Claims for Patent: 9,290,568

Summary for Patent: 9,290,568

Title:	Methods to control protein heterogeneity
Abstract:	The instant invention relates to the field of protein production and in particular to controlled protein heterogeneity compositions and processes for controlling the heterogeneity of proteins expressed in host cells.
Inventor(s):	Rives; Lisa M. (Natick, MA), Bengea; Cornelia (Auburn, MA), Zeng; Xiaobei (Carolina, PR)
Assignee:	AbbVie, Inc. (North Chicago, IL)
Application Number:	14/632,572
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,290,568
Patent Claims:	1. A process for producing a recombinantly-expressed immunoglobulin comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 2 and a light chain variable region comprising the sequence of SEQ ID NO: 7, comprising culturing a mammalian cell which recombinantly expresses the immunoglobulin during a production stage in a cell culture media comprising at least 0.4 g/L of asparagine, thereby producing the recombinantly-expressed immunoglobulin, wherein the level of agalactosyl fucosylated biantennary oligosaccharides (sum of NGA2F and NGA2F-GlcNac) present on the produced immunoglobulin is increased as compared to the level of agalactosyl fucosylated biantennary oligosaccharides (sum of NGA2F and NGA2F-GlcNac) of immunoglobulin produced in cell culture media which does not comprise said asparagine during the production stage; and/or wherein the level of galactose containing fucosylated biantennary oligossacharides (sum of NA1F and NA2F) present on the produced immunoglobulin is decreased as compared to the level of galactose containing fucosylated biantennary oligossacharides (sum of NA1F and NA2F) of immunoglobulin produced in cell culture media which does not comprise said asparagine during the production stage. 2. The process of claim 1, wherein the immunoglobulin is adalimumab. 3. The process of claim 1, wherein the cell which expresses the immunoglobulin is a CHO cell. 4. The process of claim 1, wherein the media comprises asparagine at a concentration of at least 0.6 g/L, 0.8 g/L, 1.0 g/L, 1.2 g/L, 1.4 g/L, 1.6 g/L, 1.8 g/L or 2 g/L, or between 0.4 g/L-1.4 g/L, or between 0.4 g/L-2 g/L. 5. The process of claim 1, wherein the media further comprises glutamine. 6. The process of claim 5, wherein the media comprises glutamine at a concentration of at least 0.2 g/L or between 0.1 g/L to 4 g/L. 7. The process of claim 1, wherein the level of agalactosyl fucosylated biantennary oligosaccharides (sum of NGA2F and NGA2F-GlcNAc) present on the produced immunoglobulin is 64%-88%, 70%-88% or 75%-85%; and/or wherein the level of fucosylated biantennary oligosaccharides (sum of NA1F and NA2F) present on the produced immunoglobulin is 1%-30%, 2%-25%, 5%-20%, 5%-15%, 10%-20% or 27%-31%. 8. The process of claim 1, wherein the process is a fed batch process. 9. The process of claim 1, wherein the media further comprises a yeast hydrolysate and/or a plant hydrolysate; optionally, wherein the yeast hydrolysate is selected from the group consisting of Bacto TC Yeastolate, HyPep Yeast Extract and UF Yeast Hydrolysate; and/or wherein the plant hydrolysate is selected from the group consisting of a soy hydrolysate, a wheat hydrolysate, a rice hydrolysate, a cotton seed hydrolysate, a pea hydrolysate, a corn hydrolysate, a potato hydrolysate, BBL Phytone Peptone, HyPep 1510, SE50 MAF-UF, UF Soy Hydrolysate, Wheat Peptone E1, HyPep 4601 and Proyield WGE80M Wheat. 10. The process of claim 9, wherein the yeast hydrolysate is present in the media at a concentration of between 2 g/L to 11 g/L and/or wherein the plant hydrolysate is present in the media at a concentration of between 2 g/L to 15 g/L. 11. A process for producing a recombinantly-expressed immunoglobulin comprising a heavy chain variable region comprising the sequence of SEQ ID NO:2 and a light chain variable region comprising the sequence of SEQ ID NO: 7, comprising culturing a mammalian cell which recombinantly expresses the immunoglobulin in a cell culture media comprising asparagine and at least 1 g/L of glutamine, thereby producing the recombinantly-expressed immunoglobulin, and assessing the oligosaccharide distribution of the produced immunoglobulin, wherein the level of agalactosyl fucosylated biantennary oligosaccharides (sum of NGA2F and NGA2F-GlcNac) present on the produced immunoglobulin is increased as compared to the level of agalactosyl fucosylated biantennary oligosaccharides (sum of NGA2F and NGA2F-GlcNac) of immunoglobulin produced in cell culture media which does not comprise said asparagine and glutamine; and/or wherein the level of galactose containing fucosylated biantennary oligossacharides (sum of NA1F and NA2F) present on the produced immunoglobulin is decreased as compared to the level of galactose containing fucosylated biantennary oligossacharides (sum of NA1F and NA2F) of immunoglobulin produced in cell culture media which does not comprise said asparagine and glutamine. 12. The process of claim 11, wherein the immunoglobulin is adalimumab. 13. The process of claim 11, wherein the cell which expresses the immunoglobulin is a CHO cell. 14. The process of claim 11, wherein the cell culture media comprises asparagine at a concentration of at least 0.2 g/L or between 0.1 g/L to 4 g/L. 15. The process of claim 11, wherein the cell culture media comprises at least 2 g/L of glutamine. 16. The process of claim 11, wherein the cell culture media is a chemically defined cell culture media. 17. The process of claim 11, wherein the level of agalactosyl fucosylated biantennary oligosaccharides (sum of NGA2F and NGA2F-GlcNAc) present on the produced immunoglobulin is 64%-88%, 70%-88% or 75%-85%; and/or wherein the level of fucosylated biantennary oligosaccharides (sum of NA1F and NA2F) present on the produced immunoglobulin is 1%-30%, 2%-25%, 5%-20%, 5%-15%, 10%-20% or 27%-31%. 18. The process of claim 11, wherein the process is a fed batch process. 19. The process of claim 11, wherein the culture media further comprises a yeast hydrolysate and/or a plant hydrolysate; optionally, wherein the yeast hydrolysate is selected from the group consisting of Bacto TC Yeastolate, HyPep Yeast Extract and UF Yeast Hydrolysate; and/or wherein the plant hydrolysate is selected from the group consisting of a soy hydrolysate, a wheat hydrolysate, a rice hydrolysate, a cotton seed hydrolysate, a pea hydrolysate, a corn hydrolysate, a potato hydrolysate, BBL Phytone Peptone, HyPep 1510, SE50 MAF-UF, UF Soy Hydrolysate, Wheat Peptone E1, HyPep 4601 and Proyield WGE80M Wheat. 20. The process of claim 19, wherein the yeast hydrolysate is present in the media at a concentration of between 2 g/L to 11 g/L and/or wherein the plant hydrolysate is present in the media at a concentration of between 2 g/L to 15 g/L. 21. A process for producing a recombinantly-expressed immunoglobulin comprising a heavy chain variable region comprising the sequence of SEQ ID NO:2 and a light chain variable region comprising the sequence of SEQ ID NO: 7, comprising culturing a mammalian cell which recombinantly expresses the immunoglobulin in a cell culture media comprising at least 0.6 g/L of asparagine, thereby producing the recombinantly-expressed immunoglobulin, wherein the level of agalactosyl fucosylated biantennary oligosaccharides (sum of NGA2F and NGA2F-GlcNac) present on the produced immunoglobulin is increased as compared to the level of agalactosyl fucosylated biantennary oligosaccharides (sum of NGA2F and NGA2F-GlcNac) of immunoglobulin produced in cell culture media which does not comprise said asparagine; and/or wherein the level of galactose containing fucosylated biantennary oligossacharides (sum of NA1F and NA2F) present on the produced immunoglobulin is decreased as compared to the level of galactose containing fucosylated biantennary oligossacharides (sum of NA1F and NA2F) of immunoglobulin produced in cell culture media which does not comprise said asparagine. 22. The process of claim 21, wherein the immunoglobulin is adalimumab. 23. The process of claim 21, wherein the cell which expresses the immunoglobulin is a CHO cell. 24. The process of claim 21, wherein the cell culture media comprises asparagine at a concentration of at least 0.8 g/L, 1.0 g/L, 1.2 g/L, 1.4 g/L, 1.6 g/L, 1.8 g/L or 2.0 g/L. 25. The process of claim 21, wherein the cell culture media further comprises glutamine. 26. The process of claim 21, wherein the cell culture media comprises glutamine at a concentration of at least 0.2 g/L or between 0.1 g/L to 4 g/L. 27. The process of claim 21, wherein the level of agalactosyl fucosylated biantennary oligosaccharides (sum of NGA2F and NGA2F-GlcNAc) present on the produced immunoglobulin is 64%-88%, 70%-88% or 75%-85%; and/or wherein the level of fucosylated biantennary oligosaccharides (sum of NA1F and NA2F) present on the produced immunoglobulin is 1%-30%, 2%-25%, 5%-20%, 5%-15%, 10%-20% or 27%-31%. 28. The process of claim 21, wherein the process is a fed batch process. 29. The process of claim 21, wherein the culture media further comprises a yeast hydrolysate and/or a plant hydrolysate; optionally, wherein the yeast hydrolysate is selected from the group consisting of Bacto TC Yeastolate, HyPep Yeast Extract and UF Yeast Hydrolysate; and/or wherein the plant hydrolysate is selected from the group consisting of a soy hydrolysate, a wheat hydrolysate, a rice hydrolysate, a cotton seed hydrolysate, a pea hydrolysate, a corn hydrolysate, a potato hydrolysate, BBL Phytone Peptone, HyPep 1510, SE50 MAF-UF, UF Soy Hydrolysate, Wheat Peptone E1, HyPep 4601 and Proyield WGE80M Wheat. 30. The process of claim 29, wherein the yeast hydrolysate is present in the media at a concentration of between 2 g/L to 11 g/L and/or wherein the plant hydrolysate is present in the media at a concentration of between 2 g/L to 15 g/L.

Details for Patent 9,290,568

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