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 .
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 JP2019-178577 filed 09/30/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of the Claims
Claims 1-5 and 8 are pending. Claim 5 is amended. Claims 6 and 7 are cancelled. Claims 1- 4 are withdrawn.
Claims 5 and 8 (claim set filed 03/09/2026) are examined on the merits herein.
Withdrawal of Rejections
The response and amendment filed on 03/09/2026 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The previous claim 5 objection has been withdrawn necessitated by amendment of claim 5.
The previous claims 5 and 8 rejection under 35 U.S.C. 112(b) has been withdrawn necessitated by amendment of claim 5.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 103
The following rejections are maintained and/or modified taking into consideration amendment to claim 5 filed 03/09/2026.
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) and Hunter (US 20040106097 A1).
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 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 describes that microfluidic chambers are organized in arrays and are contained within a thin membrane (paragraph 0085, Figure 61). Figure 63 demonstrates microfluidic device having 8,192 chambers arranged in 4 sub-arrays of 2,048 (paragraph 0087, Figure 63). Figure 63 demonstrates that the arrays cover the lower surface of the device frame. The arrays of chambers in a membrane in Ricicova teaching correspond to instant cell-mounting membrane. Ricicova mentions that structures containing cells can be removable (paragraph 00439). Ricicova describes 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, does not explicitly teach suction holes and does not teach an inclined surface of the inner peripheral surface of the frame.
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.
Hutter teaches method of processing a biological sample (Abstract). Hutter describes a chamber containing a chip. The chamber has the opening the walls of which are inclined forming obtuse angle with the bottom surface thus protruding towards the chip as the inclined surface extends downward (paragraph 0065, Figure 11-12). Hutter mentions that that design offers advantage of inserting chip into its position from the outside (paragraph 0066). The chip can be envisioned as the detachable membrane containing the plurality of wells of Ricicova teaching.
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 can be optimized. 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.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow Hutter teaching and make lower inner peripheral surface of the frame containing cell mounting arrays in Ricicova teaching inclined. One would have been motivated to do that since Hutter teaches that inclined surface provides advantage to insert chip into its position from the outside and Ricicova teaches that structures containing cells can be removable. Therefore addition of inclined surface of the frame in Ricicova teaching can provide easy exchanges of microfluidic chamber arrays. A skilled artisan would have reasonably expected success in that because Ricicova teaches the device for detection of secretion of a single cell and Hutter provides suggestion for easier manipulation of the device.
Thus, Ricicova, Park and Hutter 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, Ohsaka and Hutter teachings render claim 8 obvious.
Response to Arguments
Applicant's arguments filed 03/09/2026 have been fully considered but they are not persuasive.
Applicant argues (addressing p. 4-5 of the Remarks) that prior art of Ricicova and Ohsaka does not disclose or suggest a device of amended claim 5. Applicant further argues that the device of claim 1 has unexpected advantages, i.e.: “In particular, due to the formation of the inclined surface 38, when recovering secretion-producing cells from the wells 50 of the cell-mounting membrane 6 with an instrument such as a manipulator, a micropipette, or a microcapillary, the cells can be easily recovered even though the wells 50 containing the secretion-producing cells are positioned in front of the inner peripheral edge of the frame 36”. These arguments are not persuasive because:
Current rejection is based on combination of prior art of Ricicova, Ohsaka and Hutter that addresses the new limitations of claim 5 as described in the rejection above.
Regarding the unexpected advantages, it would have been obvious to one of ordinary skill in the art that inclination of the side surface of the frame provides more space around a well selected for cell recovery and hence allows easier access with various instruments. It is noted that the unexpected advantages are suggested, however, not supported by any data.
Additionally, the advantage of the inclined inner peripheral surface of the frame for easier recovery of the cell with instruments recognized by the Applicant does not make the combination of prior art non-obvious because the prior art does not need to point out all advantages if there is a motivation to combine the prior art. Pursuant MPEP 2145: "The fact that appellant 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." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention."). In instant case, Ricicova teaches microfluidic device containing chambers of cell populations organized as arrays and contained in a membrane (paragraphs 0085, 0087, Figures 61 and 63) and mentions that they are removable (paragraph 00439. Hutter teaches that inclined surface provides advantage to insert chip into its position in the frame from the outside (paragraphs 0065, 0066) providing motivation to make lower inner peripheral surface of the frame containing cell mounting arrays in Ricicova teaching inclined so that the inclined surface of the frame can support easy removal or exchange of microfluidic chamber arrays.
Therefore, the 35 U.S.C. 103 rejection is maintained and modified necessitated by amendment of claim 5.
Conclusion
No claims are allowed.
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 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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