Claims for Patent: 10,316,282

Summary for Patent: 10,316,282

Title:	Method for producing a product (e.g. polypeptide) in a continuous cell culture fermentation process
Abstract:	A method for improving productivity in microbial fermentations and mammalian cell culture bioreactors.
Inventor(s):	Laustsen; Mads (Gentofte, DK)
Assignee:	CMC BIOLOGICS A/S (Soborg, DK)
Application Number:	14/778,222
Patent Claims:	1. A method for producing a product selected from a biopolymer expressed by a cell, an intracellular or extracellular product produced by a cell or microorganism, a periplasmatic product produced by a cell or microorganism, a cell or a microorganism in a bioreactor in a chemostat fermentation process, wherein said bioreactor comprises: i) a first outlet having a separation device allowing impurities with a size below the size of the product, and medium to be removed while retaining the product in the bioreactor; (ii) a second outlet having a product harvest module allowing the product, cells, impurities and medium to be removed; and (iii) an inlet for adding a medium; wherein the method comprises the following steps: (a) fermenting the cell expressing the biopolymer, the cell or microorganism producing the intracellular product, the cell, or microorganism producing the periplasmatic product, the cell, or the microorganism in the bioreactor in a suitable medium under suitable conditions, wherein during the fermentation impurities and medium are removed via the separation device, the product, cells, impurities and medium are removed via the product harvest module and new medium is added to replenish nutrients consumed by the cells or microorganisms and to equilibrate the medium removed during removal of impurities and harvesting the product; and (b) the product is isolated from the harvested medium; and wherein the cell density in the bioreactor during the fermentation reaches at least 5 million cells per ml medium. 2. The method of claim 1, wherein the product is selected from a biopolymer. 3. The method of claim 1, wherein the product is selected from an intracellular product or from a periplasmatic product. 4. The method of claim 1, wherein the product is selected 5 from a microorganism or from a cell. 5. The method of claim 1, wherein the cell density in the bioreactor during the fermentation reaches at least 10 million cells per ml medium. 6. The method of claim 1, wherein impurities are removed via the separation device by one flow rate through the separation device and the product is harvested through the product harvest module by a second flow rate through the product harvest module, wherein the first flow rate refers to the flow rate of medium and impurities through the separation device and the second flow rate refers to the flow rate of product, cells, impurities and medium through the product harvest module, wherein the ratio between the first flow rate and the second flow rate is from 1:1 to 9:1. 7. The method of claim 1, wherein the separation device is selected from an impurity filter unit or a gravitational separation unit or a centrifugal separation unit. 8. The method of claim 1, wherein the bioreactor has a volume of at least 50 L. 9. The method of claim 1, wherein the separation device is a membrane filter having a nominal molecular weight cut-off (NMWC) pore sizes of at least 1000 NMWC. 10. The method of claim 1, wherein the separation device is a membrane filter having a nominal molecular weight cut-off (NMWC) pore size of a maximum of 80% of the MW of the product. 11. The method of claim 2, wherein the polypeptide is an antibody or fragment thereof, Human growth hormone, Follicle-stimulating hormone, Factor VIII, Factor VII, Factor IX Erythropoietin (EPO), Granulocyte colony-stimulating factor (G-CSF), alpha-glactosidase A, alpha-L-iduronidase (rhIDU; laronidase), N-acetylgalactosamine-4-sulfatase (rhASB; galsulfase), DNAse, Tissue plasminogen activator (TPA), Glucocerebrosidase, Interferon (IF), Insulin, Insulin derivative, Insulin-like growth factor 1, Tenecteplase, antihemophilic factor, human coagulation factor, Etanercept, Trastuzumab, Infliximab, Basiliximab, Belimumab, Daclizumab, Adalimumab Abciximabor, Afutuzumab, Alemtuzumab, Cetuximab, Daclizumab, Denosumab, Eculizumab, Edrecolomab, Golimumab, Ibritumomab tiuxetan, Mepolizumab, Motavizumab, Natalizumab, Ofatumumab, Omalizumab, Oregovomab, Palivizumab, Pemtumomab, Pertuzumab, Ranibizumab, Rituximab, Tefibazumab and Zanolimumab. 12. The method of claim 1, wherein the cell expressing the polypeptide is at least one cell selected from the group consisting of E. coli, Bacillus, yeast from the genus of Saccharomyces, Pichia, Aspergillus, Fusarium, Kluyveromyces, CHO (Chinese Hamster Ovary) cell, hybridomas, BHK (Baby Hamster Kidney) cell, myeloma cell, HEK-293 cell, human lymphoblastoid cell, a human cell and a mouse cell. 13. The method of claim 1, wherein the isolated polypeptide is formulated into a pharmaceutical composition. 14. The method of claim 2, wherein the biopolymer is a polypeptide or protein. 15. The method of claim 3, wherein the intracellular product is an inclusion body; wherein the periplasmatic product is a precipitated product in solid form; wherein the precipitated product in solid form is in crystalline, amorphous or denatured form. 16. The method of claim 4, wherein the microorganism is yeast or bacteria; wherein the cell is a mammalian cell. 17. The method of claim 6, wherein the separation device is an impurity filter unit. 18. The method of claim 7, wherein the separation device is a membrane filter, a gravitational separation unit or a centrifugal separation unit. 19. The method of claim 9, wherein the membrane filter has a nominal molecular weight cut-off (NMWC) pore sizes within the range of 2,000 to 15,000 NMWC. 20. The method of claim 12, wherein the human cell is a human cell.

Details for Patent 10,316,282

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Grifols Therapeutics Llc	KOATE, KOATE-DVI	antihemophilic factor (human)	For Injection	101130	January 24, 1974		2033-03-19
Takeda Pharmaceuticals U.s.a., Inc.	HEMOFIL M	antihemophilic factor (human)	For Injection	101448	March 14, 2001		2033-03-19
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	November 26, 1997		2033-03-19
Novartis Pharmaceuticals Corporation	SIMULECT	basiliximab	For Injection	103764	May 12, 1998		2033-03-19
Novartis Pharmaceuticals Corporation	SIMULECT	basiliximab	For Injection	103764	January 02, 2003		2033-03-19
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	For Injection	103770	June 19, 1998		2033-03-19
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	Injection	103770	July 23, 2004		2033-03-19