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. Applicant’s amendment to the claims filed on 08/24/2026 in response to the Non-Final Rejection mailed on 02/23/2026 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claims 1-2, 4 6-7, and 9-10 are cancelled.
4. Claims 14-15, 17, 19, 21-22, 24, 26, and 29-32 are pending.
5. Applicant’s remarks filed on 08/24/2026 in response to the Non-Final Rejection mailed on 02/23/2026 have been fully considered and are deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Information Disclosure Statement
6. The IDS filed on 08/24/2026 has been considered by the examiner and a copy of the Form PTO/SB/08 is attached to the office action.
Claim Rejections - 35 USC § 112(b)
7. The rejection of claims 2, 4, 10, 15, 17, 22, and 24 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for the relative term “about” is withdrawn in view of applicants’ amendment to the claims to cancel claims 2, 4, and 10 and amendment to remove the recited term in claims 15, 17, 22, and 24.
Claim Rejections - 35 USC § 102
8. The rejection of claim 1 under 35 U.S.C. 102(a)(1) as being anticipated by Bai et al. (Biotechnol. Prog., 2011; cited on PTO-892 mailed on 02/23/2026) is withdrawn in view of applicants’ amendment to the claims to cancel claim 1.
9. The rejection of claims 6, 10, and 12 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 (US Patent Application Publication 2008/0081356 A1; cited on IDS filed on 09/16/2024) is withdrawn in view of applicants’ amendment to the claims to cancel claims 6, 10, and 12.
Claim Rejections - 35 USC § 103
10. The rejection of claims 2 and 4 under 35 U.S.C. 103 as being unpatentable over Bai et al. (Biotechnol. Prog., 2011; cited on PTO-892 mailed on 02/23/2026) is withdrawn in view of applicants’ amendment to the claims to cancel claims 2 and 4.
11. The rejection of claims 7 and 9 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 (US Patent Application Publication 2008/0081356 A1; cited on IDS filed on 09/16/2024) is withdrawn in view of applicants’ amendment to the claims to cancel claims 7 and 9.
12. The rejection of claims 14-15, 17, 19, 21-22, 24, and 29-32 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; cited on PTO-892 mailed on 02/23/2026) is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendment to the claims.
13. As amended, claims 14-15, 17, 19, 21-22, 24, and 29-32 are drawn to a method for reducing host cell protein during recombinant protein production, the 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 700 mM and 1100 mM and citrate at a concentration of 1400 mM and 2200 mM; and decreasing the first temperature to a second temperature, wherein the second temperature is lower than 31oC.
14. 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 31oC [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 37oC [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 41oC or approximately 31oC [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].
Regarding the limitation “for reducing host cell proteins during recombinant protein production”, this recitation in the preamble of claim 14 merely recites the purpose of the process and does not limit the body of the claims, while the active steps of "culturing” and “decreasing the first temperature" in claim 14 fully and intrinsically“set forth all of the limitations of the claimed invention. See MPEP 2111.02.II.
However, Lasko et al. does not teach the method of claim 14, wherein the culture medium comprises iron at a concentration of less than 700 mM and 1100 mM and citrate at a concentration of 1400 mM and 2200 mM; 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 mM – 500 mM) and citrate a concentration of 0.125 mM – 1 mM (125 mM – 1000 mM) [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 enhances 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 the claims and the host cells are cultured at the first temperature for at least 1 day and wherein the decreasing occurs at day 3, such modifications 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.").”
15. The rejection of claim 26 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; cited on PTO-892 mailed on 02/23/2026) 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; cited on PTO-892 mailed on 02/23/2026) is maintained for the reasons of record and the reasons set forth below.
16. 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.
Response to Remarks Regarding Prior Art Rejections
17. Beginning on p. 6 of applicants’ remarks, applicants in summary contend that neither Lasko nor Bai recognize temperature shift and iron/citrate concentrations as result effective variables in relation to the reduction of host cell protein content. Applicants further contend that the office has not met the initial burden to provide a basis in fact and/or technical reasoning that the allegedly inherent characteristic necessarily flows from the teachings of the applied art.
These arguments are found to be not persuasive in view of the modified rejection set forth above and the reason set forth below. As stated above, regarding the limitation “for reducing host cell proteins during recombinant protein production”, this recitation in the preamble of claim 14 merely recites the purpose of the process and does not limit the body of the claims, while the active steps of "culturing” and “decreasing the first temperature" in claim 14 fully and intrinsically“set forth all of the limitations of the claimed invention. See MPEP 2111.02.II. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
To this end, Lasko et al. explicitly teaches in paragraph 0115 that the temperature of a cell culture will be selected based primarily on the range of temperatures at which the cell culture remains viable, the range in which a high level of glycoprotein is produced and/or range in which the expressed glycoprotein contains a desirable glycosylation pattern. Additionally, 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]. As such, one of ordinary skill in the art is aware that these components and their levels and concentrations would be a variable that would need to be optimized depending on the recombinant protein expression and cell line being used for expression. Accordingly, both Lasko et al. and Bai et al. recognize temperature and iron/citrate concentration as result effective variables.
Regarding applicants remarks that the office has not met the initial burden to provide a basis in fact and/or technical reasoning that the allegedly inherent characteristic necessarily flows from the teachings of the applied art, this argument is found to be not persuasive because the fact that the inventor 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. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the instant case, as stated above, both Lasko et al. and Bai et al. recognize temperature and iron/citrate concentration as result effective variables to be optimized.
Conclusion
18. Status of the claims:
Claims 14-15, 17, 19, 21-22, 24, 26, and 29-32 are pending.
Claims 14-15, 17, 19, 21-22, 24, 26, and 29-32 are rejected.
No claims are in condition for an allowance.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656
