DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 6/16/2026 to claim 1 and 80 have been entered. Claims 2, 4, 5, 8-10, 12-14, 16-25, 27-40, 43, 44, 47-67, 69-72, 74-77, and 79 are canceled. Claims 1, 3, 6, 7, 11, 15, 26, 41, 42, 45, 46, 68, 73, 78 and 80-83 remain pending, and are being considered on their merits. No claims are withdrawn from consideration at this time. References not included with this Office action can be found in a prior action.
The instant amendments to claims 1 and 80 have overcome the 35 U.S.C. § 103 rejections of record over Yang in view of Oshodi and Kaufmann and as evidenced by Gawlitzek, which are withdrawn. New grounds of rejection are set forth below necessitated by said amendments.
Any other rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 6, 7, 11, 15, 26, 41, 42, 45, 46, 68, 73, 78, and 80-83 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. (US 2016/0237399) in view of Oshodi et al. (WO 2014/144198), Kaufmann et al. (Biotechnol Bioeng (1999), 63: 573–582) and Yang et al. (US 2014/0154726; hereafter referred to as “the Yang ‘726 pre-grant publication), and as evidenced by Gawlitzek et al (US 2011/0091936).
This rejection addresses the embodiment of claim 1 and 80 wherein “for reduction of an amount of ammonia”, and for claim 1 “wherein the mammalian cell cultured in the glutamine-free cell culture medium … exhibits an increased expression level of the target protein compared to the same mammalian cell cultured in a glutamine-free cell culture medium not comprising hypoxanthine … and thymidine … without negatively affecting cell viability and density” are statements of intended use/outcome that does not impart any manipulative difference to the claim. See M.P.E.P. § 2111.02 and 2111.04. Prior art that reads on the hypoxanthine and thymidine concentrations of claims 1 and 80 is presumed capable of inherently meeting the functional limitations in the preamble absent any showing to the contrary, as well as the limitations of claims 1, 36, and 37. Similarly, claims 3, 6, 7, 10, 11, 15, 41, 42, 45, and 46 depend from claim 1 and claims 81-83 depend from claim 80 and further recited addition functional effects and so prior art that reads on hypoxanthine and thymidine concentrations of claim 1 is presumed capable of inherently meeting the functional limitations of these additional dependent claims absent any showing to the contrary. See the evidentiary teachings of Gawlitzek in that glutamine in cell culture medium generates ammonia as a by-product and that lowering glutamine levels then lowers ammonia levels in the culture medium and thus lowers cellular cytotoxicity (see Gawlitzek at ¶0003), and so would be reasonable construed as improving target protein production and improving cellular viability by lowering cellular cytotoxicity. Also see M.P.E.P. § 2112. Any teaching in the prior art of reduced glutamine or a glutamine-free cell culture will inherently be capable of reducing ammonia in a culture process as claimed.
This rejection addresses the embodiment of CHO cells for claims 1 and 80.
Yang teaches a method of culturing CHO cells in a glutamine-free culture medium comprising 1 mM (i.e. 1,000 µM) hypoxanthine and 0.16 mM (i.e. 160 µM) thymidine to produce immunoadhesin (¶0028 and Fig. 6A-B), reading in-part on claims 1, 3, 6, 7, 10, 11, 14, 15, 18, 41, 42, 45, 46, and 68, and 80-83 as evidenced by Gawlitzek. Yang teaches hypoxanthine concentrations in the range of 0.1-10 mM (i.e. 100-10,000 µM) and thymidine concentrations in the range of 0.005-0.5 mM (i.e. 5-500 µM (¶0114-0115), reading in part on the hypoxanthine and thymidine concentration ranges of claims 1 and 80. Yang teaches culturing the cells at temperatures conducive to the survival, growth, and viability of the cell (¶0190), reading in-part on claim 73. Yang further teaches that a person of ordinary skill in the art would understand it can be beneficial to control or regulate the internal conditions of a bioreactor such as temperature or pH (¶0190), reading in-part on claim 73. Yang teaches CHO cells grow well at 37 °C and 31 °C (¶0039), reading on claim 73. Yang teaches varying the days from 0 days to 20 or more days the cells are cultured depending upon the starting concentration of cells and temperature (¶0197), reading on claim 73. Yang further teaches producing recombinant glycoproteins such as antibodies by culturing cells engineered to express the recombinant glycoprotein of interest (¶0153), reading in-part on claim 73. Yang teaches producing recombinant glycoproteins such as antibodies by culturing cells engineered to express the recombinant glycoprotein of interest (¶0153), reading in-part on claims 26 and 78. Yang further teaches adding glucose to the culture media (¶0185), reading in-part on claim 78. Yang further teaches producing recombinant glycoproteins such as antibodies by culturing cells engineered to express the recombinant glycoprotein of interest (¶0153), reading in-part on claims 1 and 80.
Regarding claims 1 and 80, Yang does not teach a single embodiment of a method comprising hypoxanthine at a concentration range of 150-750 µM and thymidine at a concentration range of 25-200 µM. Regarding claims 1 and 80, Yang does not teach etanercept.
Regarding claim 73, Yang does not teach the embodiment of culturing the cells in a first temperature for 3 days or more and then a second temperature for 2 days and wherein the second temperature is 1-8°C lower. Regarding claim 26, Yang does not teach a culture medium further comprising magnesium and uridine. Regarding claim 78, Yang does not teach adding glucose at 2 g/L.
Oshodi teaches a cell culture medium for production of a protein of interest (Abstract). Oshodi teaches adding pyrimidines such as hypoxanthine and thymidine to cell culture media at a concentration of at least 50 µM (¶00049), reading on the concentrations of those compounds of claims 1 and 80. Oshodi teaches adding magnesium salt to the culture medium to set the osmolarity of the culture medium composition to less than about 300 (¶00013-14 and ¶00062), reading on claim 26. Oshodi teaches adding uridine as a species of nucleoside to the cell culture medium ((¶00014), reading on claim 26. Oshodi teaches adding glucose to the culture medium at a concentration of 1-20 mM and up to 10 g/L (¶00069), reading on claim 78. Oshodi teaches methods of producing a protein of interest utilizing CHO cells (¶00024), reading on claims 26 and 78.
Kauffman teaches that lowering the cultivation temperature from 37°C to 30°C after three days of growth causes growth arrest in CHO-derived cell line and improves heterologous protein production for up to 5 days (Abstract; Fig. 4 and paragraph starting “The increase of specific SEAP productivity…” through the end of the next paragraph ending “… in 30°C cultures.”), reading on claim 73.
The Yang ‘726 pre-grant publication teaches methods of culturing cells and producing recombinant proteins (Abstract and ¶0002). The Yang ‘726 pre-grant publication teaches methods of culturing cells and producing etanercept as an exemplary species of antibody (¶0190), reading on claims 1 and 80. The Yang ‘726 pre-grant publication teaches detailed methods of culturing CHO cells to produce recombinant galactosidase (Example 1), reading in-part on claims 1 and 80.
Regarding the hypoxanthine and thymidine concentration ranges of claims 1 and 80, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). In this case, both Yang and Oshodi are directed towards methods of cell culture and cell culture compositions comprising hypoxanthine and thymidine and both Yang and Oshodi teach the claimed concentration ranges, and so the claimed hypoxanthine and thymidine concentration range must be held prima facie obvious absent any showing of criticality to the contrary. See M.P.E.P. § 2144.05.
Regarding the etanercept of claims 1 and 80, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substituted the non-specified antibody of Yang with the etanercept of the Yang ‘726 pre-grant publication. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Yang and the Yang ‘726 pre-grant publication are both directed towards producing recombinant antibodies from CHO cells. The skilled artisan would have been motivated to do so because the substitution would predictably yield a method of producing a known antibody, etanercept, in the Yang’s methods of producing a protein of interest from CHO cells. See M.P.E.P. § 2143(I)(B).
Regarding claim 73, it would have been obvious to a person of ordinary skill in the art before the invention was filed to modify the cultivation methods of Yang in view of Kaufmann. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Kaufmann and Yang are directed towards cultivating CHO or CHO-derived cells to produce heterologous proteins. The skilled artisan would have been motivated to do so because Kaufmann teaches there that lower the cultivation temperature to 30°C after an initial cultivation at 37°C for three days causes growth arrest in CHO-derived cell line and improves heterologous protein production by the CHO-derived cell line, and so the modification would predictably improve heterologous protein production by the CHO cells in Yang’s methods.
Regarding claim 26, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the magnesium of Oshodi to the culture medium and methods of Yang. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Oshodi and Yang are directed towards methods of producing proteins of interest from CHO cells. The skilled artisan would have been motivated to do so because Oshodi teaches that the addition would be predictably advantageous to adjust the osmolarity culture medium compositions.
Regarding claim 26, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the uridine of Oshodi to the culture medium and methods of Yang. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Oshodi and Yang are directed towards methods of producing proteins of interest from CHO cells. The skilled artisan would have been motivated to do so because Oshodi teaches that the addition would be predictably advantageous as a species of nucleoside in cell culture media compositions for CHO cells and in methods of producing proteins of interest from CHO cells.
Regarding claim 26, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the glucose concentrations of Oshodi to the culture medium and methods of Yang. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Oshodi and Yang are directed towards methods of producing proteins of interest from CHO cells, and because Yang teaches adding glucose. The skilled artisan would have been motivated to do so because Oshodi teaches that the addition would be predictably advantageous as a specific concentration of glucose in cell culture media compositions for CHO cells and in methods of producing proteins of interest from CHO cells.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 8-11 of the reply have been fully considered over the modified grounds of rejection set forth above and necessitated by the instant amendments, but not found persuasive of error for the reasons set forth below.
On pages 8-9 of the reply, Applicant alleges that the cited references teach away from the claimed methods. This is not found persuasive because nothing in the cited references otherwise criticizes, discredits, or otherwise discourages the solution claimed; see M.P.E.P. § 2145(X)(D)(1). Applicant arguments amount to a general allegation without citing any specific portion of Yang, Oshodi, Kaufmann and/or the Yang ‘726 pre-grant publication in support of allegation of teaching away at this time.
In response to applicant's arguments against the references individually on page 9 of the reply, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Applicant’s allegation that Yang does not teach every element of claims 1 and 80 is not persuasive because Applicant’s arguments do not address the teachings of Oshodi, Kaufmann and the Yang ‘726 pre-grant publication and what the combination of references would suggest to a person of ordinary skill in the art.
On pages 9-10 of the reply, Applicant alleges the disclosed methods yield an unexpected result with respect to ammonia reduction. See M.P.E.P. § 716 for general guidance with respect to secondary considerations and allegations of unexpected results. The argument is not found persuasive of error for two reasons. First, the features upon which applicant relies (i.e., any particular degree of ammonia reduction across any particular time range and for any particular cell type) are not recited in the rejected claim(s); although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Second, there is insufficient evidence of record to determine if the disclosed ammonia reduction is really unexpected (e.g. greater than expected) relative to the cited references, see M.P.E.P. § 716.02. Fig. 1 of the disclosure as cited demonstrates operability of the claimed methods, which is not germane for considerations of nonobviousness under 35 U.S.C. § 103 and the operability of the claimed methods has not been challenged under any 35 U.S.C. § 112(a) rejection.
Conclusion
No claims are allowed. No claims are free of the art.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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