DETAILED CORRESPONDENCE Application Status 1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. 2. Applicants’ amendment to the claims filed on 08/30/2024 is acknowledged. This listing of claims replaces all prior listings of claims in the application. 3. Claims 1-2, 4, 6-7, 9-10, 12, 14-15, 17, 19, 21-22, 24, 26, and 29-32 are pending. Priority 4. Acknowledgement is made of applicants’ claimed domestic priority to U.S. Provisional Application No. 63/164988, filing date 03/23/2021. Information Disclosure Statement 5. The IDS filed on 09/16/2024 has been considered by the examiner and a copy of the Form PTO/SB/08 is attached to the office action. Drawings 6. The Drawings filed on 09/22/2023 are acknowledged and accepted by the examiner. Claim Rejections - 35 USC § 112(b) 7. 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 appl icant regards as his invention. 8. Claims 2, 4, 10, 15, 17, 22, and 24 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. Regarding claims 2, 4, 10, 15, 17, 22, and 24 , the term "about" is a relative term which renders the claim indefinite. The term "about" is a term of degree and the examiner has reviewed the specification and can find no examples or teachings that can be used for ascertaining the variance intended by the recited term of degree. Moreover, there is nothing in the specification or prior art of record to indicate that one of ordinary skill in the art could have ascertain the scope of the recited degree. It is suggested that applicant clarify the meaning of the claims. See Supplementary Examination Guidelines for Determining Compliance with 35 U.S.C. §112 and for Treatment of Related Issues in Patent Applications, 76 FR 7162 (Feb. 9, 2011), page 7165. Claim Rejections - 35 USC § 102 9. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale , or otherwise available to the public before the effective filing date of the claimed invention. 10. Claim(s) 1 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Bai et al. ( Biotechnol . Prog. , 2011; examiner cited). 11. Claims 1 and 4 are drawn to a method comprising: culturing host cells comprising a gene encoding a recombinant protein in a cell culture medium, wherein the cell culture medium comprises: ( i ) iron at a concentration of less than 1200 m M; and (ii) citrate at a concentration of less than 2400 m M. 12. With respect to claim 1, Bai et al. teach a method of culturing CHO cells comprising a gene encoding a monoclonal antibody (recombinant protein), wherein the culture medium comprises iron at a concentration of 0.1 mM – 0.5 mM (100 m M – 500 m M) and citrate a concentration of 0.125 mM – 1 mM (125 m M – 1000 m M) [see Abstract; p. 209-210]. 13. Claims 6 , 10 and 12 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Lasko et al. ( US Patent Application Publication 2008/0081356 A1; cited on IDS filed on 09/16/2024). 14. Claims 6, 10 and 12 are drawn to a method comprising: culturing host cells expressing a recombinant protein in a cell culture medium at a first temperature and decreasing the first temperature to a second temperature, wherein the second temperature is lower than 31 o C. 15. With respect to claim 6, Lasko et al. teach a method for large scale production of glycoprotein in cell culture comprising culturing host cells expressing a recombinant protein in a cell culture medium at a first temperature and decreasing the temperature to a second temperature wherein the second temperature is lower than 31 o C [see Abstract; paragraphs 0008-0009; 0115-0117; claims 3-6]. With respect to claim 10, Lasko et al. teach the method wherein the first temperature is approximately 37 o C [see Abstract; paragraphs 0008-0009; 0115-0117; claims 3-6]. With respect to claim 12, Lasko et al. teach the method wherein the second temperature range is approximately 25 to 41 o C or approximately 31 o C [see Abstract; paragraphs 0008-0009; 0115-0117; claims 3-6]. Claim Rejections - 35 USC § 103 16. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. 17. Claim (s) 2 and 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bai et al. ( Biotechnol . Prog. , 2011; examiner cited) . 18. The relevant teachings of Bai et al. as applied to claim 1 is set forth in the 102(a)(1) rejection above. Regarding claims 2 and 4, Bai et al. teach that iron plays a critical role in supporting healthy cell growth where iron deficiency causes poor growth and eventual cell death and too high concentration is potentially cytotoxic [see p. 209, column 2]. Bai et al. further teach that cell culture supplemented with iron and citrate achieves a 30-40% enhancement in production titer and demonstrates a role of these reagents in enhancing cellular translational efficiency [see p. 210, column 1]. Although Bai et al. does not teach the specific range of iron and citrate as recited in claims 2 and 4, such modification would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. MPEP 2144.05.II.A states “[g] enerally differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) .” In the instant case, one of ordinary skill in the art would desire to optimize the concentrations of iron and citrate in the methods of Bai et al. depending on the recombinant protein being expressed and host cell being utilized in order to maximize the translational efficiency and production titer of the host cell and recombinant protein. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. 19. Claims 7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Lasko et al. ( US Patent Application Publication 2008/0081356 A1; cited on IDS filed on 09/16/2024). 20. The relevant teachings of Lasko et al. as applied to claims 6, 10, and 12 are set forth in the 102(a)(1) rejection above. Regarding claims 7 and 9, Lasko et al. teach a method for large scale production of glycoprotein in cell culture comprising culturing host cells expressing a recombinant protein in a cell culture medium at a first temperature and decreasing the temperature to a second temperature wherein the second temperature is lower than 31 o C [see Abstract; paragraphs 0008-0009; 0115-0117; claims 3-6]. Lasko et al. further teach that a culture may be subjected to one or more temperature shifts during the course of the culture and it may take several hours or days to complete the temperature change [see paragraph 0116]. Furthermore, Lasko et al. teach that one of ordinary skill in the art will understand that multiple discrete temperature shifts are encompassed by the disclosure. Although Lasko et al. does not explicitly teach the host cells are cultured at the first temperature for at least 1 day and wherein the decreasing occurs at day 3, such modification would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. MPEP 2144.05.II.A states “[g] enerally differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) .” In the instant case, one of ordinary skill in the art would desire to optimize the time and temperature in order to maximize protein production and efficiency. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. 21. Claims 14-15, 17, 19, 21-22, 24, and 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Lasko et al. ( US Patent Application Publication 2008/0081356 A1; cited on IDS filed on 09/16/2024) and Bai et al. ( Biotechnol . Prog. , 2011; examiner cited). 22. Claims 14-15, 17, 19, 21-22, 24, and 29-32 are drawn to a method comprising culturing host cells expressing a recombinant protein a cell culture medium at a first temperature, wherein the cell culture medium comprises at iron at a concentration of less than 1200 m M an d citrate at a concentration of less than 2400 m M ; and decreasing the first temperature to a second temperature, wherein the second temperature is lower than 31 o C. 23. With respect to claim 14, Lasko et al. teach a method for large scale production of glycoprotein , such as an antibody, in mammalian cell culture comprising culturing host cells expressing a recombinant protein in a cell culture medium at a first temperature and decreasing the temperature to a second temperature wherein the second temperature is lower than 31 o C [see Abstract; paragraphs 0008-0009; 0042; 0055; 0115-0117; claims 3-6]. With respect to claim 22, Lasko et al. teach the method wherein the first temperature is approximately 37 o C [see Abstract; paragraphs 0008-0009; 0115-0117; claims 3-6]. With respect to claim 24 , Lasko et al. teach the method wherein the second temperature range is approximately 25 to 41 o C or approximately 31 o C [see Abstract; paragraphs 0008-0009; 0115-0117; claims 3-6]. With respect to claim 29, Lasko et al. teach the method wherein the recombinant protein is an antibody [see paragraph 0055]. With respect to claim 32, Lasko et al. teach the method wherein the cell culture medium is a chemically-defined cell culture medium [see paragraph 0046]. However, Lasko et al. does not teach the method of claim 14, wherein the culture medium comprises iron at a concentration of less than 1200 m M and citrate at a concentration of less than 2400 m M ; the concentration of iron and citrate recited in claims 15 and 17; the host cells are cultured at the first temperature for at least 1 day and wherein the decreasing occurs at day 3 of claims 19 and 21; the method of claim 30, wherein the method reduces host cell protein levels by at least 30%; and the method of claim 31, wherein the host cell protein is heat shock protein 90 and/or perilipin. Bai et al. teach similar methods of culturing CHO cells comprising a gene encoding a monoclonal antibody (recombinant protein), wherein the culture medium comprises iron at a concentration of 0.1 mM – 0.5 mM (100 m M – 500 m M) and citrate a concentration of 0.125 mM – 1 mM (125 m M – 1000 m M) [see Abstract; p. 209-210]. Bai et al. teach that iron plays a critical role in supporting healthy cell growth where iron deficiency causes poor growth and eventual cell death and too high concentration is potentially cytotoxic [see p. 209, column 2]. Bai et al. further teach that cell culture supplemented with iron and citrate achieves a 30-40% enhancement in production titer and demonstrates a role of these reagents in enhancing cellular translational efficiency [see p. 210, column 1] and teach the reduction of host cell HSP90 levels [see Table 2]. Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Lasko et al. and Bai et al. because Lasko et al. teach methods for increasing protein titer and translational efficiency of mammalian cell culture by culturing cells at a first temperature followed by a decrease to a second temperature. Bai et al. teach similar methods using cell culture supplement with iron and citrate that enhance cellular translational efficiency. One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the teachings of Lasko et al. and Bai et al. because Bai et al. acknowledges that iron and citrate in the culture medium enhance s cellular translational efficiency . Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Although the combination of Lasko et al. and Bai et al. do not teach the specific range of iron and citrate as recited in claims 15 and 17 and the host cells are cultured at the first temperature for at least 1 day and wherein the decreasing occurs at day 3, such modification s would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. MPEP 2144.05.II.A states “[g] enerally differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) .” In the instant case, one of ordinary skill in the art would desire to optimize the concentrations of iron and citrate , temperature and time in the methods of Lasko et al. and Bai et al. depending on the recombinant protein being expressed and host cell being utilized in order to maximize the translational efficiency and production titer of the host cell and recombinant protein. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Furthermore, regarding the reduction of host cell protein levels by at least 30%, MPEP 2145 states “[m] ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (Claims were directed to grooved carbon disc brakes wherein the grooves were provided to vent steam or vapor during a braking action. A prior art reference taught noncarbon disc brakes which were grooved for the purpose of cooling the faces of the braking members and eliminating dust. The court held the prior art references when combined would overcome the problems of dust and overheating solved by the prior art and would inherently overcome the steam or vapor cause of the problem relied upon for patentability by applicants. Granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) "would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art." 596 F.2d at 1022, 201 USPQ at 661.); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991) (Appellant argued that the presence of DEHP as the plasticizer in a blood collection bag unexpectedly suppressed hemolysis and therefore rebutted any prima facie showing of obviousness. However, the closest prior art utilizing a DEHP plasticized blood collection bag inherently achieved same result, although this fact was unknown in the prior art.). "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya , 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention."). ” 24. Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Lasko et al. ( US Patent Application Publication 2008/0081356 A1; cited on IDS filed on 09/16/2024) and Bai et al. ( Biotechnol . Prog. , 2011; examiner cited) as applied to claims 14-15, 17, 19, 21-22, 24, and 29-32 above, and further in view of Nejatihahidein et al. ( Biotechnology Progress , 2020; examiner cited). 25. The relevant teachings of Lasko et al. and Bai et al. as applied to claims 14-15, 17, 19, 21-22, 24, and 29-32 are set forth above. With respect to claim 26, both Lasko et al. and Bai et al. teach purifying the recombinant antibody [see paragraph 0122 of Lasko et al. and p. 216 of Bai et al.]. Lasko et al. further teach purification can be achieved by filtration [see paragraph 0122]. However, the combination of Lasko et al. and Bai et al. do not teach the method wherein the purification is by carbon depth filtration. Nejatihahidein et al. teach that depth filtration including carbon depth filtration is commonly used to remove cells and cell debris as part of the initial clarification step, but it is also effective in removing host cell protein decreasing the burden on subsequent chromatographic steps [see Abstract; p. 1-2]. Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Lasko et al., Bai et al. and Nejatihahidein et al. according to the teachings of Nejatihahidein et al. to include carbon depth filtration in the culturing and purification methods of Lasko et al. and Bai et al. because both Lascko et al. and Bai et al. teach methods of culturing cells for the recombinant production of proteins and purification of said protein. Nejatihahidein et al. teach that depth filtration including carbon depth filtration is commonly used to remove cells and cell debris as part of the initial clarification step, but it is also effective in removing host cell protein decreasing the burden on subsequent chromatographic steps . One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability and would be motivated to combine the teachings of Lasko et al., Bai et al. and Nejatihahidein et al. because Nejatihahidein et al. acknowledges that depth filtration including carbon depth filtration is commonly used to remove cells and cell debris as part of the initial clarification step, but it is also effective in removing host cell protein decreasing the burden on subsequent chromatographic steps . Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Conclusion 26. Status of claims: Claims 1-2, 4, 6-7, 9-10, 12, 14-15, 17, 19, 21-22, 24, 26, and 29-32 are pending. Claims 1-2, 4, 6-7, 9-10, 12, 14-15, 17, 19, 21-22, 24, 26, and 29-32 are rejected. No claims are in condition for an allowance. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT PAUL J HOLLAND whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)270-3537 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday to Friday from 8AM to 5PM . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Manjunath Rao can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 571-272-0939 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /PAUL J HOLLAND/ Primary Examiner, Art Unit 1656