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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/19/2025 has been entered.
Response to Amendment
Applicant amendments filed 09/19/2025 have been entered. Applicant amendments overcomes the previous claim objection set forth in the Office Action mailed 05/22/2025, the previous claim objection is withdrawn. Applicant amendments do not overcome each and every 112(b) rejection set forth in the Office Action mailed 05/22/2025, please see 112 section below.
Status of Claims
Claims 1, 3-6, 13-19, 21, 23-27, 30-31 remain pending in the application, with claims 1, 3-6, 13-14 being examined and claims 15-19, 21, 23-27, 30-31 being withdrawn pursuant to the election filed 06/28/2024.
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, 3-6, 13-14 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 1 recites “wherein the upper wall (6), the side walls (8), and the at least two porous membranes (4) define compartment volumes,” on lines 12-13, and “wherein the at least two porous membranes (4) and the side walls (8) define a volume of the at least one inner compartment (12).” on lines 16-17. From lines 12-13 it is describing that the upper wall, side walls and at least two porous membranes define compartment volumes, where the compartments described previously include an inner compartment, lower compartment, and upper compartment. Lines 16-17 make it unclear if the volume of the at least one inner compartment is the same or different from the compartment volume described on lines 12-13.
For examination, it will be interpreted that the volume described in lines 16-17 is referring to the compartment volume.
Claims 3-6, 13-14 are rejected by virtue of being dependent on a rejected claim.
Claim 5 has been amended to recite “wherein the at least two porous membranes (4) and the bottom wall (7) and/or the upper wall (6) and/or at least one of the side walls (8) of the one or more of the compartments comprise at least two additional electrodes (5) on one or more of their surfaces.” This is still unclear because claim 1 describes “wherein at least one of the at least two porous membranes (4) comprises on its surface at least one electrode (5)” on lines 14-15, where claim 5 is saying that the at least two porous membranes comprise at least two additional electrodes. Does this mean that one of the porous membranes will have at least three electrodes (or two more than however many electrodes are on the porous membrane according to claim 1)? The bottom wall, upper wall, and/or side walls having at least two additional electrodes is clear because they have not been previously described to have electrodes. The at least two porous membranes comprising at least two additional electrodes is unclear because the at least one porous membrane has already been described to have on its surface at least one electrode.
Claim 6 recites “opposite to a second one of the at least one electrode (5) on a surface of a second one of the at least two porous membranes (4) and/or the bottom wall (7) and/or the upper wall (6) of one or more of the compartments.” on lines 3-5. It is unclear if the second electrode is just on the second porous membrane, or if the electrode could be on any of the second porous membrane, bottom wall, or upper wall.
In the instance of the electrode being on any of the second porous membrane, bottom wall, or upper wall, with the phrasing “and/or” it becomes unclear how a single electrode can be on all three of the second porous membrane, bottom wall, and upper wall. In other words, how is a single electrode in multiple places at once?
Claim 14 bullets a and b are unclear due to the usage of “and/or”. Specifically, for bullet a, it recites “at least one of said at least two porous membranes (4) comprises the at least one electrode (5) facing the upper compartment (2) and/or the at least one inner compartment (12) and the upper wall (6) and/or one of the side walls (8) of the upper compartment (2) and/or the bottom wall (7) and/or one of the side walls (8) of the lower compartment (3) comprise at least one additional electrode (5) on its surface,” where it is unclear where the limitation for the at least one electrode ends, and where the limitation for the at least one additional electrode on its surface begins.
Similarly, bullet b is unclear for the same reason as a. It is unclear where the limitation for the at least one electrode ends and the limitation for the at least one additional electrode begins.
Claim Rejections - 35 USC § 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 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.
Claim(s) 1, 3-6, 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wikswo (US-2018/0326417-A1) in view of Achyuta (US-2015/0140581-A1).
Regarding claim 1, Wikswo teaches a microfluidic device for determining the transepithelial electrical resistance (TEER) of a cell layer or a cell assembly and/or for determining the impedance of cells, the cell layer or the cell assembly, said device comprising:
at least one microchannel comprising at least a lower compartment (chamber 264) and an upper compartment (chamber 261) separated by at least two porous membranes (filter membranes 268 and 267) ([0134, Figure 2B); and
at least one inner compartment (chamber 263) positioned between the lower compartment (264) and the upper compartment (261) ([0134], Figure 2B),
wherein the lower compartment (264) comprises a bottom wall (glass plate 209) and side walls ([0133], [0134], Figures 2A-B, further see Figure 2B in particular where there are understood to be side walls for each chamber 261, 262, 263, and 264 where together that make the side walls),
wherein the upper compartment (261) comprises an upper wall (upper window 239) and the side walls, and the bottom wall (209) ([0133], [0134], Figures 2A-B, see Figure 2B where there are side walls for each chamber 261, 262, 263, and 264 that together that make the side walls),
wherein the upper wall (239), and the side walls, and the at least two porous membranes (268 and 267) define compartment volumes ([0133], [0134], Figures 2A-B),
wherein the at least two porous membranes (268 and 267) and the side walls define a volume of the at least one inner compartment (263) (see Figure 2B where chamber 263 is between membranes 268 and 267).
Wikswo does teach where pumps, valves, and tubing can be configured with current-injection electrodes, voltage-sensing electrodes, and a fixed-or swept-frequency analyzer to create an integrated instrument that is capable of measuring transendothelial electrical resistance (Wikswo; [0032]), Wikswo does not teach wherein at least one of the at least two porous membranes comprise on its surface at least one electrode.
In the analogous art of measuring transendothelial electrical resistance, Achyuta teaches a device with a first and second layer of electrodes (Achyuta; [0008], [0081]).
Specifically, Achyuta teaches where a device 400 has a first layer of electrodes 432 that are countersunk into base layer 402 and a top layer of electrodes 430 on roof 430 (from Figure 4A and description of the roof being element 430, it is understood that the electrodes should be reference number 431) (Achyuta; [0081]). It is seen in Figure 4A that the electrodes 432 are on the surface of barrier 410, where from [0052] the barrier is a porous barrier that includes a membrane. Additionally, [0013] describes that the method includes measuring trans-endothelial electrical resistance across the cells, visualizing the cells in the device by microscopy, and/or removing the cells from the device and performing biochemical analysis or microscopy on the removed cells.
Examiner further finds that the prior art contained a device/method/product (i.e., a five-layer microfluidic bioreactor) which differed from the claimed device by the substitution of component(s) (i.e., electrodes in the pumps, valves, and tubing) with other component(s) (i.e., electrodes on the filter membrane and upper window), and the substituted components and their functions were known in the art as above set forth. An ordinarily skilled artisan could have substituted one known element with another (i.e., the electrodes in the pumps, valves, and tubing and instead have the electrodes on the membranes and upper window), and the results of the substitution (i.e., measuring TEER) would have been predictable.
Therefore, pursuant to MPEP §2143 (I), Examiner concludes that it would have been obvious to an ordinarily skilled artisan to substitute the electrode position of reference Wikswo with the electrode position of reference Achyuta, since the result would have been predictable.
Regarding claim 3, modified Wikswo teaches the device according to claim 1. In the device of Wikswo, there will now be electrodes on membranes 266, 267, and 268 and the upper window 239 as taught by Achyuta. It is understood that the electrodes on membrane 268 will face chamber 264, 263, 261 depending on what side of the electrodes is being used as a reference point.
Regarding claim 4, modified Wikswo teaches the device according to claim 1. The device of Wikswo has been modified with Achyuta such that there are now electrodes on upper window 239.
Regarding claim 5, modified Wikswo teaches the device according to claim 1. The device of Wikswo has been modified with Achyuta such that there will be at least two electrodes on upper window 239.
Regarding claim 6, modified Wikswo teaches the device according to claim 1. The device of Wikswo has been modified with Achyuta such that there are electrodes on filter membrane 268, where these electrodes are understood to be positioned substantially opposite to the upper window 239 and glass plate 209 depending on what surface of the electrode is being used as a reference point.
Note that while not required, filter membrane 267 also now has electrodes on its surface, and the electrodes on filter membrane 268 and the electrodes on filter membrane 267 will be opposite to one another.
Regarding claim 14, modified Wikswo teaches the device according to claim 1. The device of Wikswo has been modified with Achyuta where there are electrodes on membranes 266, 267, and 268. The electrodes on membranes 268 or 267 will face chamber 263.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wikswo (US-2018/0326417-A1) and Achyuta (US-2015/0140581-A1), and in further view of Guimera (WO-2015/181322-A1).
Regarding claim 13, modified Wikswo teaches the device according to claim 1. Wikswo has been modified by Achyuta such that there are now electrodes on filter membranes 268 and 267, however the electrodes are not arranged as interdigitated electrodes having a plurality of digits forming an electrode pattern. It is further described by [0135] of Wikswo that the vertical distance between the lowest chamber and top of the upper chamber is minimized as to allow cells in the various chambers to be within the working length of a high-power, high numerical aperture microscope objective, and [0013] of Achyuta that the method includes measuring trans-endothelial electrical resistance across the cells, visualizing the cells in the device by microscopy, and/or removing the cells from the device and performing biochemical analysis or microscopy on the removed cells.
In the analogous art of measuring trans-layer electrical impedance in an in vitro model of a cell barrier, Guimera teaches electrodes that are arranged in an interdigitated manner (Guimera; page 1 lines 7-10, page 4 lines 14-17).
Specifically, Guimera teaches where interdigitated electrodes means a plurality of electrodes arranged in an interlocking comb-shape, where each electrode comprises an array of parallel fingers, where in Figure 1 there is a first set of electrodes 6 that comprises a first electrode 6a and a second electrode 6b that are arranged in an interdigitated manner on the upper inner surface of upper chamber 1 (Guimera; page 10 lines 13-15, page 13 lines 9-12).
It would have been obvious to one skilled in the art to modify the electrodes of Wikswo that are now on the filter membranes as taught by Achyuta such that they are interdigitated electrodes as taught by Guimera because it is taught by Guimera that interdigitated electrodes are an optimal electrode configuration that allows a similar sensitivity along a defined cell culture area without impairing the optical visualization of the cell culture (Guimera; page 13 lines 19-24).
Response to Arguments
Applicant's arguments filed 09/19/2025 have been fully considered but they are not persuasive.
With regards to applicant arguments on page 10 of 13 that states Achyuta relates to shield connector structures and is from a non-analogous field, it is noted that there was a typographical error in the Office Action mailed 05/22/2025 which cited Achyuta as “US-2015/140851-A1)”. This should instead be “US-2018/0140581-A1”. Please note that this reference appeared in the Office Action mailed 11/15/2024 and was correctly cited, and also appeared on the PTO-892. Additionally, on page 11 of 13 of the remarks filed 09/19/2025 applicant correctly describes the Achyuta reference.
With regards to applicant arguments on page 10 of 13 that Wikswo teaches away from placing electrodes on the membranes themselves, where Wikswo emphasizes the importance of visualization through the membranes and windows, and that adding electrodes to the membranes would interfere with this critical visualization capability, examiner respectfully disagrees.
First, it is noted that Wikswo does not explicitly teach that electrodes on the membranes would be undesirable. In the two paragraphs cited, [0032] nor [0135] state that having electrodes on the membrane would negatively impact visualization.
Second, Achyuta [0013] recites “In certain implementations, the method also includes measuring trans-endothelial electrical resistance across the cells, visualizing the cells in the device by microscopy, and/or removing the cells from the device and performing biochemical analysis or microscopy on the removed cells.” Therefore, it is understood that having electrodes that measure TEER on the membrane and top window would not negatively impact visualization as Achyuta teaches that both TEER and microscopy are used in the device.
With regards to applicant arguments on page 11 of 13 that even if Achyuta is properly cited there is no proper motivation to modify Wikswo’s electrode configuration since Wikswo already achieves TEER measurements through a specifically designed arrangement that preserves optical visualization capabilities, and because Achyuta has no relationship to taking TEER measurements there would have been no reasonable expectation of success.
Firstly, please see above with regards to the citation of Achyuta. Second, the motivation to substitute the electrode placement in Wikswo to the placement taught by Achyuta is found in MPEP 2143.B which sets forth the rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. Please see the rejection supra which sets this forward.
With regards to the comments that can be put into a Rule 132 Declaration on page 11 of 13, even if the comments were to be put into a declaration they would not be found to be persuasive. As described in MPEP 716.01(c) “In assessing the probative value of an expert opinion, the examiner must consider the nature of the matter sought to be established, the strength of any opposing evidence, the interest of the expert in the outcome of the case, and the presence or absence of factual support for the expert’s opinion”. Currently, there is no provided evidence or factual support for the expert’s opinion provided. Additionally, the arguments (producing microstructured metal electrodes on a porous surface being extremely difficult, TEER measurement with a rectangular 12.5 Hz signal is a DC signal, which is not a sinusoidal AC signal where specific frequencies can be evaluated as an impedance spectrum) are not commensurate in scope with the presently pending claims.
Applicant argues on page 12 of 13 that combining Guimera (who teaches interdigitated electrodes) with Wikswo would still be improper since Wikswo specifically designs its system to minimize thickness and maintain visualization capabilities through membranes, where even though Guimera suggests that interdigitated electrodes can allow some optical visualization through spaces between electrodes this would still interfere with Wikswo’s emphasis on maximizing visualization capabilities through minimized thickness and careful material selection.
Examiner respectfully disagrees. Please see above, where Wikswo does not teach away from having electrodes placed on the surface, and where Achyuta teaches that a device that measures TEER can also be subject to microscopy. One skilled in the art would therefore find it obvious to have electrodes on the filter membrane and upper window of Wikswo and that they would not interfere with visualization, where this is further emphasized by Guimera which recites on page 13 lines 19-24 “That is, the use of interdigitated electrodes for performing EIS measurements is proposed as an optimal electrode configuration that allows a similar sensitivity along a defined cell culture area without impairing the optical visualization of the cell culture.”, where it is noted that page 1, lines 22-26 describes where a common technique for quantitatively evaluating the cell barrier integrity without affecting cell physiology is based on the study of passive electrical properties of the cells, which can be performed by means of electrical impedance spectroscopy (EIS) or transendothelial/epithelial electrical resistance (TEER).
With regards to the comments that can be put into a Rule 132 Declaration on page 12 of 13, please see MPEP 716.01(c), which was also described above. Applicant has not provided evidence or factual support for applicant’s opinion provided. Additionally, the arguments (more than 2 electrode layers and laterally distributed electrodes offering more measurement configurations, and different electrode pairing will investigate different sample areas- even impedance tomography is possible) are not commensurate in scope with the presently pending claims.
Conclusion
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/S.Y.L./Examiner, Art Unit 1796
/ELIZABETH A ROBINSON/Supervisory Patent Examiner, Art Unit 1796