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 Objections
Claim(s) 5, 8, and 11 is/are objected to because of the following informalities:
In claim 5, There is a typo in “the microfluidic device of claim 1
In claim 8, “areseparated” should be “are_separated”; and
In claim 11, “permitspassage” should be “permits_passage”.
Appropriate correction is required.
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 16 is 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 16 recites the limitation "the outer passages". There is insufficient antecedent basis for this limitation in the claim since the claimed “outer passages” is first mentioned in claim 15 instead of claim 1.
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.
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 1-8, 12, 14, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Ram (U.S. Pub. No. 2015/0283316 A1) in view of Govyadinov (WO 2020/159537 A1; cited in IDS), as evidenced in Jang (Microfluidic device for cell capture and impedance measurement, 2007).
Regarding claim 1, Ram teaches a microfluidic device having at least one microchannel that is configured to allow a fluid sample to flow along a length of the microchannel from a first end to a second end (shown in Fig. 3A), the at least one microchannel including a plurality of micropillar arrays (440a, 440a, 450, 460, 470, etc. shown in Fig. 3a, para. [0051]), wherein each micropillar array defines a plurality of microcapillaries having a separation distance (the spaces between which micropillars are interpreted as being microcapillaries) and the separation distance of the microcapillaries defined by each micropillar array decreases in a direction of fluid flow through the microchannel (The arrays are arranged as parallel sets of arrays in Which each subsequent array, as you move from the inlet to the outlet of the micro-pillar array assembly, includes arrays with smaller distances between the pillars. Para. [0054]).
Ram does not disclose the device includes pairs of electrodes positioned on opposite sides of each microplillar array in a direction of fluid flow through the at least one microchannel, and wherein the pairs of electrodes are configured to measure electrical impedance in each respective micropillar array.
In an analogous art, Govyadinov teaches a similar microfluidic device (Fig 7; para [0080]-(0084]) comprising pairs of electrodes positioned on opposite sides of each element of a plurality of elements (108; Fig 7; para [0080]-[0083]; each of sensors 108 are shown to be on the cellular analytic system 100 in an alternating arrangement with lysing elements 106) and wherein the pairs of electrodes are configured to measure electrical impedance in each respective element (Fig 7; para [0080]-[0083]; para [0046]: In one particular example, the sensor (108) is an impedance sensor. Specifically, the sensor (108) may include at least one pair of electrodes spaced apart from one another by a gap.).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have employed the pairs of electrodes taught by Govyadinov with the microfluidic device of Ram to derived the claimed invention. Doing so allows the device of Ram to be capable of measuring impedance of the cells passing through the microcapillaries. As discussed in evidential reference Jang, cell impedance characteristic can be used to understand biological characteristic behavior since the temperature, electric conductivity and mobility of a cell can influence its impedance characteristics directly or indirectly (Jang, Introduction, para. 2).
Regarding claim 2, Modified Ram teaches the invention as discussed above in claim 1. Ram teaches that microchannel including a substantially planar upper surface (upper plate, para. [0054]) and that the upper plate has a planar upper surface on the microchannel (as shown in Fig. 6B) and a substantially planar lower surface (base, para. [0057] with the micropillars extending from upper surface to the lower surface (In one embodiment, the micro-pillar array assembly implemented with triangular pillars 441′ may include a base of the triangle (i.e., in the cross-sectional view) where the base of the triangle sits flush with a reference line 12. Para. [0057]).
Regarding claim 3, Modified Ram teaches the invention as discussed above in claim 1. Ram discloses each of the micropillars of the plurality of micropillar arrays has a substantially rectangular cross section (non-circular and non-triangular cross-sectional micro-pillar shapes may be implemented in accordance with the teachings herein, such as, but not limited to, oblong shapes, square shapes, half-circle shapes, etc. para. [0059]).
Regarding claim 4, Modified Ram teaches the invention as discussed above in claim 1. Furthermore, Ram teaches that each of the microcapillaries has a substantially rectangular cross section (As noted above in the rejection of claim 3, Ram teaches that the micropillars can have a square cross sectional shape, in which case the microcapillary spaces between the micropillars would also have square (rectangular) cross sectional shapes).
Regarding claim 5, Modified Ram teaches the invention as discussed above in claim 1. Ram teaches that the microchannel includes at least three micropillar arrays and the widths and cross sectional areas of the microcapillaries defined by each respective micropillar array being substantially uniform (As shown in Fig. 3A, Ram teaches at least three micropillar arrays in the microchannel with substantially uniformed dimensions).
Regarding claim 6, Modified Ram teaches the invention as discussed above in claim 1. Ram teaches that the micropillar arrays include at least three rows of micropillars (450, 460, 470, Fig. 3A) with the rows extending perpendicular to fluid flow and having a substantially similar shape (Fig. 3B, inlet to outlet).
Regarding claim 7, Modified Ram teaches the invention as discussed above in claim 6. Ram discloses the distance between each micropillar in a row of a respective micropillar array is substantially the same (para. [0056]: In one embodiment the space between the pillars 475 of FIG. 3C is uniform in any single array).
Regarding claim 8, Modified Ram teaches the invention as discussed above in claim 1. Rams discloses each successive micropillar arrays (ridge 725, 730, Fig. 6; para. [0062]: In the slot-implementation 700 of the micro-pillar array assembly, the first ridge 725 is considered a first array and second ridge 730 is considered a second array.) are separated from each other in the at least one microchannel by a gap region, the gap region being free of micropillars (the spaces between the ridges in fig. 6) and wherein each gap region includes an electrode (after incorporation of electrodes of Govyadinov to the device of Ram; Govyadinov, 108, fig. 7).
Regarding claim 12, Modified Ram teaches the invention as discussed above in claim 1. Ram teaches that the fluid sample includes blood cells (para. [0054]). The recitation of the fluid sample is an intended use and, as such is not attributed patentable weight in the device claim since the fluid sample is not part of the claimed device.
Regarding claim 14, Modified Ram teaches the invention as discussed above in claim 1. Neither Ram nor Govyadinov teaches that the separation distance of the plurality of microcapillaries at the second of the microchannel occludes cells in a fluid sample perfused through the microchannel.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify Ram to configure the separation distance of the plurality of microcapillaries at a second one of the microchannel occludes cells in a fluid sample perfused through the microchannel for purposes of sorting out such cells during a sorting process.
Regarding claim 17, Modified Ram teaches the invention as discussed above in claim 1. Govyadinov (after incorporation with Ram) discloses the electrodes are planar and are provided on a lower surface channel of the microchannel (a single pair of electrodes are used, with one electrode plate placed at either end of a chamber (104). In another example, multiple pair of electrodes are used. For example, one pair of electrode plates could be placed at the inlet and another pair of electrode plates, para. [0046]).
Regarding claim 18, Modified Ram teaches the invention as discussed above in claim 1. Ram teaches that the fluid sample includes blood cells (para. [0054]). The recitation of the measured impedance is indicative of red blood cell mediated occlusion is intended use and, as such is not attributed patentable weight in the device claim since the red blood cell is not recited as part of the claimed device.
Claims 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Ram in view of Govyadinov as discussed above in claim 1, and further in view of Faustino (“A Passive Microfluidic Device Based on Crossflow Filtration for Cell Separation Measurements: A Spectrophotometric Characterization,” Biosensors 2018 8, 125) (cited in IDS).
Regarding claim 9, Modified Ram teaches the invention as discussed above in claim 1.
Neither Ram nor Govyadinov teaches the dimensions of the micropillars recited in claim 9.
In an analogous art, Faustino teaches microfluidic devices for detecting deformability changes in cells that includes micropillars that have 50 µm x 50 µm dimensions and spacings between pillars in arrays that are 14 µm to 17 µm.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify Ram in view of Govyadinov to configure microcapillaries to have separation distance sized to sort deformable cells from healthy cells as taught by Faustino.
Moreover, it would have been obvious to conduct routine experimentation to optimized the separation distance of the micropillars to sort deformable and healthy cells of any size, including providing micropillars having distance about 12µm and providing microcapillaries that each have a separation distance about 10% to about 30% less than a plurality of microcapillaries defined by a preceding micropillar array.
Regarding claim 10, Modified Ram teaches the invention as discussed above in claim 1.
Neither Ram nor Govyadinov teaches the dimensions of the micropillars recited in claim 9.
As noted above, Faustino et al. teaches microfluidic devices for detecting deformability changes in cells that includes micropillars that have 50 µm x 50 µm dimensions and spacings between pillars in arrays that are 14 µm to 17 µm.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify Ram in view of Govyadinov to configure microcapillaries to have separation distance sized to sort deformable cells from healthy cells as taught by Faustino.
Moreover, it would have been obvious to conduct routine experimentation to optimized the separation distance of the micropillars the microcapillaries to sort deformable and healthy cells of any size, including providing micropillars having separation distance of about 3 microns and providing microcapillaries that each have a separation distance about 20% to about 50% greater than a plurality of microcapillaries defined by a preceding micropillar array.
Regarding claim 11, Modified Ram teaches the invention as discussed above in claim 1. Neither Ram nor Govyadinov teaches the separation distance of the plurality of microcapillaries defined by at least one of the plurality of micropillar arrays permits passage of healthy cells in a fluid sample perfused through the microchannel but occludes cells with impaired deformability.
In an analogous art, Faustino teaches microfluidic devices for detecting deformability changes in cells (Abstract). Faustino teaches microfluidic devices for detecting deformability changes in cells that includes micropillars, including the micropillar arrays that permit passage of healthy cells in a fluid sample perfused through the microchannel but occludes cells with impaired deformability (3. Results and Discussion, para. 2: From Figure 2 it can be observed that the separation device was able to transport the RBCs through the microfluidic channels and pillars according to their deformability. Figure 2b–f present instantaneous frames of RBCs crossing the three rows of pillars of the microfluidic device. Additionally, Figure 2c,d (magnified figures of Figure 2b) show, respectively, deformable RBCs and rigid RBCs flowing within the first row of pillars (cells located inside the white circles). By analyzing these figures, it is clear that the healthy RBCs have a high elongation when subjected to high shear flow (Figure 2c), and as a consequence it is reflected in the high deformability of these cells.).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify Ram in view of Govyadinov to include micropillars that permit passage of healthy cells in a fluid sample perfused through the microchannel but occludes cells with impaired deformability as taught by Faustino for purposes of sorting deformable cells.
Claims 15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ram in view of Govyadinov as discussed above in claim 1, and further in view of Lopez (U.S. Pat. No. 6,685,841 B2)
Regarding claim 15, Modified Ram teaches the invention of claim 1. Neither Ram nor Govyadinov teaches that each of the micropillar arrays is arranged in an inner portion of the microchannel that extends the length of the microchannel, the microchannel including two parallel outer passages on opposite sides of the inner portion that extend the length of the microchannel, outer passages being in fluid communication with the plurality of microcapillaries defined by the plurality micropillar arrays.
In an analogous art, Lopez teaches an array of nano structures that are used for separating biomolecules that, as shown in Figs. 7A, includes protrusions 702 (column 11, lines 7-20) that extend upward from a substantially planar surface. Figure 7B shows two parallel outer passages on opposite sides of the inner portion that extend the length of the microchannel, outer passages being in fluid communication with the plurality of microcapillaries defined by the plurality micropillar arrays.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the device of Ram in view of Govyadinov to include two parallel outer passages on opposite sides of the inner portion that extend the length of the microchannel, outer passages being in fluid communication with the plurality of microcapillaries defined by the plurality micropillar arrays as taught by Lopez to allow sample fluid to pass through the microchannel in the event that one or more of the micropillar arrays become clogged.
Regarding claim 16, Modified Ram in view of Lopez teaches the claimed invention as discussed above in claim 15. The arts cited do not explicitly disclose the outer passages have cross sectional areas that permit cells in a fluid sample to flow through the microchannel without being occluded and/or obstructed.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify Ram in view of Govyadinov to include two parallel outer passages on opposite sides of the inner portion that extend the length of the microchannel, outer passages being in fluid communication with the plurality of microcapillaries defined by the plurality micropillar arrays as taught by Lopez to allow sample fluid to pass through the microchannel in the event that one or more of the micropillar arrays become clogged.
Claims 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Ram in view of Govyadinov as discussed above in claim 1, and further in view of Jang.
Regarding claims 19-20, Modified Ram discloses the invention as discussed above in claim 1. Neither Ram nor Govyadinov discloses the microchannel includes a substantially planar transparent wall that defines the upper surface or lower surface of the microchannel or the substantially planar transparent wall permits observation into the microfluidic channel by microscopy.
In an analogous art, Jang discloses a microfluidic device comprising a microchannel with pillar microstructures and gold electrode for impedance measurement (fig. 1). Furthermore, Jang discloses the chips can be visually inspected using an optical microscope (which requires the material of the chip to be at least partially transparent)(5. Results and discussion; Fig. 4).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have constructed the device of Modified Ram using optical transparent material of the similar microfluidic chip of Jang to derive the claimed invention. Doing so allows the chips to be visually inspected using an optical microscope and allows for confirmation the cells have successfully been trapped or passed through the microcapillaries (Jang, Figure 4(a) shows the cell-trapped structures before injection and a single cell of HeLa was trapped successfully among pillars as shown in Fig. 4(b). 5. Results and discussion, para. 1).
Claims 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Ram in view of Govyadinov as discussed above in claim 1, and further in view of Ingber (U.S. Pub. No. 2011/0250585 A1)
Regarding claim 21, Modified Ram teaches the invention as discussed above in claim 1. Neither Ram nor Govyadinov teaches a micro-gas exchanger and a chamber for controlling oxygen content prior to or after delivering blood to the microchannel.
In an analogous art, Ingber teaches a microfluidic device having a microchannel and a membrane 208 (“gas exchanger”) mounted on a chamber wall, wherein a pressure differential causes the chamber wall to flex in a desired direction to expand or contract within a central microchannel (claim 1) for purposes of monitoring cell behavior and/or passage of gases, chemicals, molecules, particulates and cells are monitored (para. [0077])
It would have been obvious to one of ordinary skill in the art before the effective filing to date to include a membrane (gas exchanger) mounted to a chamber of Ingber to control the oxygen content of blood samples for purposes of using the device of Modified Ram to study cell behavior using a gas exchanger/membrane that better mimic the bodily physiology (Ingber, para. [0018]).
Regarding claim 22, Modified Ram teaches the invention as discussed above in claim 21. Ingber (after incorporation into Modified Ram) discloses the micro-gas exchanger and the chamber providing hypoxic blood to the at least one microchannel (In an example, the gas exchange function of the tissue-tissue interface self assembled on membrane 208 may be determined by injecting different fluids, each having their own oxygen partial pressures and blood.... For example, blood can flow through the channel 250B while air is being injected into the upper channel 250A, whereby the exiting air is collected and measured to determine the oxygen level using an oximeter. Para. [0114])
Claims 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Ram in view of Govyadinov as discussed above in claim 1, and further in view of Gurkan (U.S. Pub. No. 2017/0227495 A1).
Regarding claim 23-24, Modified Ram teaches the invention as discussed above in claim 1. Neither Ram nor Govyadinov teaches at least one capturing agent that is immobilized on a surface of the at least one microchannel, the capturing agent adhering a cell of interest to the at least one surface of the at least one microchannel when a fluid sample containing cells is passed through the at least one microchannel.
In an analogous art, Gurkan teaches a biochip having microchannels in which FN (fibronectin) and LN (laminin) are immobilized microchannels (para. [0037]). Furthermore, Gurkan teaches using GMBS to covalently FN and LN to the glass slide that forms the biochip (para. [0036] and [0167]).
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to modify the device of Modified Ram to include either or both of FN or LN linked to a side wall portion of the microchannel using GMBS as taught by Gurkan for purposes of capturing cells of interest for further analysis.
Conclusion
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/M.H./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758