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 8/06/2026 to claim 2 have been entered. Claims 1, 3, 7, 11-15, are 17-19 are canceled. Claims 2, 4-6, 8-10, and 16 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 No claims are withdrawn from consideration at this time.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. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.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.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the invention was filed.
Claims 2, 4-6, 8-10, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2014/0322758; provided in the IDS dated 8/15/2024) in view of Tsuchiya et al. (Gastroenterology (2009), 136, 341-350; provided in the IDS dated 8/15/2024), Singh et al. (Journal of Neurosciences in Rural Practice (2012), 3, 301-310; provided in the IDS dated 8/15/2024), and Mather et al. (US 5,122,469; provided in the IDS dated 8/15/2024).).
Wang teaches methods of culturing mammalian cells, the method comprising contacting CHO cells expressing an antibody with a chemically defined cell culture medium composition (e.g. lacking in serum, see ¶0050) comprising iron citrate at a concentration of 100 µM to 5 mM such as produce the antibody (Example 1), reading in-part on claims 2 and 6, the embodiment of an antibody of claim 9, claim 10, and claim 16. Wang teaches perfusion culture as an alternative to fed-batch and batch-refeed configurations (¶0018), reading on claim 2. Wang teaches that the mammalian cells may be engineered to heterologous express a protein of interest (¶0071 and ¶0099), reading on claim 2. Wang teaches methods of removing a portion of the cells from the bioreactor in a “batch-refeed” configuration (¶0060), reading on the embodiment of cell bleeding (e.g. cell removal) for claim 4. Wang teaches harvesting the recombinant protein(s) produced by the cells (0058), reading on claim 8. Wang teaches that a cell concentration of 10 x 106 cells/ml at less than 5 days of culture (Fig. 11) correlates to maximal viability (Fig. 2), reading on claim 2.
Regarding claims 2 and 5, Wang does not teach a serum-free culture medium composition comprising a retinoid at a concentration of 100-400 µM. Regarding claim 5, Wang does not teach retinoic acid as a species of retinoid. Regarding claim 2, Wang, does not teach a perfusion medium having an osmolarity range of 350-450 mOsmol/kg.
Tsuchiya teaches that addition of all-trans retinoic acid (ATRA) or the acyclic retinoid NIK-333 reduces iron-induced oxidative stress in cultured liver cells as measured by the expression of iron metabolism-related genes (Abstract, Fig. 2, and the paragraph starting “We next examined the expression of…” on p343), reading on claims 1-3 and 5. Tsuchiya teaches retinoid concentrations up to 20 µM (Fig. 2 and 4), reading in-part the on retinoid concentrations of claims 1-3, the embodiment of NIK 333 for the retinoid of claims 1-3, and the embodiment of all-trans retinoic acid for claims 2 and 5.
Singh teaches that addition of retinoids such as trans-retinoic acid at 10 µM reduces iron-induced oxidative stress in cultured neuroblastoma cells (Fig. 1, with oxidative stressed measured by the MTT assay), reading on the embodiment of all-trans retinoic acid for claims 2 and 5.
Mather teaches a serum-free cell culture media composition comprising an osmolarity of 275-400 mOsm (Abstract and Col. 10, lines 58-65), reading on the osmolarity range of claim 2. Mather teaches the compositions would be used for culturing mammalian cells (Abstract).
Regarding the retinoid of claims 2 and 5, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the trans-retinoic acid of either Tsuchiya or Singh or the acyclic retinoid NIK-333 of Tsuchiya to the serum-free culture media of Wang. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Wang, Tsuchiya, and Singh are all directed towards cell culture media compositions for culturing of mammalian cells. The skilled artisan would have been motivated to do so because Tsuchiya and Singh both teach that the addition of retinoids would predictably reduce iron-induced oxidative stress in mammalian cells, and so the addition would predictably advantageous to reduce iron-induced oxidative stress potentially caused by the iron in Wang’s cell culture medium and so maintain cell density and reduce cell bleed in the methods Wang.
Regarding the retinoic acid concentration of claim 2 and wherein clause to cell viability, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case, Tsuchiya teaches that addition of all-trans retinoic acid (ATRA) or the acyclic retinoid NIK-333 at 20 µM reduces iron-induced oxidative stress in cultured liver cells as measured by the expression of iron metabolism-related genes Singh teaches that addition of retinoids such as trans-retinoic acid at 10 µM reduces iron-induced oxidative stress in cultured neuroblastoma cells, and thus sets forth that the retinoid concentration in methods of culturing animal cells is a known result-effective variable and subject to routine optimization by persons of ordinary skill in the art. Therefore, the burden is shifted back to Applicant to show the criticality of the claimed range by a preponderance of evidence.
Regarding the preamble and first and second wherein clauses of step (c) of claim 2, claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See M.P.E.P. § 2111.02 and 2111.04. In this case, these limitations have been fully considered but only appear to be a statement of intended outcome for claims 1 and 2 and so the methods of Wang in view of Tsuchiya and Singh are reasonably presumed to be capable of meeting the claim limitations absent any showing to the contrary.
Regarding the osmolarity range of claim 2, it would have been obvious to a person of ordinary skill in the art before the invention was filed to further formulate Wang’s cell culture media at 350-450 mOsm in view of Mather. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Wang and Mather are directed towards serum-free cell culture media compositions for mammalian cell culture. The skilled artisan would have been motivated to do so because the further formulation would predictably yield a suitable osmolarity for the culturing of Wang’s mammalian 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 5-10 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
On pages 5-8 of the reply, Applicant alleges that Fischer 1981 (NPL cite number 1, provided in IDS dated 8/15/2024 and a copy therewith in parent Application 16/496,523) teaches away from the claimed methods, relying on a passage from Fischer that the rate of growth of CHO cells in 10-50 μM retinol was progressively reduced in suspension culture. This is not found persuasive because Fischer does not criticize, discredit, or otherwise discourage the claimed solution of the combination of 350 μM to 3.5 mM Fe ions and 100-200 μM retinol. See M.P.E.P. § 2145(X)(D)(1). Fischer is silent regarding Fe ions, and so cannot reasonably support the allegation of teaching away because Fischer does not teach effect any particular combination of Fe ions combined with retinol concentrations > 50 μM would have on their CHO cells in suspension. While Wang as cited is directed towards CHO cells, Applicant did not amend claim 2 accordingly with the instant reply and so the arguments are not reasonably commensurate to the scope of the claims. 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).
On pages 8-9 of the reply, Applicant alleges that the claimed retinol concentration range is critical. See M.P.E.P. § 2144.05(III). In this case, Applicant’s arguments are not persuasive because “…the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Applicant’s arguments rely on the alleged teaching away by Fischer, which is not persuasive for the reasons in the preceding paragraph, and Applicant has not yet shown by a preponderance of evidence that the combination of the iron and retinol concentrations of claim 2 achieves any unexpected result. Applicant’s reliance on the disclosure is not persuasive because the disclosure as a whole only shows operability of the claimed methods, which is not germane for considerations of non-obviousness under 35 U.S.C. § 103. Separately, the arguments are not reasonably commensurate to the scope of the claims as claim 2 was not amended to recite any degree of improvement in cell viability across any range of time. 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).
Tsuchiya and Singh as a whole teach that lower retinol concentrations are known to reduce iron-induced oxidative stress in mammalian cells, and Wang teaches that the claimed iron concentration range is desirable in methods of producing an antibody from CHO cells. Because reduction of iron-induced oxidative stress in mammalian cells was known, the claimed retinol concentration must be held prima facie obvious as optimization/routine experimentation of a known result-effective variable persuasively shows otherwise. At this time, there is no evidence of any new or unexpected result which is different in kind and not merely of degree, no evidence of teaching away from the claimed parameters, no evidence that the claimed parameters are not in-fact result effective, and the prior art ranges are not so broad as to not invite routine optimization; see E. I. DuPoint de Nemours & Co. v. Synvina C. V. 904 F.3d 996 (Fed. Circ. 2018) at 1006-1007.
Conclusion
No claims are allowed. No claims are free of the art.
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 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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