Claims for Patent: 9,284,371

Summary for Patent: 9,284,371

Title:	Methods of producing adalimumab
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 D. (Solana Beach, CA), Seewoester; Thomas (Simi Valley, CA)
Assignee:	AbbVie Inc. (North Chicago, IL)
Application Number:	14/920,452
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,284,371
Patent Claims:	1. A method of producing adalimumab, comprising culturing in large-scale mammalian cells that express adalimumab in a cell culture production medium, wherein the pH of the cell culture production medium is adjusted from a first pH to a second pH during said culturing, the second pH being lower than the first pH, and the cell culture production medium is not removed but is supplemented with glucose or one or more other nutrients at least once during adalimumab production; and wherein adalimumab produced by the mammalian cells is purified from the cell culture production medium using a process including Protein A affinity purification. 2. The method of claim 1, wherein the cell culture production medium is supplemented more than once during adalimumab production, optionally wherein the culture medium is supplemented on a schedule comprising supplementation that is continuous, daily, every other day, every two days, and combinations thereof. 3. The method of claim 1, wherein the cell culture production medium is supplemented with glucose when the glucose concentration in the cell culture production medium is determined after monitoring of glucose levels to be below 2 g/L. 4. The method of claim 3, wherein the cell culture production medium is supplemented with glucose to a glucose concentration of at least 2 g/L but less than or equal to 7 g/L. 5. The method of claim 1, wherein during adalimumab production the mammalian cells are initially cultured at a first temperature and then cultured at a reduced temperature, wherein the first temperature is 35.degree. C., 37.degree. C., or 38.degree. C., and the second temperature is 32.degree. C. or 33.degree. C. 6. The method of claim 5, wherein the cell culture production medium comprises a soy-based hydrolysate and a yeast-based hydrolysate. 7. The method of claim 6, wherein the mammalian cells are Chinese Hamster Ovary (CHO) cells and the cell culture production medium is supplemented with a 25x PFCHO solution and a 33.times. solution of a combination of the soy-based hydrolysate and yeast-based hydrolysate yeastolate. 8. The method of claim 1, wherein the osmolarity of the cell culture production medium is 440 mOsm or less, the cell culture production medium is maintained at about 30% dissolved oxygen, and the mammalian cells are CHO cells. 9. The method of claim 1, wherein after said culturing, the adalimumab yield in the cell culture production medium is at least 2 g/L. 10. The method of claim 1, wherein the first pH is 8 or less, and the second pH is from 6.5 to 7. 11. The method of claim 10, wherein during adalimumab production, if the glucose concentration in the cell culture production medium decreases to below 2 g/L then glucose is added to the cell culture production medium, or glucose is added to the cell culture production medium such that the glucose concentration in the cell culture production medium is at least 2 g/L but less than or equal to 7 g/L. 12. The method of claim 11, wherein after said culturing, adalimumab yield in the cell culture production medium is at least 1.5 g/L. 13. The method of claim 11, wherein after said culturing, adalimumab yield in the cell culture production medium is at least 2 g/L. 14. The method of claim 11, wherein the osmolarity of the cell culture production medium is 440 mOsm or less, the cell culture production medium is maintained at about 30% dissolved oxygen, and the mammalian cells are CHO cells. 15. The method of claim 10, wherein during adalimumab production, the mammalian cells are initially cultured at a first temperature and then cultured at a reduced temperature. 16. The method of claim 15, wherein the first temperature is 35.degree. C., 37.degree. C., or 38.degree. C., and the second temperature is 32.degree. C. or 33.degree. C. 17. The method of claim 10, wherein the cell culture production medium comprises a non-animal-based hydrolysate. 18. The method of claim 10, wherein the cell culture production medium comprises a soy-based hydrolysate and a yeast-based hydrolysate. 19. The method of claim 10, wherein the mammalian cells are CHO cells and the cell culture production medium is supplemented with a 25.times.PFCHO solution and a 33.times. solution of a combination of the soy-based hydrolysate and yeast-based hydrolysate, yeastolate. 20. The method of claim 10, wherein the first pH is adjusted to the second pH via a pH ramp. 21. A method of producing adalimumab, comprising culturing in large-scale mammalian cells that express adalimumab in a cell culture production medium, wherein during adalimumab production, the mammalian cells are initially cultured at a first temperature and then cultured at a reduced temperature, and the cell culture production medium is not removed but is supplemented with a nutrient at least once; and the adalimumab produced by the mammalian cells is purified from the cell culture production medium using a process including Protein A affinity purification. 22. The method of claim 21, wherein during adalimumab production, if the glucose concentration in the cell culture production medium decreases to below 2 g/L then glucose is added to the cell culture production medium, or glucose is added to the cell culture production medium such that the glucose concentration in the cell culture production medium is at least 2 g/L but less than or equal to 7 g/L. 23. The method of claim 21, wherein during said culturing, the mammalian cells are initially cultured at a first pH and then cultured at a reduced pH, wherein the first pH is 8 or less and the reduced pH is 6.5 to 7, and the first pH is adjusted to the reduced pH via a pH ramp. 24. The method of claim 23, wherein the mammalian cells are CHO cells, and the cell culture production medium comprises a soy-based hydrolysate and a yeast-based hydrolysate. 25. The method of claim 23, wherein the mammalian cells are CHO cells and the cell culture production medium is supplemented with a 25.times.PFCHO solution and a 33.times. solution of a combination of the soy-based hydrolysate and yeast-based hydrolysate, yeastolate. 26. The method of claim 21, wherein the osmolarity of the cell culture production medium is 440 mOsm or less, the cell culture production medium is maintained at about 30% dissolved oxygen, and the mammalian cells are CHO cells. 27. The method of claim 21, wherein after said culturing, the adalimumab yield in the cell culture production medium is at least 2 g/L. 28. The method of claim 23, wherein after said culturing, adalimumab yield in the cell culture production medium is at least 1.5 g/L. 29. A method of producing adalimumab, comprising culturing in large-scale mammalian cells that express adalimumab in a cell culture production medium, wherein a) the mammalian cells are initially cultured at a first pH and then cultured at a reduced pH, wherein the first pH is 8 or less and the reduced pH is 6.5 to 7; b) during adalimumab production the mammalian cells are initially cultured at a first temperature and then cultured at a reduced temperature; c) during adalimumab production, the culture medium is not removed but is supplemented with glucose; d) during adalimumab production, the culture medium is supplemented with a nutrient other than glucose at least once; and e) the adalimumab produced by the mammalian cells is purified from the cell culture production medium using a process including Protein A affinity purification. 30. The culturing method of claim 29, wherein the mammalian cells are CHO cells, and the cell culture production medium comprises a soy-based hydrolysate and a yeast-based hydrolysate.

Details for Patent 9,284,371

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	December 31, 2002	9,284,371	2035-10-22
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	February 21, 2008	9,284,371	2035-10-22
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	April 24, 2013	9,284,371	2035-10-22

International Patent Family for US Patent 9,284,371

Country	Patent Number	Estimated Expiration
World Intellectual Property Organization (WIPO)	2008033517
United States of America	9234032
United States of America	9090867