Claims for Patent: 7,811,560

Summary for Patent: 7,811,560

Title:	Compositions and methods for treating collagen-mediated diseases
Abstract:	A drug product comprising a combination of highly purified collagenase I and collagenase II from Colostridium histolyticum is disclosed. The drug product includes collagenase I and collagenase II in a ratio of about 1 to 1, with a purity of greater than at least 95%. The invention further disclosed improved fermentation and purification processes for preparing the said drug product.
Inventor(s):	Sabatino; Gregory L. (Chester Springs, PA), Del Tito, Jr.; Benjamin J. (Doylestown, PA), Bassett; Phillip J. (Newcastle-under-Lyme, GB), Tharia; Hazel A. (Nr Crewe, GB), Hitchcock; Antony G. (Crewe, GB)
Assignee:	Auxilium US Holdings, LLC (Wilmington, DE)
Application Number:	11/699,302
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,811,560
Patent Claims:	1. A drug product consisting of isolated and purified collagenase I and collagenase II having the sequence of Clostridium histolyticum collagenase I and collagenase II, respectively, wherein the collagenase I and collagenase II have a mass ratio of about 1 to 1 and the drug product is at least 97% by area pure as determined by reverse phase high performance liquid chromatography. 2. The drug product of claim 1, wherein the drug product contains less than about 2% by area aggregated protein as determined by reverse phase high performance liquid chromatography. 3. The drug product of claim 1, wherein the drug product contains less than about 1% by area of clostripain as determined by reverse phase high performance liquid chromatography. 4. The drug product of claim 1, wherein the drug product contains less than about 1% by area of gelatinase as determined by anion exchange chromatography. 5. The drug product of claim 1, wherein the drug product contains less than about 1 ug/mg (w/w) of leupeptin. 6. The drug product of claim 1, wherein the drug product has a bioburden less than 1 cfu/ml, and wherein the drug product is sterile. 7. The drug product of claim 6, wherein the drug product contains less than 10 EU/ml of endotoxin. 8. The drug product of claim 6, wherein the drug product contains less than 5 EU/mg of endotoxin. 9. A drug product consisting of isolated and purified collagenase I and collagenase II having the sequence of Clostridium histolyticum collagenase I and collagenase II, respectively, wherein the collagenase I and collagenase II have a mass ratio of about 1 to 1 and the drug product is at least 97% by area pure as determined by reverse phase high performance liquid chromatography, wherein the preparation of the drug product comprises the steps of: a) fermenting Clostridium histolyticum; b) harvesting a crude fermentation comprising collagenase I and collagenase II; c) purifying collagenase I and collagenase II from the crude harvest via filtration and column chromatography comprising the steps of: i) filtering the crude harvest through an anion exchange filter; ii) adding ammonium sulphate; iii) subjecting the harvest through a HIC column; iv) adding leupeptin to the filtrate; v) removing the ammonium sulfate; vi) filtering the mixture of step (v); and vii) separating collagenase I and collagenase II using ion-exchange; d) combining the collagenase I and collagenase II purified from step (c) at a ratio of about 1 to 1. 10. The drug product of claim 9, wherein the drug product is at least 98% by area pure as determined by reverse phase high performance liquid chromatography. 11. The drug product of claim 9, wherein preparation of the drug product further comprises the step of conducting cell bank preparations in the presence of phytone peptone or vegetable peptone. 12. The drug product of claim 9, wherein the fermentation step comprises the steps of: a) inoculating the medium in a first stage with Clostridium histolyticum and agitating the mixture; b) incubating the mixture from step (a) to obtain an aliquot; c) inoculating the medium in a second stage with aliquots resulting from step (b) and agitating the mixture; d) incubating mixtures from step (c) to obtain an aliquot; e) inoculating the medium in a third stage with aliquots resulting from step (d) and agitating; f) incubating mixtures from step (e) to obtain an aliquot; g) inoculating the medium in a fourth stage with an aliquot resulting from step (f) and agitating; and h) incubating mixtures from step (g). 13. The drug product of claim 9, wherein the drug product is stored at a temperature of about -70.degree. C. 14. A process for producing a drug product consisting of isolated and purified collagenase I and collagenase II having the sequence of Clostridium histolyticum collagenase I and collagenase II, respectively, wherein the collagenase I and collagenase II have a mass ratio of about 1 to 1 and the drug product is at least 97% by area pure as determined by reverse phase high performance liquid chromatography, comprising the steps of: a) fermenting Clostridium histolyticum; b) harvesting a crude fermentation comprising collagenase I and collagenase II; c) purifying collagenase I and collagenase II from the crude harvest via filtration and column chromatography comprising the steps of: i) filtering the crude harvest through an anion exchange filter; ii) adding ammonium sulphate; iii) subjecting the harvest through a HIC column; iv) adding leupeptin to the filtrate; v) removing the ammonium sulfate; vi) filtering the mixture of step (v); and vii) separating collagenase I and collagenase II using ion-exchange; d) combining the collagenase I and collagenase II purified from step (c) at a ratio of about 1 to 1. 15. The process of claim 14, wherein the drug product is at least 98% by area pure as determined by reverse phase high performance liquid chromatography. 16. The process of claim 14, further comprising the step of conducting cell bank preparations the presence of phytone peptone or vegetable peptone. 17. The process of claim 14, wherein the fermentation step comprises the steps of a) inoculating the medium in a first stage with Clostridium histolyticum and agitating the mixture; b) incubating the mixture from step (a) to obtain an aliquot; c) inoculating the medium in a second stage with aliquots resulting from step (b) and agitating the mixture; d) incubating mixtures from step (c) to obtain an aliquot; e) inoculating the medium in a third stage with aliquots resulting from step (d) and agitating; f) incubating mixtures from step (e) to obtain an aliquot; g) inoculating the medium in a fourth stage with an aliquot resulting from step (f) and agitating; and h) incubating mixtures from step (g). 18. The process of claim 14, wherein the drug product is stored at a temperature of about -70.degree. C. 19. A pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a drug product consisting of isolated and purified collagenase I and collagenase II having the sequence of Clostridium histolyticum collagenase I and collagenase II, respectively, wherein the collagenase I and collagenase II have a mass ratio of about 1 to 1 and the drug product is at least 97% by area pure as determined by reverse phase high performance liquid chromatography. 20. The pharmaceutical formulation of claim 19, wherein the drug product is a sterile lyophilized powder and is stored at a temperature of about 5.degree. C. 21. The pharmaceutical formulation of claim 19, wherein the formulation is a lyophilized injectable composition formulated with Sucrose, Tris and with a pH level of about 8.0. 22. The pharmaceutical formulation of claim 21, wherein the formulation is a lyophilized injectable composition formulation comprising about 0.9 mg of the said drug product, about 18.5 mg of sucrose and about 1.1 mg of Tris, and wherein the targeting vial fill volume is about 0.9 mL. 23. The pharmaceutical formulation of claim 21, wherein the formulation is a lyophilized injectable composition formulation comprising about 0.58 mg of the said drug product, about 12.0 mg of sucrose and about 0.7 mg of Tris. 24. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a drug product consisting of isolated and purified collagenase I and collagenase II having the sequence of Clostridium histolyticum collagenase I and collagenase II, respectively, wherein the collagenase I and collagenase II have a mass ratio of about 1 to 1 and the drug product is at least 97% by area pure as determined by reverse phase high performance liquid chromatography, wherein the preparation of the drug product comprises the steps of: a) fermenting Clostridium histolyticum; b) harvesting a crude fermentation comprising collagenase I and collagenase II; c) purifying collagenase I and collagenase II from the crude harvest via filtration and column chromatography comprising the steps of: i) filtering the crude harvest through an anion exchange filter; ii) adding ammonium sulphate; iii) subjecting the harvest through a HIC column; iv) adding leupeptin to the filtrate; v) removing the ammonium sulfate; vi) filtering the mixture of step (v); and vii) separating collagenase I and collagenase II using ion-exchange; d) combining the collagenase I and collagenase II purified from step (c) at a ratio of about 1 to 1. 25. The pharmaceutical formulation of claim 24, wherein the drug product is a sterile lyophilized powder. 26. The pharmaceutical formulation of claim 25, wherein the formulation is a lyophilized injectable composition formulated with sucrose, Tris and with a pH level of about 8.0. 27. The pharmaceutical formulation of claim 26, wherein the formulation is a lyophilized injectable composition formulation comprising about 0.9 mg of the said drug product, about 18.5 mg of sucrose and about 1.1 mg of Tris, and wherein the targeting vial fill volume is about 0.9 mL. 28. The pharmaceutical formulation of claim 26, wherein the drug product is a lyophilized injectable composition formulation comprising about 0.58 mg of the said drug product, about 12.0 mg of sucrose and about 0.7 mg of Tris. 29. A drug product consisting of collagenase I and collagenase II, wherein the collagenase I and collagenase II are isolated and purified from Clostridium histolyticum and wherein the collagenase I and collagenase II have a mass ratio of about 1 to 1 and the drug product is at least 97% by area pure as determined by reverse phase high performance liquid chromatography.

Details for Patent 7,811,560

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2026-01-30
Auxilium Pharmaceuticals, Inc.	XIAFLEX	collagenase clostridium histolyticum	For Injection	125338	02/02/2010		2026-01-30

International Patent Family for US Patent 7,811,560

Country	Patent Number	Estimated Expiration
Australia	2007211313
Australia	2012200863
Brazil	PI0708017
Canada	2637262
China	101400788
China	105999244