CA2399832A1 - Enhancing the circulating half-life of antibody-based fusion proteins - Google Patents
Enhancing the circulating half-life of antibody-based fusion proteins Download PDFInfo
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- CA2399832A1 CA2399832A1 CA002399832A CA2399832A CA2399832A1 CA 2399832 A1 CA2399832 A1 CA 2399832A1 CA 002399832 A CA002399832 A CA 002399832A CA 2399832 A CA2399832 A CA 2399832A CA 2399832 A1 CA2399832 A1 CA 2399832A1
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- fusion protein
- antibody
- protein
- mutation
- polypeptide
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- 108020001507 fusion proteins Proteins 0.000 title claims abstract 59
- 102000037865 fusion proteins Human genes 0.000 title claims abstract 59
- 230000002708 enhancing effect Effects 0.000 title abstract 2
- 102000004169 proteins and genes Human genes 0.000 claims abstract 12
- 108090000623 proteins and genes Proteins 0.000 claims abstract 12
- 238000000034 method Methods 0.000 claims abstract 11
- 230000035772 mutation Effects 0.000 claims 19
- 108090000765 processed proteins & peptides Proteins 0.000 claims 18
- 229920001184 polypeptide Polymers 0.000 claims 16
- 102000004196 processed proteins & peptides Human genes 0.000 claims 16
- 150000001413 amino acids Chemical class 0.000 claims 12
- 210000004899 c-terminal region Anatomy 0.000 claims 6
- 125000001433 C-terminal amino-acid group Chemical group 0.000 claims 5
- 230000004075 alteration Effects 0.000 claims 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims 3
- 230000037430 deletion Effects 0.000 claims 3
- 238000012217 deletion Methods 0.000 claims 3
- 102000007644 Colony-Stimulating Factors Human genes 0.000 claims 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 claims 2
- 102000004127 Cytokines Human genes 0.000 claims 2
- 108090000695 Cytokines Proteins 0.000 claims 2
- 108060003951 Immunoglobulin Proteins 0.000 claims 2
- 102000015696 Interleukins Human genes 0.000 claims 2
- 108010063738 Interleukins Proteins 0.000 claims 2
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 claims 2
- 102000023732 binding proteins Human genes 0.000 claims 2
- 108091008324 binding proteins Proteins 0.000 claims 2
- 102000018358 immunoglobulin Human genes 0.000 claims 2
- 239000003446 ligand Substances 0.000 claims 2
- 210000004897 n-terminal region Anatomy 0.000 claims 2
- 102000005962 receptors Human genes 0.000 claims 2
- 108020003175 receptors Proteins 0.000 claims 2
- 210000002966 serum Anatomy 0.000 claims 2
- 125000006850 spacer group Chemical group 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 2
- 102000003390 tumor necrosis factor Human genes 0.000 claims 2
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 claims 1
- 229940045513 CTLA4 antagonist Drugs 0.000 claims 1
- 102000009109 Fc receptors Human genes 0.000 claims 1
- 108010087819 Fc receptors Proteins 0.000 claims 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 claims 1
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 claims 1
- 102000000588 Interleukin-2 Human genes 0.000 claims 1
- 108010002350 Interleukin-2 Proteins 0.000 claims 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 claims 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 claims 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 1
- 239000004472 Lysine Substances 0.000 claims 1
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 claims 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 claims 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 230000002209 hydrophobic effect Effects 0.000 claims 1
- 238000001727 in vivo Methods 0.000 claims 1
- 230000037431 insertion Effects 0.000 claims 1
- 238000003780 insertion Methods 0.000 claims 1
- 230000003993 interaction Effects 0.000 claims 1
- 102000002467 interleukin receptors Human genes 0.000 claims 1
- 108010093036 interleukin receptors Proteins 0.000 claims 1
- -1 lysine amino acid Chemical class 0.000 claims 1
- 231100000654 protein toxin Toxicity 0.000 claims 1
- 230000008707 rearrangement Effects 0.000 claims 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract 3
- 241000124008 Mammalia Species 0.000 abstract 2
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 2
- 206010027476 Metastases Diseases 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 230000009401 metastasis Effects 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
-
- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
-
- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- 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
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/525—Tumour necrosis factor [TNF]
-
- 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
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/55—IL-2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Abstract
Disclosed are compositions and methods for enhancing the circulating half-life of antibody-based fusion proteins. Disclosed methods and compositions rely on altering the amino acid sequence of the junction region between the antibody moiety and the fused protein moiety in an antibody-based fusion protein. An antibody-based fusion protein with an altered amino acid sequence in the junction region has a greater circulating half-life when administered to a mammal. Disclosed methods and compositions are particularly useful for reducing tumor size and metastasis in a mammal.
Claims (47)
1. An antibody-based fusion protein comprising an immunoglobulin (Ig) chain linked to a non-Ig protein via a junction point, wherein said antibody-based fusion protein comprises an amino acid alteration within 10 amino acids from said junction point, in said Ig chain or said non-Ig protein, and wherein said antibody-based fusion protein has a longer circulating half life in vivo than a corresponding antibody-based fusion protein without said amino acid alteration.
2. The fusion protein of claim 1 wherein the amino acid alteration increases the hydrophobicity of said antibody-based fusion protein.
3. The fusion protein of claim 1 or 2 wherein said Ig chain is N-terminal to said non-Ig protein.
4. The fusion protein of claim 1, 2 or 3 wherein said alteration changes the C-terminal amino acid of the Ig chain.
5. The fusion protein of claim 1, wherein said non-Ig protein is a secreted protein.
6. The fusion protein of claim 5, wherein said non-Ig protein is a mature form of said secreted protein.
7. The fusion protein of claim 1, wherein the Ig chain comprises part of an Ig heavy chain.
8. The antibody-based fusion protein of claim 7 wherein said Ig chain comprises at least the CH2 domain of an IgG2 or an IgG4 constant region.
9. The antibody-based fusion protein of claim 7, wherein said Ig chain comprises at least a portion of an IgG1 constant region having a mutation or a deletion at one or more amino acids selected from the group consisting of Leu234, Leu235, Gly236, Gly237, Asn297, and Pro378.
10. The antibody-based fusion protein of claim 7, wherein said Ig chain comprises at least a portion of an IgG3 constant region having a mutation or a deletion at one or more amino acids selected from the group consisting of Leu281, Leu282, Gly283, Gly284, Asn344, and Pro378.
11. The antibody-based fusion protein of claim 7, wherein said Ig chain has binding affinity for an immunoglobulin protection receptor.
12. The antibody-based fusion protein of claim 7, wherein said Ig chain has substantially reduced binding affinity for a Fc receptor selected from the group consisting of Fc.gamma.RI, Fc.gamma.RII and Fc.gamma.RIII.
13. The antibody-based fusion protein of claim 7, wherein said non-Ig protein is selected from the group consisting of a cytokine, a ligand-binding protein, and a protein toxin.
14. The antibody-based fusion protein of claim 13, wherein said cytokine is selected from the group consisting of a tumor necrosis factor, an interleukin, and a lymphokine.
15. The antibody-based fusion protein of claim 14, wherein said tumor necrosis factor is tumor necrosis factor alpha.
16. The antibody-based fusion protein of claim 14, wherein said interleukin is interleukin-2.
17. The antibody-based fusion protein of claim 14, wherein said lymphokine is a lymphotoxin or a colony stimulating factor.
18. The antibody-based fusion protein of claim 11, wherein said colony stimulating factor is a granulocyte-macrophage colony stimulating factor.
19. The antibody-based fusion protein of claim 13, wherein said ligand-binding protein is selected from the group consisting of CD4, CTLA-4, TNF receptor, and an interleukin receptor.
20. A method for increasing the circulating half life of an antibody-based fusion protein having an Ig chain linked to a non-Ig protein via a junction point, the method comprising the step of substituting, deleting, inserting, or otherwise altering an amino acid at or near said junction point.
21. The method of claim 20, wherein said fusion protein comprises a portion of a heavy chain.
22. The method of claim 21, wherein said fusion protein comprises at least the CH2 domain of an IgG2 or an IgG4 constant region.
23. The method of claim 20, 21, or 22, wherein said fusion protein comprises a heavy chain moiety having a mutation that affects interaction with an Fc protection receptor.
24. The fusion protein of claim 1 comprising a linker between said Ig chain and said non-Ig protein.
25. The fusion protein of claim 4, 5, 6, or 7, wherein said alteration is a substitution of one or more amino acids.
26. An antibody-based fusion protein comprising a) a first polypeptide comprising an Ig chain, and, b) a second polypeptide comprising a non-Ig protein, wherein said first polypeptide is joined to said second polypeptide to produce a junction region having at least one mutation, and wherein said fusion protein has a longer circulating half life than a fusion protein having a junction region without said mutation.
27. The fusion protein of claim 26, wherein said mutation is in the C-terminal portion of said first polypeptide.
28. The fusion protein of claim 26, wherein said mutation is in the N-terminal portion of said second polypeptide.
29. The fusion protein of claim 26 comprising a first mutation in the C-terminal portion of said first polypeptide and a second mutation in the N-terminal portion of said second polypeptide.
30. The fusion protein of claim 27 or 29 wherein said C-terminal portion comprises between 1 and 100 C-terminal amino acids of said first polypeptide.
31. The fusion protein of claim 30 wherein said C-terminal portion comprises between 1 and C-terminal amino acids of said first polypeptide.
32. The fusion protein of claim 28 or 29 wherein said N-terminal portion comprises between 1 and 100 N-terminal amino acids of said second polypeptide.
33. The fusion protein of claim 32 wherein said N-terminal portion comprises between l and 10 N-terminal amino acids of said second polypeptide.
34. The fusion protein of claim 26 wherein said Ig is IgG1.
35. The fusion protein of claim 26 wherein said mutation is selected from the group consisting of point mutations, deletions, insertions, and rearrangements.
36. The fusion protein of claim 34 wherein the C-terminal residue of said first polypeptide is mutated to be an amino acid with a non-ionizable side chain.
37. The fusion protein of claim 36 wherein said C-terminal residue is a non-lysine amino acid.
38. The fusion protein of claim 26 wherein said junction region consists of the C-terminal region of said first polypeptide and the N-terminal region of said second polypeptide, and wherein said mutation is present in one of said C-terminal and N-terminal regions.
39. The fusion protein of claim 26 wherein said junction region comprises a spacer or linker peptide.
40. The fusion protein of claim 39 wherein said mutation consists of the presence of a spacer or linker peptide between said first and said second polypeptides.
41. The fusion protein of claim 26 wherein said mutation is in a region that does not interact with FcR or FcRp.
42. A method for identifying a mutation that increases the circulating half life of an antibody-based fusion protein having an Ig moiety and a non-Ig moiety comprising the steps of a) introducing a mutation in the region spanning the junction between the Ig moiety and the non-Ig moiety;
b) comparing the serum half lives of the antibody-based fusion protein with and without a mutation; and, c) selecting a mutation that increases the serum half life of the antibody-based fusion protein.
b) comparing the serum half lives of the antibody-based fusion protein with and without a mutation; and, c) selecting a mutation that increases the serum half life of the antibody-based fusion protein.
43. An antibody-based fusion protein comprising a mutation identified according to the method of claim 42.
44. A method for treating a disease comprising the step of administering to a patient an antibody-based fusion protein of claim 26.
45. The fusion protein of claim 1, 26, or 36, having a hydrophobic or non-polar amino acid introduced via addition or substitution at or near said junction.
46. The fusion protein of claim 45, wherein said amino acid is selected from the group consisting of Leu, Ala, Trp, and Gly.
47. The fusion protein of claim 48, wherein said amino acid is Ala.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18176800P | 2000-02-11 | 2000-02-11 | |
US60/181,768 | 2000-02-11 | ||
PCT/US2001/004455 WO2001058957A2 (en) | 2000-02-11 | 2001-02-09 | Enhancing the circulating half-life of antibody-based fusion proteins |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2399832A1 true CA2399832A1 (en) | 2001-08-16 |
CA2399832C CA2399832C (en) | 2011-09-20 |
Family
ID=22665708
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2399832A Expired - Lifetime CA2399832C (en) | 2000-02-11 | 2001-02-09 | Enhancing the circulating half-life of antibody-based fusion proteins |
Country Status (16)
Country | Link |
---|---|
US (3) | US7091321B2 (en) |
EP (1) | EP1252192B1 (en) |
JP (2) | JP5179689B2 (en) |
CN (1) | CN1406249B (en) |
AT (1) | ATE336514T1 (en) |
AU (1) | AU4314801A (en) |
CA (1) | CA2399832C (en) |
CY (1) | CY1105725T1 (en) |
DE (1) | DE60122286T2 (en) |
DK (1) | DK1252192T3 (en) |
ES (1) | ES2269366T3 (en) |
HU (1) | HUP0204475A2 (en) |
MX (1) | MXPA02007733A (en) |
NO (1) | NO20023774L (en) |
PT (1) | PT1252192E (en) |
WO (1) | WO2001058957A2 (en) |
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-
2001
- 2001-02-09 ES ES01916083T patent/ES2269366T3/en not_active Expired - Lifetime
- 2001-02-09 JP JP2001558103A patent/JP5179689B2/en not_active Expired - Fee Related
- 2001-02-09 MX MXPA02007733A patent/MXPA02007733A/en active IP Right Grant
- 2001-02-09 DE DE60122286T patent/DE60122286T2/en not_active Expired - Lifetime
- 2001-02-09 US US09/780,668 patent/US7091321B2/en not_active Expired - Lifetime
- 2001-02-09 HU HU0204475A patent/HUP0204475A2/en unknown
- 2001-02-09 DK DK01916083T patent/DK1252192T3/en active
- 2001-02-09 AT AT01916083T patent/ATE336514T1/en active
- 2001-02-09 PT PT01916083T patent/PT1252192E/en unknown
- 2001-02-09 WO PCT/US2001/004455 patent/WO2001058957A2/en active IP Right Grant
- 2001-02-09 CN CN018058639A patent/CN1406249B/en not_active Expired - Lifetime
- 2001-02-09 CA CA2399832A patent/CA2399832C/en not_active Expired - Lifetime
- 2001-02-09 EP EP01916083A patent/EP1252192B1/en not_active Expired - Lifetime
- 2001-02-09 AU AU4314801A patent/AU4314801A/en active Pending
-
2002
- 2002-08-09 NO NO20023774A patent/NO20023774L/en not_active Application Discontinuation
-
2005
- 2005-11-07 US US11/268,191 patent/US7507406B2/en not_active Expired - Lifetime
-
2006
- 2006-10-24 CY CY20061101528T patent/CY1105725T1/en unknown
-
2009
- 2009-01-27 US US12/360,682 patent/US7790415B2/en not_active Expired - Fee Related
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2012
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Also Published As
Publication number | Publication date |
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ES2269366T3 (en) | 2007-04-01 |
MXPA02007733A (en) | 2004-09-10 |
CY1105725T1 (en) | 2010-12-22 |
CA2399832C (en) | 2011-09-20 |
NO20023774D0 (en) | 2002-08-09 |
JP2012176969A (en) | 2012-09-13 |
US20090264627A1 (en) | 2009-10-22 |
US7091321B2 (en) | 2006-08-15 |
ATE336514T1 (en) | 2006-09-15 |
US7790415B2 (en) | 2010-09-07 |
NO20023774L (en) | 2002-08-09 |
WO2001058957A3 (en) | 2002-05-02 |
JP5572665B2 (en) | 2014-08-13 |
WO2001058957A2 (en) | 2001-08-16 |
DE60122286D1 (en) | 2006-09-28 |
EP1252192B1 (en) | 2006-08-16 |
US20060034836A1 (en) | 2006-02-16 |
US7507406B2 (en) | 2009-03-24 |
CN1406249B (en) | 2010-06-16 |
DK1252192T3 (en) | 2006-11-20 |
US20020147311A1 (en) | 2002-10-10 |
DE60122286T2 (en) | 2007-08-02 |
EP1252192A2 (en) | 2002-10-30 |
HUP0204475A2 (en) | 2003-04-28 |
AU4314801A (en) | 2001-08-20 |
JP2003522200A (en) | 2003-07-22 |
PT1252192E (en) | 2007-01-31 |
JP5179689B2 (en) | 2013-04-10 |
CN1406249A (en) | 2003-03-26 |
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