DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
The amendment of 07/10/2026 has been entered. Claims 1-3 and 5-15 are pending in this US patent application. Claims 5-8 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/16/2024.
Claims 1-3 and 9-15 are currently under examination and were examined on their merits.
Withdrawn Rejections
All rejections of the claims under 35 U.S.C. 103 as being unpatentable over Nath are withdrawn in light of the amendment of 07/10/2026, which added multiple limitations to the independent claims. Applicant’s arguments in the remarks of 07/10/2026 that Nath does not teach the newly-added limitations in the claims of 07/10/2026 have been found persuasive.
Claim Rejections - 35 USC § 112
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 applicant regards as his invention.
Claims 1-3 and 9-15 are newly rejected as necessitated by amendment 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.
Independent claims 1, 9, and 12 have all been amended to recite a step that lacks a verb. This step is structured to recite that, when the detection result satisfies certain conditions, the processor in response to the detection result, by performing either or both of the recited processes for removing metabolites. However, the step ends there and does not recite what the processor is doing in response to a detection result by carrying out the processes for removing metabolites; the limitation does not represent a complete sentence. As a method is a series of actions that must be performed, lacking the action in a limitation introduces confusion because one of ordinary skill in the art would be unable to determine what steps are required in the method. Accordingly, claims 1, 9, and 12 are indefinite.
Because claims 2-3, 10-11, and 13-15 depend from the indefinite claims 1, 9, and 12 and provide no further clarification of the indefinite language therein, these claims are also indefinite. Therefore, claims 1-3 and 9-15 are rejected under 35 U.S.C. 112(b).
In the interest of compact prosecution, the Examiner has interpreted these limitations to state that the processor, in response to the detection result satisfying the recited condition, carries out either (claims 1 and 9) or both (claim 12) of the recited processes for removing metabolites.
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.
Claims 1-3 and 9-15 are newly rejected as necessitated by amendment under 35 U.S.C. 103 as being unpatentable over Nath et al., Bioprocess Biosyst. Eng. 40: 123-231 (2017; published online 09/16/2016), in view of Lu et al., Biotechnol. Bioeng. 110(1): 191-205 (2013).
Nath teaches a method to refine the culture medium of human induced pluripotent stem cells (hiPSCs) by dialysis (see entire document, including page 124, left column, paragraph 2; cf. claims 2, 10, and 13). The dialysis of the culture medium is important because hiPSCs produce toxic metabolites during culture, including lactic acid and ammonium, that reduce the growth of hiPSCs in suspension culture (page 123, right column, paragraph 2; the Examiner notes that ammonium ion is ammonia that has been dissolved in water). The hiPSCs were cultured in a medium refining system with a dialysis membrane filter by which used suspension culture medium was refreshed with DMEM/F-12 as the dialysate. To analyze metabolites and cytokines, medium was sampled before and after dialysis (page 124, right column, paragraph 2; cf. claims 1, 9, and 12 [“…repeatedly detecting…adding, with or without discarding the culture solution housed in a culture vessel together with the cell, the culture solution”]; the Examiner notes that the dialysis method taught by Nash requires the periodic addition of fresh medium to the culture bioreactor). Prior to dialysis, the concentrations of lactic acid and ammonium in the culture medium were 1.18 g/L and 0.01 g/L, respectively, and these compounds could not be detected in the culture medium following dialysis (page 126, Table 1; cf. claims 1, 3, 9, 11-12, and 14-15; the concentrations of lactic acid and ammonium prior to dialysis convert to 13 mM and 0.55 mM, respectively; the inability to detect lactic acid and ammonium in the culture medium following dialysis indicates that the concentrations of these metabolites following dialysis intrinsically satisfy conditions (I) and (II) in claims 1, 3, 9, 11-12, and 14-15; the Examiner notes that the undetectable concentrations of lactic acid and ammonium following dialysis indicate that the process for removing these compounds was stopped when the concentrations were lower than the concentrations recited in the instant claims). The concentration at which ammonium was removed from the culture medium was a trace amount that did not exceed the minimum inhibitory level (page 128, right column, paragraph 2). The cells retained expression of pluripotency markers (page 128, right column, paragraph 3; cf. claims 1 and 9).
However, while the lactic acid concentration in the culture medium of Nath prior to dialysis falls within the range recited in claims 1, 9, and 12 (“…7.5 mM or higher”), Nath does not teach that dialysis was initiated at the specific ammonium concentration recited in instant claims 1, 9, and 12. Nath also does not teach performing certain steps with a concentration sensor and a processor as recited in instant claims 1, 9, and 12.
Lu teaches fully automated culture of mammalian cells, including dynamic feeding and media optimization (see entire document, including page 191, abstract). Dynamic feeding processes can result in better growth and productivity with successful control of the byproducts lactate and ammonia (page 192, left column, paragraph 1). Multiple properties of the culture were automatically monitored, including ammonia and lactate concentrations (page 193, right column, paragraph 4; cf. claims 1, 9, and 12; the Examiner notes that performing these actions with automatic devices as taught by Lu would intrinsically require the involvement of a processor). Software was used to develop multiple algorithms for feeding, both a predictive method and a feedback-based algorithm (page 193, left column, paragraph 2; page 197). Automating the method reduces the labor required to perform experiments and allows for rapid optimization and development of high titer processes (page 192, right column, paragraph 1).
While Nath does not teach that dialysis was initiated at the specific ammonium concentration recited in instant claims 1, 9, and 12, it would have been obvious to one of ordinary skill in the art to initiate the removal of ammonium from the culture medium of Nath at any concentration of ammonium because Nath indicates that ammonium is a toxic metabolite that decreases iPSC growth, as discussed above. In addition, Nath indicates that the removal of ammonium occurred at an ammonium concentration that was below the minimum inhibitory concentration of the metabolite in iPSC culture medium. One of ordinary skill in the art would have a reasonable expectation that removing ammonium from iPSC culture medium at any ammonium concentration, including those recited in instant claims 1, 9, and 12, would successfully result in the removal of a toxic metabolite from the culture medium and an increase in iPSC proliferation.
While Nath does not teach the performance of the iPSC culture method in an automated manner, it would have been obvious to one of ordinary skill in the art to do so because Lu teaches automatic processes for performing measurement of metabolite concentrations, including [lactate] and [ammonia], and for dynamically feeding mammalian cell cultures in response to metabolite concentrations. One of ordinary skill in the art would have a reasonable expectation that performing the culture method of Nash in an automated fashion as taught by Lu would successfully result in the decrease of labor requirements and the rapid optimization and development of high titer processes. The Examiner notes that performing the method rendered obvious by Nath in the automated manner taught by Lu would intrinsically require “setting” the processor to desired concentrations of metabolites rendered obvious by Nath, such as the lactic acid and ammonium concentrations recited in instant claims 1, 9, and 12.
Therefore, claims 1-3 and 9-15 are rendered obvious by Nath in view of Lu and are rejected under 35 U.S.C. 103.
The Supreme Court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation…103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions……the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) (emphasis added).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Erin M. Bowers, whose telephone number is (571)272-2897. The examiner can normally be reached Tuesday-Thursday, 6:30-4:00.
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/Erin M. Bowers/Primary Examiner, Art Unit 1653 09/19/2026
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