Claims for Patent: 8,911,964

Summary for Patent: 8,911,964

Title:	Fed-batch method of making human anti-TNF-alpha antibody
Abstract:	The invention describes improved methods and compositions for producing a recombinant protein, e.g., an antibody, in mammalian cell culture. In addition, the invention provides improved cell culture media, including improved production media, feed solutions, and combination feeds, which may be used to improve protein productivity in mammalian cell culture.
Inventor(s):	Pla; Itzcoatl A. (Worcester, MA), Matuck; Joseph G. (Worcester, MA), Fann; John C. (Shrewsbury, MA), Schulz; Christof (Ayer, MA), Roy; Nichole A. (Worcester, MA), Bruton; David F. (Enfield, CT), McIntire; James (Castro Valley, CA), Chang; Yu-Hsiang David (Solana Beach, CA), Seewoester; Thomas (Simi Valley, CA)
Assignee:
Application Number:	14/226,579
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,911,964
Patent Claims:	1. A fed-batch production method of making a human anti-TNF.alpha. antibody which comprises (1) a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:1 and (2) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2, said method comprising culturing Chinese Hamster Ovary (CHO) cells comprising a nucleic acid encoding said anti-TNF.alpha. antibody in a cell culture production medium in large-scale, wherein the glucose concentration in said medium is monitored, the glucose concentration in said medium decreases to below 2 g/L, and glucose is added to said medium when the glucose concentration in said medium decreases to below 2 g/L, or the glucose concentration in said medium is monitored and glucose is added to said medium to maintain the glucose concentration in said medium at a concentration of at least 2 g/L but no greater than 7 g/L, such that said anti-TNF.alpha. antibody is produced at a titer of at least 2 g/L in said cell culture production medium. 2. The method of claim 1, wherein said anti-TNF.alpha. antibody is produced at a titer of at least 2.5 g/L in said cell culture production medium. 3. The method of claim 1, wherein said anti-TNF.alpha. antibody is produced at a titer of at least 4 g/L in said cell culture production medium. 4. The method of claim 1, wherein said culturing lasts 9-15 days. 5. The method of claim 1, wherein said cell culture production medium is a serum-free medium. 6. The method of claim 5, wherein said serum-free medium comprises at least one non-animal-based hydrolysate. 7. The method of claim 6, wherein said serum-free medium comprises a recombinant growth factor, an osmolarity regulator, a pH buffer agent, glutamine, methotrexate, and a cell protectant. 8. The method of claim 5, wherein said serum-free medium comprises galactose and manganese. 9. The method of claim 1, wherein said CHO cells are cultured at a temperature ranging from 32.degree. C. to 38.degree. C. 10. The method of claim 9, wherein said temperature is maintained as a constant temperature throughout said production method, said temperature being selected from a temperature range of 32.degree. C. to 38.degree. C. 11. A fed-batch production method of making adalimumab, comprising culturing Chinese Hamster Ovary (CHO) cells comprising a nucleic acid encoding adalimumab in a cell culture production medium in large-scale, wherein glucose concentration in said medium is monitored, the glucose concentration in said medium decreases to below 2 g/L, and glucose is added to said medium when the glucose concentration in said medium decreases to below 2 g/L, or the glucose concentration in said medium is monitored and glucose is added to said medium to maintain the glucose concentration in said medium at a concentration of at least 2 g/L but no greater than 7 g/L, such that adalimumab is produced at a titer of at least 2 g/L in said cell culture production medium. 12. The method of claim 11, wherein adalimumab is produced at a titer of at least 2.5 g/L in said cell culture production medium. 13. The method of claim 11, wherein adalimumab is produced at a titer of at least 4 g/L in said cell culture production medium. 14. The method of claim 13, wherein said culturing lasts 9-15 days. 15. The method of claim 13, wherein during said culturing, said CHO cells reach a cell density of at least 2.times.10.sup.6 cells/ml in said cell culture production medium. 16. The method of claim 13, wherein said culture production medium is a serum-free medium. 17. The method of claim 16, wherein said serum-free medium comprises at least one non-animal-based hydrolysate selected from a yeast-based hydrolysate, a soy-based hydrolysate, or a combination thereof. 18. The method of claim 17, wherein said serum-free medium comprises a recombinant growth factor, an osmolarity regulator, a pH buffer agent, glutamine, methotrexate, and a cell protectant. 19. The method of claim 16, wherein said serum-free medium comprises galactose and manganese. 20. The method of claim 13, wherein said CHO cells are cultured at a temperature ranging from 32.degree. C. to 38.degree. C. 21. The method of claim 20, wherein said temperature is maintained as a constant temperature throughout said production method, said temperature being selected from a temperature range of 32.degree. C. to 38.degree. C. 22. The method of claim 13, wherein said culturing lasts 9-15 days, and wherein said culture production medium is a serum-free medium and comprises at least one non-animal-based hydrolysate. 23. A fed-batch method of producing adalimumab, comprising expressing adalimumab in large-scale in Chinese Hamster Ovary (CHO) cells in a cell culture production medium, wherein said CHO cells comprise an expression vector encoding adalimumab, wherein glucose concentration in said medium is monitored, the glucose concentration in said medium drops to a level between 1 and 5 g/L, and then glucose is added to said medium to maintain the glucose concentration in said medium at no less than 1-5 g/L, and wherein adalimumab is produced at a titer of at least 2 g/L in said cell culture production medium. 24. The method of claim 23, wherein adalimumab is produced at a titer of at least 2.5 g/L in said cell culture production medium. 25. The method of claim 23, wherein adalimumab is produced at a titer of at least 4 g/L in said cell culture production medium. 26. The method of claim 23, wherein said culturing lasts 9-15 days. 27. The method of claim 26, wherein said culture production medium is a serum-free medium which comprises galactose and manganese. 28. The method of claim 27, wherein said serum-free medium comprises: (a) at least one non-animal-based hydrolysate selected from the group consisting of a yeast-based hydrolysate, a soy-based hydrolysate, and a combination thereof, (b) a recombinant growth factor, (c) an osmolarity regulator, (d) a pH buffer agent, (e) glutamine, (f) methotrexate, and (g) a cell protectant. 29. The method of claim 23, wherein said CHO cells are cultured at 32.degree. C. to 38.degree. C. 30. The method of claim 23, wherein said culturing lasts 9-15 days, and said CHO cells are cultured at 32.degree. C. to 38.degree. C., wherein said culture production medium is a serum-free medium, and wherein adalimumab is produced at a titer of at least 4 g/L in said cell culture production medium.

Details for Patent 8,911,964

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	12/31/2002		2026-09-13
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	02/21/2008		2026-09-13
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	04/24/2013		2026-09-13
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	09/23/2014		2026-09-13
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	11/23/2015		2026-09-13