DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/27/2026 has been entered.
Claim 1 has been amended. No claims have been newly canceled or newly added.
Claims 1, 3-20, 22-23, 25-29 and 40-41 are currently pending.
Claim 23 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/19/2018.
Claims 1, 3-20, 22, 25-29 and 40-41 have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are newly applied. They constitute the complete set presently being applied to the instant application.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. 15/028521, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The prior filed application ‘521 does not provide support for a second seed train culture, nor does it provide support for the claimed ranges of viable cell concentration as recited in claim 1. Recognizing this Applicant has filed the current Application as a CIP due to the additional limitations added to the claims and specification.
Accordingly, claims 1, 3-20, 22, 25-29 and 40-41 are not entitled to the benefit of the prior application.
The claims are examined with the filing date of the current Application of 04/15/2016.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 3-6, 10-20, 22, 25-29 and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-22, 24, 26-32, 34-38 of copending Application No. 16/984531 in view of Templeton et al (Biotechnology and Bioengineering, published online March 4,2013, from IDS filed 09/04/2018), Drapeau et al (US 2006/0121568-previously cited), Zhu et al (Biotech. Prog. 2005-from IDS filed 07/14/2016-previously cited) and Thudupathy et al (WO 2014/170866-previously cited).
The claims of copending ‘531 are drawn to methods of culturing CHO cells and producing a polypeptide of interest comprising culturing cells, determining a metabolic shift to lactate consumption has occurred, transferring cells from the first culture to a second culture after said shift to lactate consumption has been determined, maintaining the second culture for a period of time so that a polypeptide of interest accumulates, harvesting and purifying the polypeptide of interest.
The copending claims do not recite a second seed train culture prior to the production culture.
One of ordinary skill in the art would have been motivated to modify the copending method claims to transfer the cells from the first cell culture (seed train culture) to the subsequent cell cultures (passaging to provide additional seed cultures and production cultures) after determining a metabolic shift to lactate consumption has occurred because Templeton teach that during this shift is when the cells transition from peak growth to peak antibody production. The seed train culture is for the purpose of growing (expanding) the cells to an optimal amount and the production culture is for the purpose of producing and collecting proteins (antibodies) in an optimal amount.
Therefore, culturing the cells in first cultures (the seed train cultures) under seed train conditions when cell growth is at its peak is desirable and beneficial and culturing the cells in later cultures (production culture) under production conditions when antibody production is at its peak is desirable and beneficial. One of ordinary skill in the art would need to measure and track lactate levels in the seed train cultures to determine optimal lactate levels and would find reduced lactate accumulation in later (second) seed cultures as the cells switch to lactate consumption as compared to otherwise identical cell cultures that were switched too early.
Additional motivation would be provided by Drapeau because Drapeau teach that the practitioner will be able to choose the duration of an initial growth phase depending on the polypeptide or protein production requirements and the needs of the cells themselves (page 12 para 169) and that shifting of the cell cultures to produce a metabolic shift characterized by a reduction in the ratio of a specific lactate production rate to a specific glucose consumption rate is suggested as beneficial (pages 12-13 para 171). Drapeau also suggest the benefit and suitability of the addition of intermediate cell cultures (second seed train culture) to optimize the cell density for the practitioner. Drapeau suggest that multiple cell cultures are suitable between the initial cell culture (seed culture) and the final production cell culture by stating that initial and intermediate cell cultures may be grown to any desired density before seeding the next intermediate of final production bioreactor (page 12 para 162). This renders obvious including multiple seeding cultures in the method of the copending claims as well.
One of ordinary skill in the art would have had a reasonable expectation of success because copending claims teach wherein their method includes monitoring of lactate levels in the culture which allow assuring optimal cultivation and Templeton teach how to monitor and determine the shift from lactate production to lactate consumption.
The copending claims are silent with regard to the pCO2 level in the cell cultures.
Zhu et al teach that when pCO2 is elevated to high levels in bioreactors that this can adversely affect CHO cell culture and recombinant protein production (abstract). It was determined that elevating the pCO2 from 50 to 150 mmHg resulted in a 9% reduction in the specific growth rate (page 76 Conclusion). Zhu et al teach that an increase in pCO2 from 60 to 100 mmHg does not affect cell growth significantly, as depicted in Figure 2 (page 73). Zhu et al teach that these results are useful to understand the response of CHO cells to elevated pCO2 at a different stage of cultivation in bioreactors and thus are valuable in guiding bioreactor optimization toward improving protein production (abstract, page 70).
Thudupathy teach that it is beneficial to manipulate pCO2 when culturing mammalian cells to produce a protein product and to start with a lower pCO2 and then raise it to an elevated level of greater than 70 mmHg (page 4 lines 12-16), preferably wherein the elevated level is about 70 mmHg to about 110 mmHg (page 11 claim 1).
Therefore, one of ordinary skill in the art would have been motivated to select a pCO2 levels that was below 110 mmHg and preferably between 60 mmHg and 100 mmHg when culturing CHO cells for protein production because Zhu et al indicate that this level of pCO2 provides better cell growth than cultures with a higher pCO2 level. One of ordinary skill in the art would have been motivated to raise the pCO2 level from the start of culture (seed culture) to before the protein is produced (production culture) because Thudupathy suggest that this tactic provides an enhanced protein product. One of ordinary skill in the art would have been motivated to keep the elevated pCO2 below 100 mmHg because Zhu suggests that this is preferred for cell growth. One of ordinary skill in the art would have had a reasonable expectation of success because both the copending claims and Zhu are directed to culturing cells for recombinant protein production.
Zhu suggest the optimization of cell culture conditions, specifically pC02, to maximize viable cell densities and to prolong culture lifetime to increase final product titers is an important goal (page 70, Introduction). Thus allowing the culturing to take place in the preferred range disclosed by Zhu of about 60 to 100 mmHg would be an obvious technique to use in the method of the copending claims.
Therefore, the combined teachings of copending ‘531, Templeton et al, Drapeau et al, Zhu et al, and Thudupathy et al render obvious Applicant’s invention as claimed.
This is a provisional nonstatutory double patenting rejection.
Claims 7-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-22, 24, 26-32, 34-38 of copending Application No. 16/984531 in view of Templeton et al (Biotechnology and Bioengineering, published online March 4,2013, from IDS filed 09/04/2018), Drapeau et al (US 2006/0121568-previously cited), Zhu et al (Biotech. Prog. 2005-from IDS filed 07/14/2016-previously cited) and Thudupathy et al (WO 2014/170866-previously cited) as applied to claims 1, 3-6, 10-20, 22, 25-29 and 41 above and further in view of Khetan et al (US 2013/0096283-previously cited).
Regarding claims 7-9, the combined teachings of the copending claims of ‘531, Templeton, Drapeau, Zhu and Thudupathy render obvious the claimed invention as described above, however, they do not teach wherein the production cell culture is cultured in a production scale vessel of at least 100L in volume.
Zhu et al teach that experiments are conducted in bench-scale bioreactors to more closely reflect the pCO2 levels observed at large scale (abstract). A 40% loss in specific production rate is disclosed when pCO2 is increased from 68 to 179 mmHg in a large scale bioreactor greater than 100 L in volume (page 71, column 1).
Khetan et al teach that a CHO culture can be successfully scaled up from a 2 L bench scale to a 200L manufacturing bioreactor scale (page 15 para 155).
One of ordinary skill in the art would have been motivated to scale-up the method of copending ‘531 to a commercial level bioreactor with a volume greater than 100L because Zhu suggest that it is desirable and beneficial to do so. One of ordinary skill in the art would have had a reasonable expectation of success because Zhu indicates that experiments are conducted in bench-scale bioreactors to more closely reflect the pCO2 levels observed at large scale (abstract). One of ordinary skill in the art would have been motivated with a reasonable expectation of success to select a scaled-ep bioreactor of about 200 L (or approximately 160 L through routine optimization) because Khetan et al suggest that CHO cells can be successfully scaled up to a 200 L bioreactor from a 2L benchtop culture.
Therefore the combined teachings of copending ‘531, Templeton et al, Drapeau et al, Zhu et al, Thudupathy et al and Khetan et al render obvious Applicant’s invention as claimed.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-6, 10-20, 22, 25-29 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12-15 of U.S. Patent No. 11,390,663 in view of Drapeau et al (US 2006/0121568), Zhu et al (Biotech. Prog. 2005-from IDS filed 07/14/2016) and Thudupathy et al (WO 2014/170866).
The claims of patent ‘663 are drawn to methods of culturing cells and producing a polypeptide of interest comprising culturing cells, determining a metabolic shift to lactate consumption has occurred, transferring cells from the first culture to a second seed train culture after said shift to lactate consumption has been determined, maintaining the second culture for a period of time and then transferring an amount of cells to a production bioreactor so that a polypeptide of interest accumulates, harvesting and purifying the polypeptide of interest.
The patent ‘663 claims do not specifically recite using CHO cells as the cell type cultured.
Drapeau teach methods of producing proteins in cell cultures (abstract). Any mammalian cell type susceptible to cell culture may be utilized including CHO cells (page 9 para 144). Drapeau suggest that multiple cell cultures are suitable between the initial cell culture (seed culture) and the final production cell culture by stating that initial and intermediate cell cultures may be grown to any desired density before seeding the next intermediate or final production bioreactor (page 12 para 162). The practitioner will be able to choose the duration of the initial growth phase depending on the polypeptide or protein production requirements and the needs of the cells themselves (page 12 para 169). Shifting of the cell cultures to produce a metabolic shift characterized by a reduction in the ratio of a specific lactate production rate to a specific glucose consumption rate is suggested as beneficial (pages 12-13 para 171). Consumption of lactate is noted in those cultures with improved productivity (page 27 para 289-290).
One of ordinary skill in the art would have been motivated to use CHO cells in the culture method of Patent ‘663 because Drapeau teach and suggest that CHO cells are a suitable and beneficial type of cell for the culture and production of a polypeptide of interest. One of ordinary skill in the art would have had a reasonable expectation of success because Drapeau teach that shifting of the cell cultures to produce a metabolic shift characterized by a reduction in the ratio of a specific lactate production rate to a specific glucose consumption rate is suggested as beneficial (pages 12-13 para 171) and consumption of lactate is noted in those cultures with improved productivity (page 27 para 289-290).
The patent claims are silent with regard to the pCO2 level in the cell cultures.
Zhu et al teach that when pCO2 is elevated to high levels in bioreactors that this can adversely affect CHO cell culture and recombinant protein production (abstract). It was determined that elevating the pCO2 from 50 to 150 mmHg resulted in a 9% reduction in the specific growth rate (page 76 Conclusion). Zhu et al teach that an increase in pCO2 from 60 to 100 mmHg does not affect cell growth significantly, as depicted in Figure 2 (page 73). Zhu et al teach that these results are useful to understand the response of CHO cells to elevated pCO2 at a different stage of cultivation in bioreactors and thus are valuable in guiding bioreactor optimization toward improving protein production (abstract, page 70).
Thudupathy teach that it is beneficial to manipulate pCO2 when culturing mammalian cells to produce a protein product and to start with a lower pCO2 and then raise it to an elevated level of greater than 70 mmHg (page 4 lines 12-16), preferably wherein the elevated level is about 70 mmHg to about 110 mmHg (page 11 claim 1).
Therefore, one of ordinary skill in the art would have been motivated to select a pCO2 levels that was below 110 mmHg and preferably between 60 mmHg and 100 mmHg when culturing CHO cells for protein production because Zhu et al indicate that this level of pCO2 provides better cell growth than cultures with a higher pCO2 level. One of ordinary skill in the art would have been motivated to raise the pCO2 level from the start of culture (seed culture) to before the protein is produced (production culture) because Thudupathy suggest that this tactic provides an enhanced protein product. One of ordinary skill in the art would have been motivated to keep the elevated pCO2 below 100 mmHg because Zhu suggests that this is preferred for cell growth. One of ordinary skill in the art would have had a reasonable expectation of success because both the patent ‘663 claims and Zhu are directed to culturing cells for recombinant protein production.
Zhu suggest the optimization of cell culture conditions, specifically pC02, to maximize viable cell densities and to prolong culture lifetime to increase final product titers is an important goal (page 70, Introduction). Thus allowing the culturing to take place in the preferred range disclosed by Zhu of about 60 to 100 mmHg would be an obvious technique to use in the method of the patent ‘663 claims.
Therefore, the combined teachings of patent ‘663, Drapeau et al, Zhu et al, and Thudupathy et al render obvious Applicant’s invention as claimed.
Claims 7-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12-15 of U.S. Patent No. 11,390,663 in view of Drapeau et al (US 2006/0121568), Zhu et al (Biotech. Prog. 2005-from IDS filed 07/14/2016) and Thudupathy et al (WO 2014/170866) as applied to claims 1, 3-6, 10-20, 22, 25-29 and 41 above and further in view of Khetan et al (US 2013/0096283).
Regarding claims 7-9, the combined teachings of patent ‘663, Drapeau, Zhu and Thudupathy render obvious the claimed invention as described above, however, they do not teach wherein the production cell culture is cultured in a production scale vessel of at least 100L in volume.
Zhu et al teach that experiments are conducted in bench-scale bioreactors to more closely reflect the pCO2 levels observed at large scale (abstract). A 40% loss in specific production rate is disclosed when pCO2 is increased from 68 to 179 mmHg in a large scale bioreactor greater than 100 L in volume (page 71, column 1).
Khetan et al teach that a CHO culture can be successfully scaled up from a 2 L bench scale to a 200L manufacturing bioreactor scale (page 15 para 155).
One of ordinary skill in the art would have been motivated to scale-up the method of patent ‘663 to a commercial level bioreactor with a volume greater than 100L because Zhu suggest that it is desirable and beneficial to do so. One of ordinary skill in the art would have had a reasonable expectation of success because Zhu indicates that experiments are conducted in bench-scale bioreactors to more closely reflect the pCO2 levels observed at large scale (abstract). One of ordinary skill in the art would have been motivated with a reasonable expectation of success to select a scaled-up bioreactor of about 200 L (or approximately 160 L through routine optimization) because Khetan et al suggest that CHO cells can be successfully scaled up to a 200 L bioreactor from a 2L benchtop culture.
Therefore, the combined teachings of patent ‘663, Drapeau et al, Zhu et al, Thudupathy et al and Khetan et al render obvious Applicant’s invention as claimed.
Claims 1, 3-6, 10-20, 22, 25-29 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12-15 of U.S. Patent No. 12,291,563 in view of Drapeau et al (US 2006/0121568), Zhu et al (Biotech. Prog. 2005-from IDS filed 07/14/2016) and Thudupathy et al (WO 2014/170866).
The claims of patent ‘563 are drawn to methods of culturing cells and producing a polypeptide of interest comprising culturing cells, determining a metabolic shift to lactate consumption has occurred, transferring cells from the first culture to a second seed train culture after said shift to lactate consumption has been determined, maintaining the second culture for a period of time and then transferring an amount of cells to a production culture so that a polypeptide of interest accumulates, harvesting and purifying the polypeptide of interest.
The patent ‘563 claims do not specifically recite using CHO cells as the cell type cultured.
Drapeau teach methods of producing proteins in cell cultures (abstract). Any mammalian cell type susceptible to cell culture may be utilized including CHO cells (page 9 para 144). Drapeau suggest that multiple cell cultures are suitable between the initial cell culture (seed culture) and the final production cell culture by stating that initial and intermediate cell cultures may be grown to any desired density before seeding the next intermediate or final production bioreactor (page 12 para 162). The practitioner will be able to choose the duration of the initial growth phase depending on the polypeptide or protein production requirements and the needs of the cells themselves (page 12 para 169). Shifting of the cell cultures to produce a metabolic shift characterized by a reduction in the ratio of a specific lactate production rate to a specific glucose consumption rate is suggested as beneficial (pages 12-13 para 171). Consumption of lactate is noted in those cultures with improved productivity (page 27 para 289-290).
One of ordinary skill in the art would have been motivated to use CHO cells in the culture method of Patent ‘563 because Drapeau teach and suggest that CHO cells are a suitable and beneficial type of cell for the culture and production of a polypeptide of interest. One of ordinary skill in the art would have had a reasonable expectation of success because Drapeau teach that shifting of the cell cultures to produce a metabolic shift characterized by a reduction in the ratio of a specific lactate production rate to a specific glucose consumption rate is suggested as beneficial (pages 12-13 para 171) and consumption of lactate is noted in those cultures with improved productivity (page 27 para 289-290).
The patent claims are silent with regard to the pCO2 level in the cell cultures.
Zhu et al teach that when pCO2 is elevated to high levels in bioreactors that this can adversely affect CHO cell culture and recombinant protein production (abstract). It was determined that elevating the pCO2 from 50 to 150 mmHg resulted in a 9% reduction in the specific growth rate (page 76 Conclusion). Zhu et al teach that an increase in pCO2 from 60 to 100 mmHg does not affect cell growth significantly, as depicted in Figure 2 (page 73). Zhu et al teach that these results are useful to understand the response of CHO cells to elevated pCO2 at a different stage of cultivation in bioreactors and thus are valuable in guiding bioreactor optimization toward improving protein production (abstract, page 70).
Thudupathy teach that it is beneficial to manipulate pCO2 when culturing mammalian cells to produce a protein product and to start with a lower pCO2 and then raise it to an elevated level of greater than 70 mmHg (page 4 lines 12-16), preferably wherein the elevated level is about 70 mmHg to about 110 mmHg (page 11 claim 1).
Therefore, one of ordinary skill in the art would have been motivated to select a pCO2 levels that was below 110 mmHg and preferably between 60 mmHg and 100 mmHg when culturing CHO cells for protein production because Zhu et al indicate that this level of pCO2 provides better cell growth than cultures with a higher pCO2 level. One of ordinary skill in the art would have been motivated to raise the pCO2 level from the start of culture (seed culture) to before the protein is produced (production culture) because Thudupathy suggest that this tactic provides an enhanced protein product. One of ordinary skill in the art would have been motivated to keep the elevated pCO2 below 100 mmHg because Zhu suggests that this is preferred for cell growth. One of ordinary skill in the art would have had a reasonable expectation of success because both the patent ‘563 claims and Zhu are directed to culturing cells for recombinant protein production.
Zhu suggest the optimization of cell culture conditions, specifically pC02, to maximize viable cell densities and to prolong culture lifetime to increase final product titers is an important goal (page 70, Introduction). Thus allowing the culturing to take place in the preferred range disclosed by Zhu of about 60 to 100 mmHg would be an obvious technique to use in the method of the patent ‘563 claims.
Therefore, the combined teachings of patent ‘563, Drapeau et al, Zhu et al, and Thudupathy et al render obvious Applicant’s invention as claimed.
Claims 7-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12-15 of U.S. Patent No. 12,291,563 in view of Drapeau et al (US 2006/0121568), Zhu et al (Biotech. Prog. 2005-from IDS filed 07/14/2016) and Thudupathy et al (WO 2014/170866) as applied to claims 1, 3-6, 10-20, 22, 25-29 and 41 above and further in view of Khetan et al (US 2013/0096283).
Regarding claims 7-9, the combined teachings of patent ‘563, Drapeau, Zhu and Thudupathy render obvious the claimed invention as described above, however, they do not teach wherein the production cell culture is cultured in a production scale vessel of at least 100L in volume.
Zhu et al teach that experiments are conducted in bench-scale bioreactors to more closely reflect the pCO2 levels observed at large scale (abstract). A 40% loss in specific production rate is disclosed when pCO2 is increased from 68 to 179 mmHg in a large scale bioreactor greater than 100 L in volume (page 71, column 1).
Khetan et al teach that a CHO culture can be successfully scaled up from a 2 L bench scale to a 200L manufacturing bioreactor scale (page 15 para 155).
One of ordinary skill in the art would have been motivated to scale-up the method of patent ‘563 to a commercial level bioreactor with a volume greater than 100L because Zhu suggest that it is desirable and beneficial to do so. One of ordinary skill in the art would have had a reasonable expectation of success because Zhu indicates that experiments are conducted in bench-scale bioreactors to more closely reflect the pCO2 levels observed at large scale (abstract). One of ordinary skill in the art would have been motivated with a reasonable expectation of success to select a scaled-up bioreactor of about 200 L (or approximately 160 L through routine optimization) because Khetan et al suggest that CHO cells can be successfully scaled up to a 200 L bioreactor from a 2L benchtop culture.
Therefore, the combined teachings of patent ‘563, Drapeau et al, Zhu et al, Thudupathy et al and Khetan et al render obvious Applicant’s invention as claimed.
Claims 1, 3-6, 10-20, 22, 25-29 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,545,717 in view of Templeton et al (Biotechnology and Bioengineering, published online March 4,2013, from IDS filed 09/04/2018), Drapeau et al (US 2006/0121568-previously cited), Zhu et al (Biotech. Prog. 2005-from IDS filed 07/14/2016-previously cited) and Thudupathy et al (WO 2014/170866-previously cited).
The claims of patent ‘717 are drawn to methods of culturing cells and producing a polypeptide of interest comprising culturing cells, determining a metabolic shift to lactate consumption has occurred, transferring cells from the first culture to a second culture after said shift to lactate consumption has been determined, maintaining the second culture for a period of time so that a polypeptide of interest accumulates, harvesting and purifying the polypeptide of interest. CHO cells are claimed as the cell type used.
The patent ‘717 claims do not recite a second seed train culture prior to the production culture.
One of ordinary skill in the art would have been motivated to modify the patent ’717 method claims to transfer the cells from the first cell culture (seed train culture) to the subsequent cell cultures (passaging to provide additional seed cultures and production cultures) after determining a metabolic shift to lactate consumption has occurred because Templeton teach that during this shift is when the cells transition from peak growth to peak antibody production. The seed train culture is for the purpose of growing (expanding) the cells to an optimal amount and the production culture is for the purpose of producing and collecting proteins (antibodies) in an optimal amount.
Therefore, culturing the cells in first cultures (the seed train cultures) under seed train conditions when cell growth is at its peak is desirable and beneficial and culturing the cells in later cultures (production culture) under production conditions when antibody production is at its peak is desirable and beneficial. One of ordinary skill in the art would need to measure and track lactate levels in the seed train cultures to determine optimal lactate levels and would find reduced lactate accumulation in later (second) seed cultures as the cells switch to lactate consumption as compared to otherwise identical cell cultures that were switched too early.
Additional motivation would be provided by Drapeau because Drapeau teach that the practitioner will be able to choose the duration of an initial growth phase depending on the polypeptide or protein production requirements and the needs of the cells themselves (page 12 para 169) and that shifting of the cell cultures to produce a metabolic shift characterized by a reduction in the ratio of a specific lactate production rate to a specific glucose consumption rate is suggested as beneficial (pages 12-13 para 171). Drapeau also suggest the benefit and suitability of the addition of intermediate cell cultures (second seed train culture) to optimize the cell density for the practitioner. Drapeau suggest that multiple cell cultures are suitable between the initial cell culture (seed culture) and the final production cell culture by stating that initial and intermediate cell cultures may be grown to any desired density before seeding the next intermediate of final production bioreactor (page 12 para 162). This renders obvious including multiple seeding cultures in the method of the copending claims as well.
One of ordinary skill in the art would have had a reasonable expectation of success because patent ‘717 claims teach wherein their method includes monitoring of lactate levels in the culture which allow assuring optimal cultivation and Templeton teach how to monitor and determine the shift from lactate production to lactate consumption.
The patent ‘717 claims are silent with regard to the pCO2 level in the cell cultures.
Zhu et al teach that when pCO2 is elevated to high levels in bioreactors that this can adversely affect CHO cell culture and recombinant protein production (abstract). It was determined that elevating the pCO2 from 50 to 150 mmHg resulted in a 9% reduction in the specific growth rate (page 76 Conclusion). Zhu et al teach that an increase in pCO2 from 60 to 100 mmHg does not affect cell growth significantly, as depicted in Figure 2 (page 73). Zhu et al teach that these results are useful to understand the response of CHO cells to elevated pCO2 at a different stage of cultivation in bioreactors and thus are valuable in guiding bioreactor optimization toward improving protein production (abstract, page 70).
Thudupathy teach that it is beneficial to manipulate pCO2 when culturing mammalian cells to produce a protein product and to start with a lower pCO2 and then raise it to an elevated level of greater than 70 mmHg (page 4 lines 12-16), preferably wherein the elevated level is about 70 mmHg to about 110 mmHg (page 11 claim 1).
Therefore, one of ordinary skill in the art would have been motivated to select a pCO2 levels that was below 110 mmHg and preferably between 60 mmHg and 100 mmHg when culturing CHO cells for protein production because Zhu et al indicate that this level of pCO2 provides better cell growth than cultures with a higher pCO2 level. One of ordinary skill in the art would have been motivated to raise the pCO2 level from the start of culture (seed culture) to before the protein is produced (production culture) because Thudupathy suggest that this tactic provides an enhanced protein product. One of ordinary skill in the art would have been motivated to keep the elevated pCO2 below 100 mmHg because Zhu suggests that this is preferred for cell growth. One of ordinary skill in the art would have had a reasonable expectation of success because both the patent ‘717 claims and Zhu are directed to culturing cells for recombinant protein production.
Zhu suggest the optimization of cell culture conditions, specifically pC02, to maximize viable cell densities and to prolong culture lifetime to increase final product titers is an important goal (page 70, Introduction). Thus allowing the culturing to take place in the preferred range disclosed by Zhu of about 60 to 100 mmHg would be an obvious technique to use in the method of the patent ‘717 claims.
Therefore, the combined teachings of patent ‘717, Templeton et al, Drapeau et al, Zhu et al, and Thudupathy et al render obvious Applicant’s invention as claimed.
Claims 7-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,545,717 in view of Templeton et al (Biotechnology and Bioengineering, published online March 4,2013, from IDS filed 09/04/2018), Drapeau et al (US 2006/0121568), Zhu et al (Biotech. Prog. 2005-from IDS filed 07/14/2016) and Thudupathy et al (WO 2014/170866) as applied to claims 1, 3-6, 10-20, 22, 25-29 and 41 above and further in view of Khetan et al (US 2013/0096283).
Regarding claims 7-9, the combined teachings of the patent ‘717 claims, Templeton, Drapeau, Zhu and Thudupathy render obvious the claimed invention as described above, however, they do not teach wherein the production cell culture is cultured in a production scale vessel of at least 100L in volume.
Zhu et al teach that experiments are conducted in bench-scale bioreactors to more closely reflect the pCO2 levels observed at large scale (abstract). A 40% loss in specific production rate is disclosed when pCO2 is increased from 68 to 179 mmHg in a large scale bioreactor greater than 100 L in volume (page 71, column 1).
Khetan et al teach that a CHO culture can be successfully scaled up from a 2 L bench scale to a 200L manufacturing bioreactor scale (page 15 para 155).
One of ordinary skill in the art would have been motivated to scale-up the method of patent ‘717 to a commercial level bioreactor with a volume greater than 100L because Zhu suggest that it is desirable and beneficial to do so. One of ordinary skill in the art would have had a reasonable expectation of success because Zhu indicates that experiments are conducted in bench-scale bioreactors to more closely reflect the pCO2 levels observed at large scale (abstract). One of ordinary skill in the art would have been motivated with a reasonable expectation of success to select a scaled-up bioreactor of about 200 L (or approximately 160 L through routine optimization) because Khetan et al suggest that CHO cells can be successfully scaled up to a 200 L bioreactor from a 2L benchtop culture.
Therefore, the combined teachings of patent ‘717, Templeton et al, Drapeau et al, Zhu et al, Thudupathy et al and Khetan et al render obvious Applicant’s invention as claimed.
Allowable Subject Matter
Claim 40 appears to be free of the prior art, but would be allowable if rewritten in independent form including all of the limitations of the base claim, any intervening claims and if limited to the enabled scope of culturing CHO cells.
Response to Arguments
Applicant's arguments filed 02/27/2026 have been fully considered but they are not fully persuasive.
Applicant’s amendments to the claims have overcome the obviousness rejection under 35 USC 103 as the cited prior art does not teach or fairly suggest the new combination of limitations recited in the claims.
However, the double patenting rejections remain and have been expanded to include additional double patenting rejections as recited above.
Applicant argues that their reasons for traversing the obviousness rejections with respect to Templeton, Drapeau, Zhu and Thudupathy apply to the double patenting rejections as well and consider that the claims are patentable over the identified claims of copending Application 16/984531.
This is not found persuasive. Templeton, Drapeau, Zhu and Thudupathy were relied upon for the motivation to modify the method of Heidenmann to arrive at the claimed method. The double patenting rejections are drawn to claimed cell culture methods that are very similar to the currently claimed method and contain many of the same limitations as recited in the current claims.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Rodriguez et al., “Seed Train optimization for suspension cell culture”, BMC Proceedings, 2013, (Suppl 6) pp. 1-3.
(Rodriguez discloses the optimization of seed train cultures for the production of biopharmaceuticals)
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/LAURA SCHUBERG/ Primary Examiner, Art Unit 1631
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