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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/09/2025 has been entered.
Priority
This application is a 371 of PCT/JP2020/036534 filed 09/28/2020. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). based on JP2019-1 78577 filed 09/30/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of the Claims
Claims are 1-5 and 8 are pending. Claim 5 is amended. Claims 9 and 10 are cancelled. Claims 1- 4 are withdrawn.
Claims 5 and 8 (claim set filed 09/09/20245) are examined on the merits herein.
Withdrawal of Rejections
The response and amendment filed on 09/09/2025 are acknowledged. All of the amendment and arguments have been thoroughly reviewed and considered.
For the purposes of clarity of the record, the reasons for the Examiner's withdrawal and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner's response to arguments section.
The previous claims 5 and 8-10 rejections under 35 U.S.C. 112(b) have been withdrawn necessitated by amendment of claim 5 and cancellation of claims 9 and 10.
Claim Objections
Claim 5 is objected to because of the following informalities:
Claim 5 recites: “a bottom section 2 to 10 through-holes”. Applicant is suggested to replace recitation with : “a bottom section with 2 to 10 through-holes”.
Appropriate correction is required.
New Rejection
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 5 and 8 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.
The term “together near the center” in claim 5 is a relative term which renders the claim indefinite. The term “together near the center” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what distance is considered to be “near the center” and how close the through-holes need to be disposed to be considered disposed “together”. The scope and boundaries of claim 5 are not certain making claim 5 indefinite.
Claim 8 does not resolve the issue mentioned above and is rejected.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 103
The following rejections are maintained and/or modified taking into consideration amendment to claim 5 filed 09/09/2025.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 5 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Ricicova (WO 2014153651 A1) in view of Ohsaka (EP 3357998 A1 on record in IDS).
Regarding claim 5, Ricicova teaches a method and device to identify cell population exhibiting an extracellular effect (Abstract). Ricicova discloses a microfluidic platform for the analysis of the extracellular effect of a single cell which can secret a biological factor such as antibody (paragraph 0009). Ricicova mentions that this approach can be used for identification and selection of a single cell producing antibodies in high-throughput screening format (paragraph 0026). Ricicova describes the microreactor (chamber) which can comprise a single cell and readout particles within the microreactor assaying the cell population for the presence of the extracellular effect by direct or indirect readout (Abstract). Ricicova describes that when effector cell is antibody-secreting cell, the particle comprises epitope or antigen for antibody binding (paragraph 0023). Ricicova further describes that the particle can be any particle, including beads and cells, e.g. it can be bead functionalized to bind secreted antibody or cell displaying surface antigen for secreted antibody (paragraph 00252). Beads functionalized to capture antibody by a particular epitope (paragraph 00254) in Ricicova teaching correspond to instant immobilization of a substance having binding affinity to secretion. Secretion binding to a bead or cell can be detected with secondary antibody that serves as detection reagent (paragraph 00255). Ricicova provides an example of identification of the peripheral blood mononuclear cells secreting interferon (IFN) by capturing IFN to beads coated with anti-IFN antibody and detected with a fluorescently labeled secondary antibody (paragraph 00580). Ricicova teaches that the chambers in the microfluidic device house a cell population and a readout particle population to demonstrate the extracellular effect on a readout particle population (paragraph 00274). Ricicova mentions that microfluidic device has flow channel for active fluids and can include wash step and perfusion to exchange reagents. Perfusion and flow of the liquid is controlled by integrated micro-valves and micro-pumps and is pressure driven, e.g. by pumps (paragraphs 0049, 00278-00280). That indicates that the flow of liquid during wash/exchange steps can involve suction through flow channels.
Ricicova does not teach 2-10 through-holes disposed together near the center of the bottom section and having minimum diameter of 10 nm to 20 µm and does not explicitly teach suction holes.
Ohsaka teaches cell-sorting method based on a structure composed of two substrates facing each other (Abstract). The first substrate has a plurality of depressions with upward opening and capturing one cell unit. At least some depressions have communication holes which enable secretion secreted from cells to move to the second structure to accumulation areas (paragraph 0027). Ohsaka mentions that secretions are preferably antibodies (paragraph 0058). Ohsaka describes that the second substrate has a flow channel to remove the substance non-specifically bound to the accumulated secretions or detection reagent and for flowing through a wash solution. The flow channel has connection ports shown on Fig. 3, i.e. ports 4a and 4b and washing solution flows from port 4a to port 4b (paragraphs 0082-0084). Ohsaka describes that capturing is performed by different substances such as cells (paragraph 0076) and detection involves secondary antibody for secreted antibodies. Although the capturing and detection of secretion in Ohsaka teaching is performed on the second substrate and not in the same chamber where cell is located (paragraph 0030), the method of identification of secretion producing cells of Ohsaka has the same steps as described by Ricicova, i.e. plating a single cell in microchambers, capturing of secretion by carriers (cells or beads) and detection with detection reagent (secondary antibodies).
Ohsaka describes that depressions/wells have diameter of 1 to 100 µm (paragraph 0053) and the diameter of communication holes is 10 to 2000 nm (paragraph 0067) that is within the claimed range for the minimum diameter of through-holes. Ohsaka mentions that the number, position, shape and size of communication holes are not particularly limited (paragraph 0066). Ohsaka does not describe position of communication holes, however, mentions different shape of the bottom of wells, including concave shape (paragraph 0045) that may require positioning of holes in the center.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow Ohsaka teaching and add through-holes to the bottom of wells in the device for screening of a secretion-producing cell based on Ricicova teaching. One would have been motivated to do so since Ohsaka provides description of the microfluidic device for the same purpose, i.e. screening of secretion producing cells as Ricicova and involving similar steps and removal of unbound secretion and detection reagent from the well via through-holes at the bottom of the well will increase the detection signal and reduce background signal.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow Ohsaka teaching and add microfluidic channel with ports and holes communicating with the channel to the device for detection of secretion of a single cell based on Ricicova teaching. One would have been motivated to do so to provide washing and exchange of reagents in the chamber or well as described by Ricicova and apply suction since Ricicova described flow of the liquid during wash/exchange steps operated by pumps (paragraph 00278-00280) and hence involving suction. A skilled artisan would have reasonably expected success in the combination of prior art because Ricicova and Ohsaka describe detection of single cells producing secretion and teach detection of cells secreting antibodies.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that wells in Ohsaka teaching can have 2-10 through-holes. One would have been motivated to assume so since the ranges of diameters for the well and communication holes in Ohsaka teaching overlap, for instance the lower limit for well diameter is 1 µm and the higher limit for communication hole is 2 µm and additionally Ohsaka does not limit the number of holes. One would have been motivated with reasonably expected success to optimize the number of communication holes depending of the diameter of the well capturing cell and through-holes and the size of cell and secretion passing through the holes.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that positioning of through-holes on the bottom of wells is a result effective variable. One would have been motivated to try either even distribution of holes and centering holes on the bottom of the well depending on the type of cell and shape of the bottom of the well to obtain the most effective detection of the cell producing a secretion of interest. A skilled artisan would have reasonably expected success in that because selection of the optimal positioning of through-holes is within the skill of the artisan in the field.
Thus, Ricicova and Park teachings render claim 5 obvious.
Regarding claim 8, Ricicova teaches screening of cells secreting different biological factors including antibody (paragraph 0009, 0023). Ohsaka teaches that secretions are preferably antibodies (paragraph 0058). Thus, Ricicova and Ohsaka teachings render claim 8 obvious.
Response to Arguments
Applicant's arguments filed 09/09/2025 have been fully considered but they are not persuasive.
Applicant argues (addressing p. 4-5 of the Remarks) that: “Claim 5 as amended recites that each of the wells has a bottom section with 2 to 10 through-holes sized such that the cell does not pass through, and the 2 to 10 through-holes disposed together near the center of the bottom section. Neither Cai nor Ricicova discloses or suggests anything relating to wells having a bottom section with a though hole.” Applicant further argues that: “Ohsaka fails to disclose anything that would suggest the recited 2 to 10 communication holes disposed together near the center of the bottom section of the depression. … in the device of Ohsaka, the secretion of interest passes through the communication holes … Thus, Ohsaka requires these communication holes to be sufficiently large to allow such pass through to occur. In contrast, claim 5 as amended recites that the 2 to 10 through-holes are sized with a minimum diameter of 10 nm to 20 μm such that the cell does not pass through. In other words, Ohsaka teaches the opposite of that is recited in claim 1, and does not remedy the deficiency in the teachings of Cai and Ricicova.”, these arguments are not persuasive because:
Applicant’s arguments with respect to Cai prior art are moot because the new ground of rejection does not rely on prior art of Cai and is based on combination of prior art of Ricicova and Ohsaka as described above. The pertinent arguments regarding Ricicova and Ohsaka will be addressed.
Although Ricicova does not teach a bottom section with a through-hole, the rejection is based on the combination of prior art of Ricicova and Ohsaka, wherein Ohsaka does teach the bottom of the well to have communication through-holes through which secretion of interest can pass (paragraph 027). In instant case the through-hole are claimed to be designed so that the cell and the carrier particle do not pass through, however, the secretion not bound to carrier particle can pass through similar to Ohsaka teaching. The difference is that Ohsaka teaches detection of secretion not in the well where cell is located but in the lower chamber after passing thought communication hole. However, Ricicova, the primary reference, teaches the presence of the carrier particles for detection in the same well where the cell is located (Abstract) as described above.
Regarding the size of the through-holes, Ohsaka teaches the communication hole to have diameter from 10 nm to 2 µm (paragraph 067) which is within the range of the claimed minimum diameter. Please note that claimed minimum diameter sets the lower limit for diameter, however, does not limit the further diameter increase. The through-holes in Ohsaka teaching do not need to be larger since the secretion of interest, such as antibodies have size close to lower limit of Ohsaka through-holes, i.e. of approximately 12 nm (length) × 12 nm (width) × 3 nm (height) as evidenced by Yeow (Yeow et al., Scientific Reports, 2017, 7, 41956, 1-7; p. 2, 3rd paragraph). The limitation on the number of the through-holes and their positioning on the bottom of the well are addressed in the rejection as described above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIOUBOV G KOROTCHKINA whose telephone number is (571)270-0911. The examiner can normally be reached Monday-Friday: 8:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila G 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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/L.G.K./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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