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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/10/2026 has been entered.
Response to Amendments
Applicant's amendments filed 4/10/2026 to claims 2, 4-6, 8, 10, and 16 have been entered. Claims 1, 3, 7, 11, and 17-19 are canceled. Claims 2, 4-6, 8-10, and 12-16 remain pending, of which claims 2, 4-6, 8-10, and 16 are being considered on their merits. Claims 12-15 remain withdrawn from consideration. 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 Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.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 1, 2, 6, 7, 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 claims 1 and 2. Wang teaches that the mammalian cells may be engineered to heterologous express a protein of interest (¶0071 and ¶0099), reading on claims 1 and 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 1.
Regarding claims 1, 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 1, 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 1-3 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 1-3 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 17. Mather teaches the compositions would be used for culturing mammalian cells (Abstract).
Regarding the retinoid of claims 1, 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 at 100 µM 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 claims 1 and 2, 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 first and second wherein clauses of step (c) of claim 1, and the preamble 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 1, 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.
Applicant’s remarks on pages 5-6 of the reply are not found persuasive, because they respond to the Examiner’s reply to Applicant’s remarks in the last Office action and not the obviousness rejections of record set forth above.
In response to applicant’s argument on pages 6-8 of the reply that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, 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 at 100 µM 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.
On page 8 of the reply, Applicant alleges that modifying Wang with the retinoids of Tsuchiya and Singh would render Wang unsatisfactory for its intended purpose (see M.P.E.P. § 2143.01(V-VI), and noting that any given course of action often has simultaneous advantages and disadvantages and this does not necessarily obviate motivation to combine). In this case, the argument is not found persuasive because the antioxidant effect of Tsuchiya and Singh’s retinoids would predictably reduce iron-induced oxidative stress in mammalian cells and so maintain or improve cell density and reduce cell bleed in the methods Wang. In other words, the iron concentration in Wang’s methods is not the only determinant of successful culturing of mammalian cells, and Applicant has not provided any factual evidence that the addition of retinoids at the claimed concentrations to Wang’s culture methods would otherwise be detrimental because of the retinoid addition.
Furthermore, Applicant’s arguments are directly contradicted by the further arguments on pages 8-9 of the reply extolling the merits of the disclosed invention. If Applicant is alleging that the claimed method produces unexpected results, than this argument is not persuasive for several reasons. First, 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 this case, the skilled artisan would have been motivated to add the trans-retinoic acid of either Tsuchiya or Singh or the acyclic retinoid NIK-333 of Tsuchiya at 100 µM to the serum-free culture media of Wang 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. Second, Applicant has not shown by a preponderance of evidence that the claimed method produces any unexpected result; see M.P.E.P. § 716 as a whole and particularly 716.01-02.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at 571-272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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