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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-17 in the reply filed on 03/27/2026 is acknowledged.
Claims 18-20 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/27/2026.
Priority
The instant application claims benefit to PCT/JP2022/000292 (filed on 01/07/2022) and JP2021-001262 (filed 01/07/2021) and is acknowledged. The instant claims herein are examined using the effective filing date of 01/07/2021 for the basis of any prior art rejections.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 09/19/2023, 10/03/2025, and 02/06/2026 were properly filed in compliance with 37 CFR 1.97. Accordingly, the information disclosure statement(s) were considered.
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.
Claim 8 and 17 are rejected 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.
Claim 8 recites “a plurality of the micro flow passages are used, and the micro flow passages are exchanged to evaluate the damage resistance of the cell.” It is unclear what is meant by “the micro flow passages are exchanged to evaluate the damage resistance of the cell”, especially given that the term “exchanged” is not defined anywhere in the specification. How are the microflow passages “exchanged”? Does Applicant mean that the damage resistances of the cells put through the passages are compared to one another? Thus, the claim is indefinite. For the purposes of compact prosecution, the examiner is interpreting the claims under broadest reasonable interpretation to mean the damage resistances of the cells put through the passages are compared to one another.
Claim 17 recites “the cells are cells obtained by increasing the number of monoclonal cells”. There is insufficient antecedent basis for this limitation in the claim because instant claim 1 does not require any particular cell type and does not require any monoclonal cells.
It is noted any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (abstract idea/mental step) without significantly more. This judicial exception is not integrated into a practical application does not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
Step 1 (Statutory Category): This part of the eligibility analysis evaluates whether the
claims fall within any statutory category. Here, the claims recite, inter alia, “A method for selecting cells, comprising: introducing cells into a micro flow passage and allowing the cells to pass through the micro flow passage; evaluating damage resistance of the cells to damage received by the cells due to passing through the micro flow passage; and selecting cells based on the evaluation of the damage resistance.” This is a method/process, therefore the claims fall within a statutory category of invention. [Step 1: YES]
Step 2A (Judicial Exceptions), Prong 1: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. A claim “recites” a judicial exception when the exception is “set forth” or “described” in the claim (see MPEP 2106.04(II)). The claims recite at least one judicial exception. The claims provide a description of a mental step (an abstract idea) in drawing a conclusion from and selecting cells based on introducing cells into a microflow passage, evaluating the resistance to damage that the cells exhibit, and selecting cells based on that evaluation. Thus, the claim recites at least one judicial exception. [Step 2A, Prong 1: YES].
Therefore, the analysis proceeds to Step 2A Prong 2.
Step 2A (Judicial Exceptions), Prong 2: This part of the eligibility analysis evaluates whether the claims as a whole integrate the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claims beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claims as a whole integrate the exception into a practical application. In totality, the claims recite “evaluating damage resistance of the cells to damage received by the cells due to passing through the micro flow passage; and selecting cells based on the evaluation of the damage resistance” as in claim 1, which includes observations and evaluations/analyses which can be performed in the human mind with or without physical aid. This step is a data gathering step that does not integrate the judicial exception into a practical application. It is considered to be insignificant extra-solution activity (see MPEP 2106.05(g)). Note that the recitation of “the damage received by the cell is stress received from a fluid” (claim 2), “the damage resistance of the cell is evaluated based on a damage state of the cell” (claim 3), “evaluated based on viability with respect to an energy dissipation rate” (claim 4), “evaluated based on a lactate dehydrogenase release rate of the cell with respect to an energy dissipation rate” (claim 5), “evaluated based on viability against shear stress” (claim 6), “evaluated based on a lactate dehydrogenase release rate of the cell against shear stress” (claim 7), “a plurality of the micro flow passages are used, and the micro flow passages are exchanged to evaluate the damage resistance of the cell” (claim 8), “an inner diameter dimensional tolerance in the plurality of the micro flow passages is less than ±10%” (claim 9), “the micro flow passage is an electroforming tube” (claim 10), “an inner diameter of the micro flow passage is 10 μm to 3000 μm” (claim 11), “the micro flow passage is a groove” (claim 12), “the groove consists of a combination of a metal plate and a metal plate with a groove” (claim 13), “a width of each side of a cross section of the groove is 10 μm to 3000 μm” (claim 14), “the cell is a Chinese hamster ovary-derived cell or a human embryonic kidney cell 293” (claim 15), “the cells to be selected are a cell for producing a protein” (claim 16), and “the cells are cells obtained by increasing the number of monoclonal cells” (claim 17) are also considered to be extra-solution activities. This is because the limitations merely describe how the “evaluation” steps are performed using microflow passages that have particular physical requirements, the cell type to be sorted/selected, and how the cells are obtained. Thus, the claims do not integrate the recited judicial exception into a practical application of the exception because there are no additional elements recited in the claims beyond the judicial exception [Step 2A, Prong 2: NO]
Step 2B (Significantly More): This part of the eligibility analysis evaluates whether the claims as a whole amount to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (MPEP 2106.05). This is based on an additional consideration of whether the elements in addition to the judicial exception add beyond what was well-understood, routine, and conventional to the claims.
Arena et al (WO2020132231A1; see Applicant’s IDS) evidences the use of a flow constriction microfluidic device to assess the impact of shear stress on HEK293 and HEK293 DKO cells. Briefly, a syringe pump (Harvard Apparatus, Model# 33) was used to pass the cells through the FCD at a flow rate of 70 mL/min or an energy dissipation rate (EDR) of 2.67 x 107 W/m3. The samples were thawed and assayed for lactate dehydrogenase (LDH) using a Cedex Bio HT Analyzer (Roche). Total lysis after FCD (%) was calculated using equation 1 below. Cultures were also sampled for viable cell density (VCD) and viability before and after passing through the FCD. Arena also evidences selection of HEK293 DKO cells (cells used to produce recombinant protein) based on their resistance to apoptosis shear stress in comparison to the parent HEK293 cells (see para 156-169; claims; abstract).
The art demonstrates that using a microfluidic device to sort/select cells based on ability to withstand, e.g., cell damage and shear stress when passed through a micro flow passage would have been routine and conventional in the art. The claims recite the use of such a device to evaluate the ability of cells to withstand such stress at a high level of generality, thus Applicant is relying on the conventional and well-understood use of the device. The additional limitations of claims 2-17 (recited above), and selection of cells based on the ability to withstand cell damage are directly informed by the judicial exception, and therefore are not evidence of additional features over the judicial exception itself. [Step 2B: NO]
In view of the above, the claims are considered to be directed to the judicial exception without integration into a practical application, or adding significantly more to the claim over the judicial exception. Therefore, the claims do not qualify as eligible subject matter under 35 USC § 101.
Claim Rejections - 35 USC § 102/103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-7, and 11-16 are rejected under 35 U.S.C. 102((a)(1)/(a)(2)) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Arena as evidenced by Mollet et al. ((2007), Acute hydrodynamic forces and apoptosis: A complex question. Biotechnol. Bioeng., 98: 772-788; hereinafter “Mollet”).
Arena teaches methods for the production of recombinant polypeptides using apoptosis resistant cells (see title, abstract). Arena teaches the use of a flow constriction device to assess viability and the impact of shear stress on HEK293 and HEK293 DKO cells. Briefly, a syringe pump was used to pass the cells through the FCD (introducing cells into a flow passage and allowing the cells to pass through as in claim 1) at a flow rate of 70 mL/min or an energy dissipation rate (EDR) of 2.67 x 107 W/m3. The samples were assayed for lactate dehydrogenase (LDH) using a Cedex Bio HT Analyzer (Roche). Total lysis after FCD (%) was calculated using equation 1 (see paragraph 0157). Cultures were also sampled for viable cell density (VCD) and viability before and after passing through the FCD (evaluating damage resistance of cells due to passing through the flow passage). Arena also evidences selection of HEK293 DKO cells (cells used to produce recombinant protein) based on their resistance to apoptosis and shear stress in comparison to the parent HEK293 cells (see para 156-169; claims; abstract). Arena further teaches selection of cells maintaining greater than 75% cell viability after exposure to a shear stress of 2.67 x 107 W/m3 energy dissipation rate (EDR) (paragraph 0012).
While Arena doesn’t explicitly teach the passages are microflow passages, Mollet evidences the FCD device used by Arena (see paragraph 0156). Mollet describes the flow device as having 30-gauge stainless steel sheet between PMMA transparent plates, boring of the flow channel using electrical discharge machining, and the flow channel of the device that has 225.4 or 304 um diameter and 5.7 x 7.6 um at the constriction point (see pg. 774 and Fig. 2). Thus, absent evidence to the contrary, the passages of Arena are microflow passages.
In the alternative, it would have been prima facie obvious to one of ordinary skill at the time of filing to use the method of Arena to assess shear stress, energy dissipation rate, and lactate dehydrogenase release of cells using microflow constriction device to arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill would have been motivated to use the method of Arena because Arena explicitly teaches the successful use of the method to select cells with high resistance to apoptosis and shear stress for the production of recombinant proteins.
Regarding claim 2, the damage received by the cell is stress received from a fluid when subject to acute hydrodynamic force (see paragraph 0156 and 0166).
Regarding claims 3-7, Arena teaches evaluating damage, e.g., lysis/apoptosis of the cells, evaluation based on energy dissipation rate, lactate dehydrogenase release, and shear stress (see para 0127, 156-169).
Regarding claim 11 and 14, Arena teaches the diameter of the microflow passage width as 225.4 um (see above).
Regarding claim 12, Mollet evidences the passage is created using boring of a passage channel (i.e., a groove; see Fig. 2).
Regarding claim 13, Mollet evidences the use of stainless steel (i.e., metal plate) to make the microflow passage with a groove.
Regarding claim 15-16, Arena teaches using HEK293 cells for the production of recombinant proteins.
Accordingly, the claimed invention was anticipated by, or in the alternative, rendered prima facie obvious by the teachings of Arena.
Claim Rejections - 35 USC § 103
First rejection
Claims 8-9 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Arena and Mollet.
As discussed above, the claimed invention was anticipated by, or in the alternative, rendered prima facie obvious by the teachings of Arena.
As further discussed above, Arena teaches successful use of the method to select cells with high resistance to apoptosis and shear stress for the production of recombinant proteins.
Arena does not explicitly teach using a plurality of microflow passages and the passages are exchanged to evaluate the damage resistance of the cell.
However, Mollet teaches the use of a flow constriction device as having 30 gauge stainless steel sheet between PMMA transparent plates, boring of the flow channel using electrical discharge machining, and the flow channel of the device that has 225.4 or 304 um diameter and 5.7 x 7.6 um at the constriction point and evaluating hydrodynamic stress and cell damage/lysis of the cells in units of EDR during passage of CHO cells (WT CHO) and CHO-K1 cells transfected with Bcl-2-delta through the passage (see pg. 774 and Fig. 2, 5, and 7). While the microflow device of Mollet contains only one channel, it would have been a matter of routine optimization using standard laboratory techniques available at the time of filing to utilize multiple microflow channels (such as the one of Mollet) with a reasonable expectation of successfully evaluating hydrodynamic stress and cell damage/lysis of the cells (see MPEP 2144.05).
Furthermore, it would have been prima facie obvious to one of ordinary skill at the time of filing to compare damage resistance in the cells using multiple flow passages with a reasonable expectation of success. One of ordinary skill would have been motivated to do so to evaluate the damage of the cells with respect to sensitivity to cell damage/lysis when subjected to well-defined hydrodynamic forces and further quantify the highest level of EDR that a cell can repeatedly sustain and still perform normally (see abstract, see pg. 782, col 2; see pg. 787, col 2).
Regarding claim 9, none of the references explicitly teach the inner diameter dimensional tolerance of the microflow passages is less than ±10%. However, Applicant’s specification evidences the use of microflow passage having an inner diameter of 0.1 mm has a dimensional tolerance of ±2%. As discussed above, the passage of Arena is 225.4 um, which is 0.225 mm. Thus, absent evidence to the contrary, the dimensional tolerance of the passage of Arena has a tolerance of less than ±10%.
Regarding claim 17, Mollet teaches using a cloned CHO cell line overexpressing Bcl-2 gene (i.e., monoclonal cells obtained by increasing the number of cells).
Second rejection
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Arena as applied to claim 1-7, and 11-16 above, and further in view of Chatzipirpiridis et al. (Electroforming of implantable tubular magnetic microrobots for wireless ophthalmologic applications. Adv Healthc Mater. 2015 Jan 28;4(2):209-14; hereinafter “Chatzipirpiridis”).
As discussed above, the claimed invention was anticipated by, or in the alternative, rendered prima facie obvious by the teachings of Arena.
As further discussed above, Arena teaches successful use of the method to select cells with high resistance to apoptosis and shear stress for the production of recombinant proteins.
Arena does not explicitly teach the micro flow passage is an electroforming tube.
However, Chatzipirpiridis teaches that the “fabrication of tubular microstructures has been extensively investigated for several applications such as drug delivery, biosensing, microfluidics, and 3D cell microreactors. Fabrication methods include rolling-up processes, template-assisted atomic layer deposition, spin forming, or water-jet cutting. However, these methods are either time consuming or do not produce the desired geometries of required dimensions but that electrochemical deposition methods offer a high level of tuneability in shape, size, and chemical composition. Moreover, ED is compatible with other micro and nanofabrication processes” (pg. 1, col 2-pg. 2, col1). Chatzipirpiridis teaches the creation of microtubes using electroforming techniques widely used to manufacture complex macroscale shapes and surfaces using cobalt-nickel on aluminum wire. Fig. 1b,c show the electroformed tube with outer and inner diameters of 300 and 125 um, respectively (see pg. 2, col 2).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of Arena by using the electroformed tubes of Chatzipirpiridis to arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Chatzipirpiridis explicitly teaches that electroformed tubular microstructures can be successfully used for microfluidics and offer a high level of tuneability in shape, size, and chemical composition.
Conclusion
NO CLAIMS ALLOWED.
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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