Claims for Patent: 9,150,645

Summary for Patent: 9,150,645

Title:	Cell culture methods to reduce acidic species
Abstract:	The instant invention relates to the field of protein production and purification, and in particular to compositions and processes for controlling the amount of acidic species expressed by host cells, as well as to compositions and processes for controlling the amount of acidic species present in purified preparations.
Inventor(s):	Subramanian; Kartik (Northborough, MA), Zeng; Xiaobei (Carolina, PR), Dong; Diane D. (Shrewsbury, MA), Lim; Wen Chung (Worcester, MA), Gifford; Kathreen A. (Marlborough, MA), Chumsae; Christopher (North Andover, MA)
Assignee:	AbbVie, Inc. (North Chicago, IL)
Application Number:	13/830,583
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,150,645
Patent Claims:	1. A method for producing a composition comprising adalimumab, the method comprising culturing a mammalian cell producing adalimumab in cell culture media comprising 2 g/L to 11 g/L of each of one or more basic amino acids selected from the group consisting of arginine, lysine, ornithine and histidine, and combinations thereof, to produce a composition comprising adalimumab, wherein the composition comprises less than 20% total acidic species of adalimumab, wherein the acidic species of adalimumab do not include process-related impurities selected from the group consisting of host cells and lysed host cells and wherein the acidic species of adalimumab correspond to the peaks that elute earlier than the main peak in a WCX-10 HPLC chromatogram of adalimumab, and wherein the WCX-10 HPLC chromatogram is generated using a first mobile phase of 10 mM Sodium Phosphate dibasic (pH 7.5) and a second mobile phase of 10 mM Sodium Phosphate dibasic, 500 mM Sodium Chloride (pH 5.5), and wherein the WCX-10 HPLC chromatogram is generated using detection at 280 nm. 2. The method of claim 1, wherein the cell culture media further comprises calcium. 3. The method of claim 2, wherein the calcium concentration in the cell culture media is between 0.005 and 5 mM. 4. The method of claim 2, wherein the calcium concentration in the cell culture media is 0.7 to 1.4 mM. 5. The method of claim 1 or 2, wherein the cell culture media further comprises niacinamide. 6. The method of claim 5, wherein the one or more basic amino acids are arginine and lysine. 7. The method of claim 1 or 2, wherein the pH of the cell culture media is 6.7 or lower. 8. The method of claim 1, wherein the one or more basic amino acids comprises arginine. 9. The method of claim 1, wherein the one or more basic amino acids comprises lysine. 10. The method of claim 1, wherein the one or more basic amino acids comprises histidine. 11. The method of claim 1, wherein the one or more basic amino acids comprises ornithine. 12. The method of claim 1, wherein the one or more basic amino acids are arginine, lysine, histidine, and ornithine. 13. The method of claim 1, wherein the one or more basic amino acids are arginine and lysine. 14. The method of claim 1, wherein the cell culture media comprises 3 g/L to 11 g/L of each of the one or more basic amino acids. 15. The method of claim 1, wherein the cell culture media comprises 2 g/L to 9 g/L of each of the one or more basic amino acids. 16. The method of claim 1, wherein the cell culture media comprises 3 g/L to 8 g/L of each of the one or more basic amino acids. 17. The method of claim 1, wherein the cell culture media comprises 4 g/L to 7 g/L of each of the one or more basic amino acids. 18. The method of claim 1 or 13, wherein the cell culture media comprises 2 g/L of arginine and 4 g/L of lysine. 19. The method of claim 1 or 13, wherein the cell culture media comprises 2 g/L of arginine and 6 g/L of lysine. 20. The method of claim 1 or 13, wherein the cell culture media comprises 4 g/L of arginine and 2 g/L of lysine. 21. The method of claim 1 or 13, wherein the cell culture media comprises 4 g/L of arginine and 6 g/L of lysine. 22. The method of claim 1 or 10, wherein the cell culture media comprises 3 g/L of histidine. 23. The method of claim 1 or 10, wherein the cell culture media comprises 2 g/L of histidine. 24. The method of claim 1 or 10, wherein the cell culture media comprises 4 g/L of histidine. 25. The method of claim 1 or 10, wherein the cell culture media comprises 6 g/L of histidine. 26. The method of claim 1 or 10, wherein the cell culture media comprises 8 g/L of histidine. 27. The method of claim 1 or 10, wherein the cell culture media comprises 10 g/L of histidine. 28. The method of claim 1 or 11, wherein the cell culture media comprises 2 g/L of ornithine. 29. The method of claim 1 or 11, wherein the cell culture media comprises 4 g/L of ornithine. 30. The method of claim 1 or 11, wherein the cell culture media comprises 6 g/L of ornithine. 31. The method of claim 1 or 11, wherein the cell culture media comprises 8 g/L of ornithine. 32. The method of claim 1 or 11, wherein the cell culture media comprises 10 g/L of ornithine. 33. The method of claim 1 or 11, wherein the cell culture media comprises 12 g/L of ornithine. 34. The method of claim 1, wherein said mammalian cell is a CHO cell. 35. The method of claim 1, wherein said mammalian cell is an NS0 cell. 36. The method of claim 1, wherein said culture media is production media. 37. The method of claim 1, wherein said culture media is growth media. 38. The method of claim 1, wherein said culture media is both production media and growth media. 39. The method of claim 1, wherein said mammalian cell is cultured to a maximum viable cell density (VCD) of at least 18.times.10.sup.6 cells/ml. 40. The method of claim 1, wherein said mammalian cell is cultured to a maximum viable cell density (VCD) of at least 7.times.10.sup.6 cells/ml. 41. A method for producing a composition comprising adalimumab, the method comprising culturing a mammalian cell producing adalimumab in cell culture media comprising 2 g/L to 11 g/L of each of one or more basic amino acids selected from the group consisting of arginine, lysine, ornithine and histidine, and combinations thereof, wherein the one or more amino acids is present in the cell culture media at a concentration sufficient to produce a composition that has at least 10% fewer acidic species of adalimumab than a composition comprising adalimumab produced by culturing the cell in a cell culture media comprising less than 2 g/L of each of the one or more basic amino acids, wherein the acidic species of adalimumab do not include process-related impurities selected from the group consisting of host cells and lysed host cells and wherein the acidic species of adalimumab correspond to the peaks that elute earlier than the main peak in a WCX-10 HPLC chromatogram of adalimumab, and wherein the WCX-10 HPLC chromatogram is generated using a first mobile phase of 10 mM Sodium Phosphate dibasic (pH 7.5) and a second mobile phase of 10 mM Sodium Phosphate dibasic, 500 mM Sodium Chloride (pH 5.5), and wherein the WCX-10 HPLC chromatogram is generated using detection at 280 nm. 42. The method of claim 41, wherein the cell culture media comprises 3 g/L to 11 g/L of each of the one or more basic amino acids. 43. The method of any one of claim 1 or 41, further comprising isolating adalimumab. 44. The method of claim 41, wherein said mammalian cell is a CHO cell. 45. The method of claim 41, wherein said mammalian cell is an NS0 cell. 46. The method of claim 41, wherein said culture media is production media. 47. The method of claim 41, wherein said culture media is growth media. 48. The method of claim 41, wherein said culture media is both production media and growth media. 49. The method of claim 41, wherein said mammalian cell is cultured to a maximum viable cell density (VCD) of at least 18.times.10.sup.6 cells/ml. 50. The method of claim 41, wherein said mammalian cell is cultured to a maximum viable cell density (VCD) of at least 7.times.10.sup.6 cells/ml. 51. The method of any one of claims 1, 8-13, 14-17, 34-42 and 44-50, wherein the composition comprises less than 15% total acidic species of adalimumab. 52. The method of any one of claims 1, 8-13, 14-17, 34-42 and 44-50, wherein the composition comprises less than 12% total acidic species of adalimumab. 53. The method of any one of claims 1, 8-13, 14-17, 34-42 and 44-50, wherein the composition comprises less than 10% total acidic species of adalimumab. 54. The method of any one of claims 1, 8-13, 14-17, 34-42 and 44-50, wherein the composition comprises less than 9% total acidic species of adalimumab. 55. The method of any one of claims 1, 8-13, 14-17, 34-42 and 44-50, wherein the composition comprises 9% to 15% total acidic species of adalimumab.

Details for Patent 9,150,645

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	12/31/2002		2032-04-20
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	02/21/2008		2032-04-20
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	04/24/2013		2032-04-20
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	09/23/2014		2032-04-20
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	11/23/2015		2032-04-20
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	03/09/2016		2032-04-20
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	10/17/2016		2032-04-20