ID=22795174
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1995/003206 WO1995025170A1 (en) | 1994-03-15 | 1995-03-13 | NOVEL MUTEINS OF IFN-$g(b) |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US5545723A (en) |
| EP (1) | EP0750668B1 (en) |
| JP (2) | JP3822903B2 (en) |
| AT (1) | ATE414152T1 (en) |
| AU (1) | AU695208B2 (en) |
| CA (1) | CA2185352C (en) |
| DE (1) | DE69535883D1 (en) |
| DK (1) | DK0750668T3 (en) |
| FI (1) | FI120356B (en) |
| NO (1) | NO318989B1 (en) |
| NZ (2) | NZ329970A (en) |
| WO (1) | WO1995025170A1 (en) |
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| US6514729B1 (en) | 1999-05-12 | 2003-02-04 | Xencor, Inc. | Recombinant interferon-beta muteins |
| US6531122B1 (en) * | 1999-08-27 | 2003-03-11 | Maxygen Aps | Interferon-β variants and conjugates |
| US7431921B2 (en) * | 2000-04-14 | 2008-10-07 | Maxygen Aps | Interferon beta-like molecules |
| US7144574B2 (en) * | 1999-08-27 | 2006-12-05 | Maxygen Aps | Interferon β variants and conjugates |
| JP2003516360A (en) * | 1999-12-09 | 2003-05-13 | カイロン コーポレイション | Method of administering cytokine to central nervous system and lymphatic system |
| US20020169290A1 (en) * | 2000-11-02 | 2002-11-14 | Claus Bornaes | New multimeric interferon beta polypeptides |
| WO2002074806A2 (en) | 2001-02-27 | 2002-09-26 | Maxygen Aps | New interferon beta-like molecules |
| WO2002072019A2 (en) * | 2001-03-13 | 2002-09-19 | Vical Incorporated | Interferon-beta polynucleotide therapy for autoimmune and inflammatory diseases |
| US6887462B2 (en) | 2001-04-09 | 2005-05-03 | Chiron Corporation | HSA-free formulations of interferon-beta |
| EP1435979A4 (en) * | 2001-09-18 | 2008-01-23 | Novartis Vaccines & Diagnostic | Methods for treating multiple sclerosis |
| EP2305311A3 (en) | 2001-10-10 | 2011-07-20 | BioGeneriX AG | Glycoconjugation of peptides |
| ES2411007T3 (en) | 2001-10-10 | 2013-07-04 | Novo Nordisk A/S | Remodeling and glycoconjugation of peptides |
| WO2004022593A2 (en) * | 2002-09-09 | 2004-03-18 | Nautilus Biotech | Rational evolution of cytokines for higher stability, the cytokines and encoding nucleic acid molecules |
| KR20050059195A (en) * | 2002-09-27 | 2005-06-17 | 바이오겐 아이덱 엠에이 인코포레이티드 | THERAPIES FOR CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY USING INTERFERON-β |
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| DOP2006000117A (en) * | 2005-05-19 | 2007-11-30 | Schering Ag | INTERFERON-BETA GENE THERAPY USING AN IMPROVED REGULATED EXPRESSION SYSTEM |
| US20070179113A1 (en) * | 2005-05-19 | 2007-08-02 | Schering Aktiengesellachaft | GM-CSF gene therapy for Crohn's disease using an improved regulated expression system |
| TW200724679A (en) * | 2005-05-19 | 2007-07-01 | Schering Ag | Treatment of disease using an improved regulated expression system |
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| DK1917276T3 (en) * | 2005-08-26 | 2018-05-07 | Ares Trading Sa | Process for Preparation of Glycosylated Interferon Beta |
| WO2007110231A2 (en) * | 2006-03-28 | 2007-10-04 | Nautilus Biotech, S.A. | MODIFIED INTERFERON-β (IFN-β) POLYPEPTIDES |
| WO2008125222A2 (en) * | 2007-04-11 | 2008-10-23 | Bayer Schering Pharma Aktiengesellschaft | New modulation molecules for an improved regulated expression system |
| WO2008134406A1 (en) * | 2007-04-25 | 2008-11-06 | The Board Of Trustees Of The Leland Stanford Junior University | Ischemia-induced neovascularization is enhanced by hcns-sc transplantation |
| WO2008137471A2 (en) * | 2007-05-02 | 2008-11-13 | Ambrx, Inc. | Modified interferon beta polypeptides and their uses |
| WO2009045553A1 (en) * | 2007-10-05 | 2009-04-09 | Barofold, Inc. | High pressure treatment of aggregated interferons |
| US20100158878A1 (en) * | 2008-12-23 | 2010-06-24 | Alexandra Capela | Target populations of oligodendrocyte precursor cells and methods of making and using same |
| WO2019073315A1 (en) | 2017-10-09 | 2019-04-18 | Mansour Poorebrahim | Interferon-beta analog peptide |
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1994
- 1994-03-15 US US08/213,448 patent/US5545723A/en not_active Expired - Lifetime
-
1995
- 1995-03-13 AT AT95914045T patent/ATE414152T1/en not_active IP Right Cessation
- 1995-03-13 DK DK95914045T patent/DK0750668T3/en active
- 1995-03-13 NZ NZ329970A patent/NZ329970A/en not_active IP Right Cessation
- 1995-03-13 NZ NZ283217A patent/NZ283217A/en not_active IP Right Cessation
- 1995-03-13 CA CA002185352A patent/CA2185352C/en not_active Expired - Lifetime
- 1995-03-13 AU AU21202/95A patent/AU695208B2/en not_active Expired
- 1995-03-13 DE DE69535883T patent/DE69535883D1/en not_active Expired - Lifetime
- 1995-03-13 EP EP95914045A patent/EP0750668B1/en not_active Expired - Lifetime
- 1995-03-13 JP JP52414595A patent/JP3822903B2/en not_active Expired - Lifetime
- 1995-03-13 WO PCT/US1995/003206 patent/WO1995025170A1/en active Application Filing
-
1996
- 1996-09-13 NO NO19963837A patent/NO318989B1/en not_active IP Right Cessation
- 1996-09-13 FI FI963630A patent/FI120356B/en not_active IP Right Cessation
-
1997
- 1997-08-18 US US08/912,768 patent/US6127332A/en not_active Expired - Lifetime
-
2006
- 2006-04-17 JP JP2006113870A patent/JP2006199711A/en not_active Withdrawn
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