Office Action 1: Non-Final Rejection (2024-06-18)
Rejection types: 112 - Written Description/Enablement, Double Patenting

CLAIMS:
AMENDMENTS TO CLAIMS:

This listing of claims will replace all prior versions and listings of claims in the instant application.

1\. (Currently Amended) A method for culturing cells comprising:
(a) culturing cells in a first seed train ulture to a viable cell concentration of greater than 3.0 x 106 cells/mL, whereby a metabolic shift to lactate consumption has occurred in the first seed train culture;
()(b) transferring an amount of cells from the first seed train ulture to a second seed train culture in another culture vessel ;
(d)(c) culturing the cells in a-the second seed train culture; and
(e)(d) transferring an amount of cells from the second seed train culture to a production ulture after the cells in the second seed train culture have reached a predetermined viable cell concentration greater than 3.0 x 106 cells/mL.

2\. (Canceled)

3\. (Currently Amended) The method of Claim 21, wherein the cells in said first seed train culture are cultured to a viable cell concentration of 3.5 x 106 cells/mL to 5.0 x 106 cells/mL.

4\. (Currently Amended) The method of Claim 3, wherein the cells in said first seed train culture are cultured to a viable cell concentration of 4.0 x 106 cells/mL, 4.5 x 106 cells/mL or 5.0 x 106 cells/mL.

5\. (Currently Amended) The method of Claim 1, wherein the cells in said first cell culture are cultured to a viable cell concentration of at least 4.5 x 106 cells/mL.

6\. (Canceled)
7\. (Currently Amended) The method of Claim 61, wherein said predetermined viable cell concentration is 3.5 x 106 cells/mL to 5.0 x 106 cells/mL.

8\. (Original) The method of Claim 7, wherein said predetermined viable cell concentration is 3.5 x 106 cells/mL, 4.0 x 106 cells/mL, 4.5 x 106 cells/mL or 5.0 x 106 cells/mL.

9\. (Canceled)

10\. (Canceled)

11\. (Canceled)

12\. (Currently Amended) The method of Claim 1, further comprising detecting a reduced rate of lactate accumulation in the second seed train culture prior to transfer to the production culture compared to that determined in an otherwise identical cell culture under otherwise identical conditions except transferring cells to the second seed train culture is performed prior to a metabolic shift, or is performed prior to the viable cell count reaching 3.0 x 106 cell s/mL-.

13\. (Canceled)

14\. (Currently Amended) The method of Claim 1, wherein said metabolic shift to lactate consumption is detected by pH, lactate or base measurement in said first seed train culture.

15\. (Currently Amended) The method of Claim 14, wherein said metabolic shift to lactate consumption is detected after pH increases in said first seed train culture medium without addition of base.

16\. (Currently Amended) The method of Claim 14, wherein said metabolic shift occurs when lactate levels plateau in said first seed train culture.

17\. (Currently Amended) The method of Claim 1, wherein the metabolic shift occurs when said cells emerge from log growth phase or have reached stationary phase in said first seed train culture.
18\. (Currently Amended) The method of Claim I, wherein the cells in said first seed train culture are transfected with DNA encoding a polypeptide of interest prior to culturing cells in a first seed train ulture.

19\. (Currently Amended) The method of Claim 18, further comprising maintaining said second seed train culture and said production culture under conditions that allow expression of said polypeptide of interest, and harvesting said polypeptide of interest from said production culture.

20\. (Original) The method of Claim 19, wherein said protein of interest is selected from the group consisting of antibody, antigen-binding protein, and fusion protein.

21\. (Currently Amended) A production culture produced by the method of Claim 1.

22.-29. (Canceled) 2328
2 3 4

OFFICE ACTION:
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 .
Applicant’s amendment filed on 10-3-22 has been entered.  Claims 1, 3-5, 7, 12, 14-19 and 21 have been amended.  Claims 2, 6, 9-11, 13 and 22-29 have been canceled.  Claims 1, 3-5, 7-8, 12 and 14-21 are pending and under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6-17-22, 3-10-23, 10-26-23 and 4-11-24 was filed before the mailing date of the Non-Final Office Action.  The submission is in compliance with the provisions of 37 CFR 1.97.  Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b)  CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5 and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA  35 U.S.C. 112, the applicant), regards as the invention.
The phrase “said first cell culture” in line 1 of claim 5 is vague and renders the claim indefinite.  Claim 5 depends from claim 1, which recites “a first seed train culture”.  It is unclear whether the “first cell culture” is meant to be the “first seed train culture” or it is meant to be some other cell culture.  A seed train culture includes a series of steps used to generate sufficient amounts of viable cells.  It appears that a seed train culture can encompass a series of different cell cultures.  It is unclear which cell culture the phrase “said first cell culture” is referring to.
The phrase “compared to that determined in an otherwise identical cell culture under otherwise identical conditions except transferring cells to the second seed train culture is performed prior to a metabolic shift, or is performed prior to the viable cell count reaching 3.0 x 106 cells/ml” in lines 3-6 of claim 12 is vague and renders the claim indefinite.  Claim 12 depends from claim 1, which recites the cells in the first seed train are transferred to second seed train after the viable cell concentration is greater than 3.0 x 106 cells/ml, or a metabolic shift to lactate consumption has occurred in the first seed train culture.  However, claim 12 recites “transferring cells to the second seed train culture is performed prior to a metabolic shift, or is performed prior to the viable cell count reaching 3.0 x 106 cells/ml”.  The step recited in claim 12 is in conflict to the steps recited in claim 1.  It is unclear what is intended to be claimed in claim 12.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-5, 7-8, 12 and 14-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,390,663 B2 (‘663). Although the claims at issue are not identical, they are not patentably distinct from each other because, although drawn to different scopes, they encompass the same invention and obvious variants thereof.
Claims 1, 3-5, 7-8, 12 and 14-21 of the present application are directed to a method for culturing cells comprising (a) culturing cells in a first seed train culture to a viable cell concentration of greater than 3.0 x 106 cells/ml, whereby a metabolic shift to lactate consumption has occurred in the first seed train culture, (b) transferring an amount of cells from the first seed train culture to a second seed train culture in another culture vessel, (c) culturing the cells in the second seed train culture and transferring an amount of cells from the second seed train culture to a production culture after the cells in the second seed train culture have reached a predetermined viable cell concentration greater than 3.0 x 106 cells/ml.  Claim 3 specifies the cells in said first seed train culture are cultured to a viable cell concentration of 3.0 x 106 cells/ml to 5.0 x 106 cells/ml.  Claim 4 specifies the cells in said first seed train culture are cultured to a viable cell concentration of 4.0 x 106 cells/ml, 4.5 x 106 cells/ml, or 5.0 x 106 cells/ml.  Claim 5 specifies the cells in said first cell culture are cultured to a viable cell concentration of at least 4.5 x 106 cells/ml.  Claim 7 specifies the predetermined viable cell concentration is 3.5 x 106 cells/ml to 5.0 x 106 cells/ml.  Claim 8 specifies said predetermined viable cell concentration is 3.5 x 106 cells/ml, 4.0 x 106 cells/ml, 4.5 x 106 cells/ml, or 5.0 x 106 cells/ml.  Claim 12 further comprising detecting a reduced rate of lactate accumulation in the second seed train culture prior to transfer to the production culture compared to that determined in an otherwise identical cell culture under otherwise identical conditions except transferring cells to the second seed train culture is performed prior to a metabolic shift, or is performed prior to the viable cell count reaching 3.0 x 106 cells/ml.  Claim 14 specifies said metabolic shift to lactate consumption is detected by pH, lactate or base measurement in said first seed train culture.  Claim 15 specifies said metabolic shift to lactate consumption is detected after pH increases in said first seed train culture medium without addition of base.  Claim 16 specifies said metabolic shift occurs when lactate levels plateau in said first seed train culture.  Claim 17 specifies the metabolic shift occurs when said cells emerge from log growth phase or have reached stationary phase in said first seed train culture.  Claim 18 specifies the cells in said first seed train culture are transfected with DNA encoding a polypeptide of interest prior to culturing cells in a first seed train culture.  Claim 19 further comprising maintain said second seed train culture and production culture under conditions for expression of said polypeptide of interest, and harvesting said polypeptide of interest from said production culture.  Claim 20 specifies said protein of interest is antibody, antigen-binding protein or fusion protein.  Claim 21 reads on a production culture produced by the method of claim 1.
Claim 1-15 of ‘663 are directed to a method for culturing cells comprising (a) culturing cells in a first cell culture to a viable cell concentration of 3.0 x 106 cells/ml to 5.0 x 106 cells/ml, whereby a metabolic shift to lactate consumption has occurred, wherein the first cell culture is a seed train cell culture and lactate accumulates in the first cell culture, (b) transferring an amount of cells from the first cell culture to a second cell culture, which is a seed train cell culture in another culture vessel, and wherein the second cell culture exhibits a reduced rate of lactate accumulation compared to that in an otherwise identical cell culture under identical conditions except transfer of cells from the first cell culture to the second cell culture is performed prior to the viable cell count reached 3.0 x 106 cells/ml, (c) culturing the transferred cells in the second cell culture, and (d) transferring an amount of cells from the second cell culture to a product bioreactor after the cells in the second cell culture reached a viable cell concentration of 3.0 x 106 cells/ml to 5.0 x 106 cells/ml.  Claim 2 specifies the cells in said first cell culture are cultured to a viable cell concentration of 3.5 x 106 cells/ml to 5.0 x 106 cells/ml.  Claim 3 specifies the cells in said first cell culture are cultured to a viable cell concentration of 4.0 x 106 cells/ml, 4.5 x 106 cells/ml, or 5.0 x 106 cells/ml.  Claim 4 specifies the cells in said first cell culture are cultured to a viable cell concentration of at least 4.5 x 106 cells/ml to 5.0 x 106 cells/ml.  Claim 5 specifies said viable cell concentration of the second cell culture is 3.5 x 106 cells/ml to 5.0 x 106 cells/ml.  Claim 6 specifies said viable cell concentration of the second cell culture is 3.5 x 106 cells/ml, 4.0 x 106 cells/ml, 4.5 x 106 cells/ml, or 5.0 x 106 cells/ml.  Claim 7 specifies said viable cell concentration of the second cell culture is 4.0 x 106 cells/ml to 5.0 x 106 cells/ml.  Claim 8 further comprising detecting a reduced rate of lactate accumulation in the second cell culture prior to transfer to the production bioreactor compared to that determined in an otherwise identical cell culture under otherwise identical conditions except transferring cells to the second cell culture is performed prior to the viable cell count reaching 3.0 x 106 cells/ml.  Claim 9 further comprising detecting said metabolic shift to lactate consumption by measuring the pH, lactate or base measurement in said first cell culture prior to step (b).  Claim 10 specifies said metabolic shift to lactate consumption is detected based on an increase in the pH of the first cell culture medium without addition of base.  Claim 11 specifies said metabolic shift is detected based on measuring the lactate levels in the first cell culture.  Claim 12 specifies the metabolic shift occurs when said cells emerge from log growth phase or have reached stationary phase in said first cell culture.  Claim 13 specifies the cells in the first cell culture are transfected with DNA encoding a polypeptide of interest prior to culturing cells in a first cell culture.  Claim 14 further comprising maintain the second cell culture and the cell culture in the production bioreactor under conditions for expression of said polypeptide of interest, and harvesting said polypeptide of interest from said production bioreactor.  Claim 15 specifies said protein of interest is antibody, antigen-binding protein or fusion protein.
The range of viable cell concentration greater than 3.0 x 106 cells/ml of the present application would encompass the range of viable cell concentration of 3.0 x 106 cells/ml to 5.0 x 106 cells/ml recited in ‘663.  Further, the production culture produced by the method of claim 1 of the present application would be obvious to one of ordinary skill in the art in view of the disclosure of ‘663.  Therefore, the subject matter of claims 1, 3-5, 7-8, 12 and 14-21 of the present application would be obvious to one of ordinary skill in the art in view of the disclosure of claims 1-15 of ‘663.
Conclusion
No claim is allowed.


NEXT OFFICE 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 .
Reasons for allowance
Claims 1,3-5,7-8,12 and 14-21 are allowed.
Applicant’s claim amendments, arguments and terminal disclaimer, filed 10/17/2024, have overcome the 35 USC 112 (b) and nonstatutory time double patenting rejections.
The closest prior art of record is Heidemann, US 2003/0113915, (of record), which teaches a method for seed-train expansion of cryopreserved cells by using an inoculation bioreactor having an inoculation well for expanding the cells prior to their transfer to a production bioreactor, and monitoring and adjusting the condition of the media and environment, and thereafter incrementally increasing the volume of the media within the reactor so that optimal cell growth is maintained (e.g. Abstract, [0010]).
However, Heidemann does not teach and does not fairly suggest the recited viable cell concentration (VCC) of either the first seed train culture or after the second seed train culture reaches the claimed VCC range prior to passaging of the cells.
Conclusion

CITED REFERENCE SUMMARIES: Ref US11390663B2: Claims:
What is claimed: 1. A method for culturing cells comprising: (a) culturing cells in a first cell culture to a viable cell concentration of 3.1×106 cells/mL to 5.0×106 cells/mL whereby a metabolic shift to lactate consumption has occurred, wherein the first cell culture is a seed train cell culture, wherein lactate accumulates in the first cell culture, and wherein said lactate in the first cell culture consists of lactate produced by the cells in the first cell culture; (b) transferring an amount of cells from the first cell culture to a second cell culture, wherein the second cell culture is another seed train cell culture in another culture vessel, and wherein the second cell culture exhibits a reduced rate of lactate accumulation compared to that in an otherwise identical cell culture under otherwise identical conditions except transfer of cells from the first cell culture to the second cell culture is performed prior to the viable cell count reaching 3.0×106 cells/mL; (c) culturing the transferred cells in the second cell culture; and (d) transferring an amount of cells from the second cell culture to a production bioreactor after the cells in the second cell culture have reached a viable cell concentration of 3.0×106 cells/mL to 5.0×106 cells/mL. 2. The method of claim 1, wherein the cells in the first cell culture are cultured to a viable cell concentration of 3.5×106 cells/mL to 5.0×106 cells/mL. 3. The method of claim 2, wherein the cells in the first cell culture are cultured to a viable cell concentration of 4.0×106 cells/mL, 4.5×106 cells/mL or 5.0×106 cells/mL. 4. The method of claim 1, wherein the cells in the first cell culture are cultured to a viable cell concentration of 4.5×106 cells/mL to 5.0×106 cells/mL. 5. The method of claim 1, wherein said viable cell concentration of the second cell culture is 3.5×106 cells/mL to 5.0×106 cells/mL. 6. The method of claim 5, wherein said viable cell concentration of the second cell culture is 3.5×106 cells/mL, 4.0×106 cells/mL, 4.5×106 cells/mL or 5.0×106 cells/mL. 7. The method of claim 1, wherein said viable cell concentration of the second cell culture is 4.0×106 cells/mL to 5.0×106 cells/mL. 8. The method of claim 1, further comprising detecting a reduced rate of lactate accumulation in the second cell culture prior to transfer to the production bioreactor compared to that determined in an otherwise identical cell culture under otherwise identical conditions except transferring cells to the second cell culture is performed prior to the viable cell count reaching 3.0×106 cells/mL. 9. The method of claim 1, further comprising detecting said metabolic shift to lactate consumption by measuring the pH, lactate or base in the first cell culture prior to step (b). 10. The method of claim 9, wherein said metabolic shift to lactate consumption is detected based on an increase in the pH of the first cell culture medium without addition of base. 11. The method of claim 9, wherein said metabolic shift is detected based on measuring the lactate levels in the first cell culture. 12. The method of claim 1, wherein the metabolic shift occurs when the cells emerge from log growth phase or have reached stationary phase in the first cell culture. 13. The method of claim 1, wherein the cells in the first cell culture are transfected with DNA encoding a polypeptide of interest prior to culturing cells in the first cell culture. 14. The method of claim 13, further comprising maintaining the second cell culture and the cell culture in the production bioreactor under conditions that allow expression of said polypeptide of interest, and harvesting said polypeptide of interest from the cell culture in the production bioreactor. 15. The method of claim 14, wherein said protein of interest is selected from the group consisting of antibody, antigen-binding protein, and fusion protein.
A method for culturing cells comprising: (a) culturing cells in a first cell culture to a viable cell concentration of 3.1×106 cells/mL to 5.0×106 cells/mL whereby a metabolic shift to lactate consumption has occurred, wherein the first cell culture is a seed train cell culture, wherein lactate accumulates in the first cell culture, and wherein said lactate in the first cell culture consists of lactate produced by the cells in the first cell culture; (b) transferring an amount of cells from the first cell culture to a second cell culture, wherein the second cell culture is another seed train cell culture in another culture vessel, and wherein the second cell culture exhibits a reduced rate of lactate accumulation compared to that in an otherwise identical cell culture under otherwise identical conditions except transfer of cells from the first cell culture to the second cell culture is performed prior to the viable cell count reaching 3.0×106 cells/mL; (c) culturing the transferred cells in the second cell culture; and (d) transferring an amount of cells from the second cell culture to a production bioreactor after the cells in the second cell culture have reached a viable cell concentration of 3.0×106 cells/mL to 5.0×106 cells/mL.
The method of claim 1, wherein the cells in the first cell culture are cultured to a viable cell concentration of 3.5×106 cells/mL to 5.0×106 cells/mL.
The method of claim 2, wherein the cells in the first cell culture are cultured to a viable cell concentration of 4.0×106 cells/mL, 4.5×106 cells/mL or 5.0×106 cells/mL.
The method of claim 1, wherein the cells in the first cell culture are cultured to a viable cell concentration of 4.5×106 cells/mL to 5.0×106 cells/mL.
The method of claim 1, wherein said viable cell concentration of the second cell culture is 3.5×106 cells/mL to 5.0×106 cells/mL.
The method of claim 5, wherein said viable cell concentration of the second cell culture is 3.5×106 cells/mL, 4.0×106 cells/mL, 4.5×106 cells/mL or 5.0×106 cells/mL.
The method of claim 1, wherein said viable cell concentration of the second cell culture is 4.0×106 cells/mL to 5.0×106 cells/mL.
The method of claim 1, further comprising detecting a reduced rate of lactate accumulation in the second cell culture prior to transfer to the production bioreactor compared to that determined in an otherwise identical cell culture under otherwise identical conditions except transferring cells to the second cell culture is performed prior to the viable cell count reaching 3.0×106 cells/mL.
The method of claim 1, further comprising detecting said metabolic shift to lactate consumption by measuring the pH, lactate or base in the first cell culture prior to step (b).
The method of claim 9, wherein said metabolic shift to lactate consumption is detected based on an increase in the pH of the first cell culture medium without addition of base.
The method of claim 9, wherein said metabolic shift is detected based on measuring the lactate levels in the first cell culture.
The method of claim 1, wherein the metabolic shift occurs when the cells emerge from log growth phase or have reached stationary phase in the first cell culture.
The method of claim 1, wherein the cells in the first cell culture are transfected with DNA encoding a polypeptide of interest prior to culturing cells in the first cell culture.
The method of claim 13, further comprising maintaining the second cell culture and the cell culture in the production bioreactor under conditions that allow expression of said polypeptide of interest, and harvesting said polypeptide of interest from the cell culture in the production bioreactor.
The method of claim 14, wherein said protein of interest is selected from the group consisting of antibody, antigen-binding protein, and fusion protein.