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Last Updated: March 29, 2024

Claims for Patent: 8,945,897


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Summary for Patent: 8,945,897
Title:Materials and methods for conjugating a water soluble fatty acid derivative to a protein
Abstract: The invention relates to materials and methods of conjugating a water soluble fatty acid derivative to a therapeutic protein comprising contacting the therapeutic protein with an activated water soluble fatty acid derivative under conditions that allow conjugation.
Inventor(s): Siekmann; Juergen (Vienna, AT), Sheinecker; Richard (Vienna, AT), Rottensteiner; Hanspeter (Vienna, AT), Turecek; Peter (Klosterneuburg, AT)
Assignee: Baxter International Inc. (Deerfield, IL) Baxter Healthcare SA (Glattpark (Opfikon), CH)
Application Number:13/329,002
Patent Claims:1. A water soluble fatty acid derivative comprising a fatty acid or fatty acid ester attached to a water soluble linker, said fatty acid derivative stably attached to a therapeutic protein, wherein the water soluble linker comprises a water soluble polymer, at least one first functional group attached to the therapeutic protein, wherein the first functional group is an aminooxy group, and a second functional group attached to the fatty acid or fatty acid ester, wherein the second functional group is an aminooxy group.

2. The fatty acid derivative according to claim 1 that binds human serum albumin (HSA) in vitro or in vivo, has increased half-life relative to a native therapeutic protein, and wherein the fatty acid is a saturated fatty acid or unsaturated fatty acid.

3. The fatty acid derivative of claim 2 wherein the fatty acid is a branched chain fatty acid.

4. The fatty acid derivative according to claim 1 wherein the fatty acid comprises a chain length selected from the group consisting of C10, C12, C14, C16, C18, C20, C22, and C24.

5. The fatty acid derivative according to claim 1 wherein the fatty acid is attached to the water soluble linker at a group on the fatty acid selected from the group consisting of: terminal carboxyl group and .omega.-group, wherein the .omega.-group is selected from the group consisting of: hydroxyl, amino, thio, and carboxyl.

6. The fatty acid derivative according to claim 1 wherein the fatty acid is 16-hydroxyhexadecanoic acid.

7. The fatty acid derivative according claim 1 wherein the fatty acid ester is selected from the group consisting of: methyl ester and ethyl ester.

8. The fatty acid derivative of claim 7 wherein the fatty acid ester is 16-hydroxyhexadecanoic acid methyl ester.

9. The fatty acid derivative according to claim 1 wherein the water soluble polymer is selected from the group consisting of: polyethylene glycol (PEG), branched PEG, polysialic acid (PSA), carbohydrate, polysaccharides, pullulane, chitosan, hyaluronic acid, chondroitin sulfate, dermatan sulfate, dextran, carboxymethyl-dextran, polyalkylene oxide (PAO), polyalkylene glycol (PAG), polypropylene glycol (PPG), polyoxazoline, polyacryloylmorpholine, polyvinyl alcohol (PVA), polycarboxylate, polyvinylpyrrolidone, polyphosphazene, polyoxazoline, polyethylene-co-maleic acid anhydride, polystyrene-co-maleic acid anhydride, poly(1-hydroxymethylethylene hydroxymethylformal) (PHF), and 2-methacryloyloxy-2' -ethyltrimethylammoniumphosphate (MPC).

10. The fatty acid derivative according to claim 9 wherein the water soluble polymer is PEG and comprises a chain length selected from the group consisting of O3, O5, O7, O9, O11, O13 and O15.

11. The fatty acid derivative according to claim 10 wherein the water soluble linker is selected from the group consisting of: a) 3-oxapentane-1,5-dioxyamine of the formula: ##STR00040## b) 3,6,9-triaoxaundecane-1,11-dioxyamine of the formula: ##STR00041## c) 3,6,9,12,15-penatoxaheptadecane-1,17-dioxyamine of the formula: ##STR00042## and d) 3,6,9,12,15,18,21-heptaoxatricosane-1,23-dioxyamine of the formula: ##STR00043##

12. The fatty acid derivative according to claim 1 wherein the fatty acid derivative is stably attached to the therapeutic protein by an oxime linkage, wherein the oxime linkage is formed between an oxime group on the water soluble linker and an aldehyde group of an oxidized carbohydrate on the therapeutic protein.

13. The fatty acid derivative according to claim 1 wherein the fatty acid derivative is selected from the group consisting of: a) 16-(2-(2-(2-(2-aminooxyethoxy)-ethoxy)-ethoxy)-ethoxyimino)-hexadecanoic acid sodium salt of the formula: ##STR00044## and b) 16-(2-(2-(2-(2-aminooxyethoxy)-ethoxy)-ethoxy)-ethoxyamino)-hexadecanoic acid methyl ester, ##STR00045##

14. The fatty acid derivative according claim 1 wherein the therapeutic protein is selected from the group consisting of: Factor IX (FIX), Factor VIII (FVIII), Factor VIIa (FVIIa), von Willebrand Factor (VWF), Factor FV (FV), Factor X (FX), Factor XI (FXI), Factor XII (FXII), thrombin (FII), protein C, protein S, tPA, PAI-1, tissue factor (TF),ADAMTS 13 protease, IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-11, colony stimulating factor-1 (CSF-1), M-CSF, SCF, GM-CSF, granulocyte colony stimulating factor (G-CSF), EPO, interferon-alpha (IFN-alpha), consensus interferon, IFN-beta, IFN-gamma, IFN-omega, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-31, IL-32 alpha, IL-33, thrombopoietin (TPO), Ang-1, Ang-2, Ang-4, Ang-Y, angiopoietin-like polypeptide 1 (ANGPTL1), angiopoietin-like polypeptide 2 (ANGPTL2), angiopoietin-like polypeptide 3 (ANGPTL3), angiopoietin-like polypeptide 4 (ANGPTL4), angiopoietin-like polypeptide 5 (ANGPTL5), angiopoietin-like polypeptide 6 (ANGPTL6), angiopoietin-like polypeptide 7 (ANGPTL7), vitronectin, vascular endothelial growth factor (VEGF), angiogenin, activin A, activin B, activin C, bone morphogenic protein-1, bone morphogenic protein-2, bone morphogenic protein-3, bone morphogenic protein-4, bone morphogenic protein-5, bone morphogenic protein-6, bone morphogenic protein-7, bone morphogenic protein-8, bone morphogenic protein-9, bone morphogenic protein-10, bone morphogenic protein-11bone morphogenic protein-12, bone morphogenic protein-13, bone morphogenic protein-14, bone morphogenic protein-15, bone morphogenic protein receptor IA, bone morphogenic protein receptor IB, bone morphogenic protein receptor II, brain derived neurotrophic factor, cardiotrophin-1, ciliary neutrophic factor, ciliary neutrophic factor receptor, cripto, cryptic, cytokine-induced neutrophil chemotactic factor 1, cytokine-induced neutrophil, chemotactic factor 2.alpha., cytokine-induced neutrophil chemotactic factor 2.beta., .beta. endothelial cell growth factor, endothelin 1, epidermal growth factor, epigen, epiregulin, epithelial-derived neutrophil attractant, fibroblast growth factor 4, fibroblast growth factor 5, fibroblast growth factor 6, fibroblast growth factor 7, fibroblast growth factor 8, fibroblast growth factor 8b, fibroblast growth factor 8c, fibroblast growth factor 9, fibroblast growth factor 10, fibroblast growth factor 11, fibroblast growth factor 12, fibroblast growth factor 13, fibroblast growth factor 16, fibroblast growth factor 17, fibroblast growth factor 19, fibroblast growth factor 20, fibroblast growth factor 21, fibroblast growth factor acidic, fibroblast growth factor basic, glial cell line-derived neutrophic factor receptor .alpha.1, glial cell line-derived neutrophic factor receptor .alpha.2, growth related protein, growth related protein .alpha., growth related protein .beta., growth related protein .gamma., heparin binding epidermal growth factor, hepatocyte growth factor, hepatocyte growth factor receptor, hepatoma-derived growth factor, insulin-like growth factor I, insulin-like growth factor receptor, insulin-like growth factor II, insulin-like growth factor binding protein, keratinocyte growth factor, leukemia inhibitory factor, leukemia inhibitory factor receptor .alpha., nerve growth factor nerve growth factor receptor, neuropoietin,neurotrophin-3, neurotrophin-4, oncostatin M (OSM), placenta growth factor, placenta growth factor 2, platelet-derived endothelial cell growth factor, platelet derived growth factor, platelet derived growth factor A chain, platelet derived growth factor AA, platelet derived growth factor AB, platelet derived growth factor B chain, platelet derived growth factor BB, platelet derived growth factor receptor .alpha., platelet derived growth factor receptor .beta., pre-B cell growth stimulating factor, stem cell factor (SCF), stem cell factor receptor, TNF, TNF0, TNF1, TNF2, transforming growth factor .alpha., transforming growth factor .beta., transforming growth factor .beta.1, transforming growth factor .beta.1.2, transforming growth factor .beta.1, transforming growth factor .beta.3, transforming growth factor .beta.5, latent transforming growth factor .beta.1, transforming growth factor .beta. binding protein I, transforming growth factor .beta. binding protein II, transforming growth factor .beta. binding protein III, thymic stromal lymphopoietin (TSLP), tumor necrosis factor receptor type I, tumor necrosis factor receptor type II, urokinase-type plasminogen activator receptor, phospholipase-activating protein (PUP), insulin, lectin ricin, prolactin, chorionic gonadotropin, follicle-stimulating hormone, thyroid-stimulating hormone, tissue plasminogen activator, IgG, IgE, IgM, IgA, and IgD, .alpha.-galactosidase, .beta.-galactosidase, DNAse, fetuin, leutinizing hormone, estrogen, insulin, albumin, lipoproteins, fetoprotein, transferrin, thrombopoietin, urokinase, integrin, thrombin, leptin, adalimumab, denosumab, etanercept, and a protein in Table 1.

15. The fatty acid derivative of claim 14 wherein the therapeutic protein is FVIIa.

16. The fatty acid derivative of claim 14 wherein the therapeutic protein is FVIII.

17. The fatty acid derivative of claim 14 wherein the therapeutic protein is FIX.

18. A method of preparing a fatty acid derivative according to claim 1 comprising: a) oxidizing an .omega.-hydroxy group on a fatty acid to generate an aldehyde group on the fatty acid; and b) coupling a water soluble linker comprising an active aminooxy group to the aldehyde group to form a stable oxime linkage; wherein said fatty acid derivative is water soluble; wherein the .omega.-hydroxy group is oxidized by an oxidation reagent selected from the group consisting of: Dess Martin periodinane reagent, Tempo reagent, oxalyl chloride/DMSO, tetrapropylammoniumperruthenate (TPAP) and crome VI reagents (Collins reagent, pyridinium chloro chromate (PCC) and pyridinium dichromate); wherein the fatty acid is a saturated fatty acid or unsaturated fatty acid.

19. The method of claim 18 wherein the fatty acid is a branched chain fatty acid.

20. The method according to claim 18 wherein the fatty acid comprises a chain length selected from the group consisting of C10, C12, C14, C16, C18, C20, C22, and C24.

21. The method according to claim 20 wherein the fatty acid is 16-hydroxyhexadecanoic acid.

22. The method according to claim 18 wherein the water soluble linker comprises a water soluble polymer and at least one aminooxy group, wherein the water soluble polymer is selected from the group consisting of: polyethylene glycol (PEG), branched PEG, polysialic acid (PSA), carbohydrate, polysaccharides, pullulane, chitosan, hyaluronic acid, chondroitin sulfate, dermatan sulfate, dextran, carboxymethyl-dextran, polyalkylene oxide (PAO), polyalkylene glycol (PAG), polypropylene glycol (PPG), polyoxazoline, polyacryloylmorpholine, polyvinyl alcohol (PVA), polycarboxylate, polyvinylpyrrolidone, polyphosphazene, polyoxazoline, polyethylene-co-maleic acid anhydride, polystyrene-co-maleic acid anhydride, poly(1-hydroxymethylethylene hydroxymethylformal) (PHF), and 2-methacryloyloxy-2'-ethyltrimethylammoniumphosphate (MPC).

23. The method according to claim 22 wherein the water soluble polymer is PEG and comprises a chain length selected from the group consisting of O3, O5, O7, O9, O11, O13 and O15.

24. The method of claim 23 wherein the water soluble linker is selected from the group consisting of: a) 3-oxapentane-1,5-dioxyamine of the formula: ##STR00046## b) 3,6,9-triaoxaundecane-1,11-dioxyamine of the formula: ##STR00047## c) 3,6,9,12,15-penatoxaheptadecane-1,17-dioxyamine of the formula: ##STR00048## and d) 3,6,9,12,15,18,21-heptaoxatricosane-1,23-dioxyamine of the formula: ##STR00049##

25. A method of preparing a fatty acid derivative according to claim 1 comprising: a) esterifying a carboxyl group on a fatty acid to generate an ester on the fatty acid; b) activating an .omega.-hydroxy group on a fatty acid to generate a mesyl group on the fatty acid of step a); and c) coupling a water soluble linker comprising an active aminooxy group by substituting the mesyl group of step b) thereby forming a stable oxyimine-methylene bond; wherein said fatty acid derivative is water soluble; wherein the carboxyl group is esterified by an esterifying agent selected from the group consisting of: acetyl chloride, methanol in the presence of acid, ethanol in the presence of acid, diazomethane, and methyliodide; wherein the .omega.-hydroxy group is activated by an activating agent selected from the group consisting of: mesyl chloride, tosyl chloride and nosyl chloride; and wherein the fatty acid is a saturated fatty acid or unsaturated fatty acid.

26. The method of claim 25 wherein the fatty acid is a branched chain fatty acid.

27. The method according to claim 25 wherein the fatty acid comprises a chain length selected from the group consisting of C10, C12, C14, C16, C18, C20, C22, and C24.

28. The method according to claim 27 wherein the fatty acid is 16-hydroxyhexadecanoic acid.

29. The method according to claim 25 wherein the water soluble linker comprises a water soluble polymer selected from the group consisting of: polyethylene glycol (PEG), branched PEG, polysialic acid (PSA), carbohydrate, polysaccharides, pullulane, chitosan, hyaluronic acid, chondroitin sulfate, dermatan sulfate, dextran, carboxymethyl-dextran, polyalkylene oxide (PAO), polyalkylene glycol (PAG), polypropylene glycol (PPG), polyoxazoline, polyacryloylmorpholine, polyvinyl alcohol (PVA), polycarboxylate, polyvinylpyrrolidone, polyphosphazene, polyoxazoline, polyethylene-co-maleic acid anhydride, polystyrene-co-maleic acid anhydride, poly(1-hydroxymethylethylene hydroxymethylformal) (PHF), and 2-methacryloyloxy-2'-ethyltrimethylammoniumphosphate (MPC).

30. The method according to claim 29 wherein the water soluble polymer comprises is PEG and a chain length selected from the group consisting of O3, O5, O7, O9, O11, O13 and O15.

31. The method of claim 30 wherein the water soluble linker is selected from the group consisting of: a) 3-oxapentane-1,5-dioxyamine of the formula: ##STR00050## b) 3,6,9-triaoxaundecane-1,11-dioxyamine of the formula: ##STR00051## c) 3,6,9,12,15-penatoxaheptadecane-1,17-dioxyamine of the formula: ##STR00052## and d) 3,6,9,12,15,18,21-heptaoxatricosane-1,23-dioxyamine of the formula: ##STR00053##

32. A method of preparing a conjugated therapeutic protein comprising contacting an oxidized carbohydrate moiety on the therapeutic protein with a fatty acid derivative according to claim 1 under conditions that allow conjugation; said carbohydrate moiety oxidized by incubation with a buffer comprising an oxidizing agent selected from the group consisting of sodium periodate (NaIO.sub.4), lead tetraacetate (Pb(OAc).sub.4) and potassium perruthenate (KRuO.sub.4); wherein an oxime linkage is formed between the oxidized carbohydrate moiety and an active aminooxy group on the fatty acid derivative; and wherein said oxime linkage formation is catalyzed by a nucleophilic catalyst selected from the group consisting of aniline, o-amino benzoic acid, m-amino benzoic acid, p-amino benzoic acid, sulfanilic acid, o-aminobenzamide, o-toluidine, m-toluidine, p-toluidine, o-anisidine, m-anisidine, and p-anisidine.

33. The method according to claim 32 wherein the therapeutic protein is selected from the group consisting of: Factor IX (FIX), Factor VIII (FVIII), Factor VIIa (FVIIa), von Willebrand Factor (VWF), Factor FV (FV), Factor X (FX), Factor XI (FXI), Factor XII (FXII), thrombin (FIT), protein C, protein S, tPA, PAI-1, tissue factor (TF),ADAMTS 13 protease, IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-11, colony stimulating factor-1 (CSF-1), M-CSF, SCF, GM-CSF, granulocyte colony stimulating factor (G-CSF), EPO, interferon-alpha (IFN-alpha), consensus interferon, IFN-beta, IFN-gamma, IFN-omega, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-31, IL-32 alpha, IL-33, thrombopoietin (TPO), Ang-1, Ang-2, Ang-4, Ang-Y, angiopoietin-like polypeptide 1 (ANGPTL1), angiopoietin-like polypeptide 2 (ANGPTL2), angiopoietin-like polypeptide 3 (ANGPTL3), angiopoietin-like polypeptide 4 (ANGPTL4), angiopoietin-like polypeptide 5 (ANGPTL5), angiopoietin-like polypeptide 6 (ANGPTL6), angiopoietin-like polypeptide 7 (ANGPTL7), vitronectin, vascular endothelial growth factor (VEGF), angiogenin, activin A, activin B, activin C, bone morphogenic protein-1, bone morphogenic protein-2, bone morphogenic protein-3, bone morphogenic protein-4, bone morphogenic protein-5, bone morphogenic protein-6, bone morphogenic protein-7, bone morphogenic protein-8, bone morphogenic protein-9, bone morphogenic protein-10, bone morphogenic protein-11, bone morphogenic protein-12, bone morphogenic protein-13, bone morphogenic protein-14, bone morphogenic protein-15, bone morphogenic protein receptor IA, bone morphogenic protein receptor IB, bone morphogenic protein receptor II, brain derived neurotrophic factor, cardiotrophin-1, ciliary neutrophic factor, ciliary neutrophic factor receptor, cripto, cryptic, cytokine-induced neutrophil chemotactic factor 1, cytokine-induced neutrophil, chemotactic factor 2.alpha., cytokine-induced neutrophil chemotactic factor 2.beta., .beta. endothelial cell growth factor, endothelin 1, epidermal growth factor, epigen, epiregulin, epithelial-derived neutrophil attractant, fibroblast growth factor 4, fibroblast growth factor 5, fibroblast growth factor 6, fibroblast growth factor 7, fibroblast growth factor 8, fibroblast growth factor 8b, fibroblast growth factor 8c, fibroblast growth factor 9, fibroblast growth factor 10, fibroblast growth factor 11, fibroblast growth factor 12, fibroblast growth factor 13, fibroblast growth factor 16, fibroblast growth factor 17, fibroblast growth factor 19, fibroblast growth factor 20, fibroblast growth factor 21, fibroblast growth factor acidic, fibroblast growth factor basic, glial cell line-derived neutrophic factor receptor .alpha.1, glial cell line-derived neutrophic factor receptor .alpha.2, growth related protein, growth related protein .alpha., growth related protein .alpha., growth related protein .gamma., heparin binding epidermal growth factor, hepatocyte growth factor, hepatocyte growth factor receptor, hepatoma-derived growth factor, insulin-like growth factor I, insulin-like growth factor receptor, insulin-like growth factor II, insulin-like growth factor binding protein, keratinocyte growth factor, leukemia inhibitory factor, leukemia inhibitory factor receptor .alpha., nerve growth factor nerve growth factor receptor, neuropoietin,neurotrophin-3, neurotrophin-4, oncostatin M (OSM), placenta growth factor, placenta growth factor 2, platelet-derived endothelial cell growth factor, platelet derived growth factor, platelet derived growth factor A chain, platelet derived growth factor AA, platelet derived growth factor AB, platelet derived growth factor B chain, platelet derived growth factor BB, platelet derived growth factor receptor .alpha., platelet derived growth factor receptor .beta., pre-B cell growth stimulating factor, stem cell factor (SCF), stem cell factor receptor, TNF, TNF0, TNF1, TNF2, transforming growth factor .alpha., transforming growth factor .beta., transforming growth factor .beta.1, transforming growth factor .beta.1.2, transforming growth factor .beta.2, transforming growth factor .beta.3, transforming growth factor .beta.5, latent transforming growth factor .beta.1, transforming growth factor .beta.binding protein I, transforming growth factor .beta. binding protein II, transforming growth factor .beta. binding protein III, thymic stromal lymphopoietin (TSLP), tumor necrosis factor receptor type I, tumor necrosis factor receptor type II, urokinase-type plasminogen activator receptor, phospholipase-activating protein (PUP), insulin, lectin ricin, prolactin, chorionic gonadotropin, follicle-stimulating hormone, thyroid-stimulating hormone, tissue plasminogen activator, IgG, IgE, IgM, IgA, and IgD, .alpha.-galactosidase, .beta.-galactosidase, DNAse, fetuin, leutinizing hormone, estrogen, insulin, albumin, lipoproteins, fetoprotein, transferrin, thrombopoietin, urokinase, integrin, thrombin, leptin, adalimumab, denosumab, etanercept, and a protein in Table 1.

34. The method according to claim 33 wherein the therapeutic protein is FVIIa.

35. The method according to claim 33 wherein the therapeutic protein is FVIII.

36. The method according to claim 33 wherein the therapeutic protein is FIX.

37. The method according to claim 18 wherein the oxidation reagent is Dess Martin periodinane.

Details for Patent 8,945,897

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 01/15/1974 ⤷  Try a Trial 2039-02-26
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 12/27/1984 ⤷  Try a Trial 2039-02-26
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 02/15/1985 ⤷  Try a Trial 2039-02-26
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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