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
Claims 1-8, 10, 11, 13, 14, 18-25 and 52-54 are objected to because of the following informalities:
Claim 1 should recite that cells with impaired deformability are retained by the microcapillaries as described in applicant’s paragraphs [0006], [0051], [0078], [00172] and [00186].
Appropriate correction is required.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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, 10, 11, 13, 14, 18, 19 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Ram et al. in view of Faustino et al., Lopez et al., Kim et al. (“Advances in the measurement of red blood cell deformability: A brief review,” The Journal of Cellular Biotechnology, July 16, 2015) and U.S. Patent Application Publication No. 2007/0026381 to Huang et al.
Ram et al. 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 as shown in Fig. 3A.
The microchannel includes a plurality of micropillar arrays 440a, 440a, 450, 460, 470, etc. shown in Fig. 3a [0051]. The spaces between which micropillars are interpreted as being microcapillaries.
Ram et al. teaches that “as you move from the inlet to the outlet of the micro-pillar array assembly, includes arrays with smaller distances between the pillars.” [0054].
Ram et al. does not teach the width and/or cross sectional area 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.
Faustino et al. teaches microfluidic devices for detecting deformability changes in cells that includes micropillars, including the micropillar arrays having pillars that are spaced apart that permit passage of healthy cells in a fluid sample perfused through the microchannel but occludes cells with impaired deformability. (Fig. 2 and paragraph bridging pages 4-5) As such, Faustino et al. teaches that cells with impaired deformability would be occluded or retained “in” microcapillaries formed between the micropillar arrays in the same manner as applicant discloses.
It would have been obvious to one of ordinary skill in the art to modify Ram et al. to include micropillars that permit passage of healthy cells in a fluid sample perfused through the microchannel but occlude cells with impaired deformability as taught by Faustino et al. for purposes of sorting deformable cells as taught by Faustino et al.
Ram et al. in view of Faustino et al, does not teach that the plurality of micropillars are arranged in rows extending perpendicular to fluid flow through the at least one microchannel.
Lopez et al. teaches that the row of pillars extend perpendicular to the fluid flow direction.
It would have been obvious to one of ordinary skill in the art to modify Ram et al. in view of Faustino et al. to arrange the micropillars to extend perpendicular to the fluid flow directed as taught by Lopez et al. for purposes of separating particles as taught by Lopez et al.
Ram et al. in view of Faustino et al. and Lopez et al. does not teach a micropillar array at the first end that includes a plurality of micropillars defining a plurality of microcapillaries that each have a width of about 18 µm to about 22 µm and/or across sectional area of about 200 µm2 to about 250 µm2 and each successive micropillar array in the direction of fluid flow through the at least one microchannel includes a plurality of micropillars defining a plurality microcapillaries that each have a width and/or a cross sectional area about 5% to about 50% less than a plurality of microcapillaries defined by a preceding micropillar array, wherein the at least one microchannel includes a micropillar array at the second end that includes a plurality of micropillars defining plurality of microcapillaries having a width of about 3 um to about 6 um, and wherein the width and/or cross sectional area of the plurality of microcapillaries defined by the plurality of micropillars of at least one of the micropillar arrays at the second end of the at least one microchannel permits passage of healthy cells in a fluid sample perfused through the length of the at least one microchannel but occludes cells with impaired deformability.
Ram et al. teaches pillars that are 5 to 30 microns apart, and a gradual decrease in the distance between pillars in subsequent arrays. [0050]
Faustino et al. teaches 14 µm to 17 µm spacing between pillars for purposes of occluding cells with impaired deformability. (page 8, first paragraph)
Kim et al. teaches that RBCs are biconcave discs, typically 6–8 μm in diameter and 2 μm thick, and their deformation can involve a change in cell curvature or uniaxial deformation. (sentence bridging pages 1 and 2)
In Ram et al. in view of Faustino et al. and Lopez et al. it would have been obvious to one of ordinary skill in the art to perform routine engineering optimization experimentation to configure the spacing between the micropillars and the decrease in spacing between subsequent rows of micropillars and between the micropillars in the first row and last row that are sufficient to filter/separate cellular materials and occlude cells with impaired deformability, including providing at least one microchannel includes a micropillar array at the first end that includes a plurality of micropillars defining a plurality of microcapillaries that each have a width of about 18 µm to about 22 µm that is within the range of Ram et al., and each successive micropillar array in the direction of fluid flow through the at least one microchannel includes a plurality of micropillars defining a plurality microcapillaries that each have a width and at least one microchannel includes a micropillar array at the second end that includes a plurality of micropillars defining plurality of microcapillaries having a width of about 3 µm to about 6 µm, which is commensurate with the size of RBCs as taught by Kim et al., and wherein the width and/or cross sectional area of the plurality of microcapillaries defined by the plurality of micropillars of at least one of the micropillar arrays at the second end of the at least one microchannel permits passage of healthy cells in a fluid sample perfused through the length of the at least one microchannel but occludes cells with impaired deformability for purposes of filtering/separating desired cellular materials.
Ram et al. in view of Faustino et al. and Lopez does not teach that the microchannel includes two parallel outer passages on opposite sides of the inner portion that extend the length of the at least one microchannel, the outer passages being in fluid communication with the plurality of microcapillaries defined by the plurality of micropillar arrays, and the outer passages have cross sectional areas that permit cells in the fluid sample to flow through the at least one microchannel without being occluded and/or obstructed.
Huang et al. teaches the use of a bypass channel shown in Fig. 9 along the side of an array of obstacles that is provided so that large particles, e.g., cells, that could cause clogging downstream are deflected first, and these deflected particles need to bypass the downstream stages to avoid clogging. [0107]
It would have been obvious to one of ordinary skill in the art to modify Ram et al. in view of Faustino et al. and Lopez et al. to include bypass channels along the sides of the micropillar arrays as taught by Huang et al. to allow cells to flow through the micropillar arrays without being occluded and/or obstructed based on the spacing between pillars in the micropillar arrays.
I.) As noted above, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. teaches all the limitations of claim 1.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious.
II.) Regarding applicant’s claim 2, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 2 depends.
Claim 2 recites that microchannel including a substantially planar upper surface and a substantially planar lower surface, micropillars of the plurality of micropillar arrays extending from upper surface to the lower surface.
While Ram et al. teaches that the height of the pillars is confined by the upper plate [0054] and that the upper plate has a planar upper surface on the microchannel as shown in Fig. 6B, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. does not teach that the microchannel includes a substantially planar upper surface and a substantially planar lower surface with the micropillars extending from upper surface to the lower surface.
Lopez et al. 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.
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to modify Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. to provide the microchannel with a substantially planar lower surface with the micropillars extending between the planar upper and lower surfaces as taught by Lopez et al. since such Lopez et al. teaches that such a configuration can be used to separate biomolecules. Having the micropillars extending from between the upper and lower surfaces to only allow for cells to pass between the micropillars and not over or under the micropillars would have been obvious.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 2 obvious.
III.) Regarding applicant’s claim 3, as noted above, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 3 depends.
Claim 3 recites that each of the micropillars of the plurality of micropillar arrays has a substantially rectangular cross section.
At [0059] Ram et al. teaches that “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.”
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 3 obvious.
IV.) Regarding applicant’s claim 4, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 4 depends.
Claim 4 recites that each of the microcapillaries has a substantially rectangular cross section.
As noted above, Ram et al. 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.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 4 obvious.
V.) Regarding applicant’s claim 5, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 5 depends.
Claim 5 recites 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 et al. teaches at least three micropillar arrays in the microchannel.
Further, Lopez et al. illustrates 5 rows of micropillars in Fig. 6.
Therefore. Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 5 obvious.
VI.) Regarding applicant’s claim 6, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 6 depends.
Claim 6 recites that each micropillar array includes at least three rows of micropillars, the rows extending perpendicular to fluid flow and having a substantially similar shape.
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. does not teach that the micropillar arrays include at least three rows of micropillars with the rows extending perpendicular to fluid flow and having a substantially similar shape.
Lopez et al. teaches that the row of pillars extend perpendicular to the fluid flow direction.
It would have been obvious to one of ordinary skill in the art to modify Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. to arrange the micropillars to extend perpendicular to the fluid flow directed as taught by Lopez et al. for purposes of separating particles as taught by Lopez et al.
Further, including at least three rows of micropillars in each array of micropillars would have been obvious since the mere duplication of parts has no patentable significance unless a new and unexpected result is produced. (See MPEP2144.04(IV)(B)). Alternatively, it would have been obvious to include multiple rows of micropillars in each array in order to improve the likelihood of separation.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 6 obvious.
VII.) Regarding applicant’s claim 7, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 6 obvious from which claim 7 depends.
Claim 7 recites that the distance between each micropillar in a row of a respective micropillar array is substantially the same.
In Ram et al. as modified by Faustino et al., Lopez et al., Kim et al. and Huang et al. it would have been obvious to make the distance between each micropillar in a row of a respective micropillar array substantially the same for purposes of ensuring the same type of particles are sorted by the array.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 7 obvious.
VIII.) Regarding applicant’s claim 8, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 8 depends.
Claim 8 recites that successive micropillar arrays are separated from each other in the microchannel by a gap region, the gap region being free of micropillars.
As shown in Fig. 3A, Ram et al. teaches gaps between the micropillar arrays that are free from micropillars.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 8 obvious.
IX.) Regarding applicant’s claim 10, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 10 depends.
Claim 10 recites that the microchannel includes a micropillar array at the second end that includes a plurality of micropillars defining a plurality of microcapillaries that each have a cross sectional area of about 40 µm2 to about 50 µm2 and each preceding micropillar array in opposite the direction of fluid flow through the microchannel includes a plurality of micropillars defining a plurality of microcapillaries that each have a width and/or a cross sectional area about 5% to about 50% greater than a plurality of microcapillaries defined by a preceding micropillar array.
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. does not teach a micropillar array at the second end that defines a plurality of microcapillaries that each have a width of about 3 µm to about 6 µm and/or a cross sectional area of about 40 µm2 to about 50 µm2 and each preceding micropillar array in opposite the direction of fluid flow through the microchannel defines a plurality of microcapillaries that each have a width and/or a cross sectional area about 5% to about 50% greater than a plurality of microcapillaries defined by a preceding micropillar array.
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 spaced apart by 17 µm. Faustino et al. does not provide dimensions for pillars that are spaced apart by 14 µm and 16 µm.
As also noted above, Ram et al. teaches pillars that are spaced apart by 5 to 30 microns, but does not teach the widths and heights or cross-sectional area of the pillars
As also noted above Kim et al. teaches that RBCs are typically 6-8 µm in diameter and 2 µm. thick.
As noted above, in Ram et al. in view of Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. it would have been obvious to one of ordinary skill in the art to perform routine engineering optimization experimentation to configure the spacing between the micropillars and the decrease in spacing between subsequent rows of micropillars and between the micropillars in the first row and last row that are sufficient to filter/separate cellular materials and occlude cells with impaired deformability, including providing at the second end that includes a plurality of micropillars defining plurality of microcapillaries having a width of about 3 µm to about 6 µm, which is commensurate with the size of RBCs as taught by Kim et al., for purposes of filtering/separating desired cellular materials and occluding cells with impaired deformably.
As to the cross-section of the pillars it would have been obvious to one of ordinary skill in the art to conduct routine engineering optimization experimentation to configure the pillars to have a suitable height and width that provides for passage of healthy cells in a fluid sample perfused through the length of the at least one microchannel but occludes cells with impaired deformability for purposes of filtering/separating desired cellular materials, including a height and width that provides a cross-sectional areas of about 40 µm2 to 50 µm2, absent a showing of unexpected results. Note, changes in size are obvious unless they perform differently and changes in shape are obvious unless shapes are significant. (MPEP 2104.04 (IV)(A), (IV)(B))
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 10 obvious.
X.) Regarding applicant’s claim 11, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 11 depends.
Claim 11 recites at least eight micropillar arrays, the configured along the length of the microchannel, the micropillar array at the first end including a plurality of micropillars defining a plurality of microcapillaries that each have a width of about 18 µm to about 22 µm and a cross sectional area of about 200 µm2 to about 250 µm2 and a micropillar array at the second end including a plurality of micropillars that defines a plurality of microcapillaries that each have a width of about 3 µm to about 5 µm and a cross sectional area of about 40 µm2 to about 50 µm2.
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. does not teach at least eight micropillar arrays, the configured along the length of the microchannel, a micropillar array at the first end defining a plurality of microcapillaries that each have a width of about 18 µm to about 22 µm and a cross sectional area of about 200 µm2 to about 250 µm2 and a micropillar array at the second end that defines a plurality of microcapillaries that each have a width of about 3 µm to about 5 µm and a cross sectional area of about 40 µm2 to about 50 µm2.
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 spaced apart by 17 µm. Faustino et al. does not provide dimensions to pillars that are spaced apart by 14 µm and 16 µm.
As also noted above, Ram et al. teaches pillars that are spaced apart by 5 to 30 microns, but does not teach the widths and heights or cross-sectional area of the pillars
As also noted above Kim et al. teaches that RBCs are typically 6-8 µm in diameter and 2 µm. thick.
As noted above, in Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. it would have been obvious to one of ordinary skill in the art to perform routine engineering optimization experimentation to configure the spacing between the micropillars and the decrease in spacing between subsequent rows of micropillars and between the micropillars in the first row and last row that are sufficient to filter/separate cellular materials and occlude cells with impaired deformability, including providing the micropillar array at the first end with a plurality of microcapillaries that each have a width of about 18 µm to about 22 µm that is within the range of Ram et al., and providing the at the second end a plurality of microcapillaries having a width of about 3 µm to about 6 µm, which is commensurate with the size of RBCs as taught by Kim et al., for purposes of filtering/separating desired cellular materials and occluding cells with impaired deformability.
As to the cross-section of the pillars it would have been obvious to one of ordinary skill in the art to conduct routine engineering optimization experimentation to configure the pillars in the micropillar array at the first end to have a suitable height and width that provides to a biological sample to enter and be subject to cellular component sorting, including a height and width that provides a cross-sectional areas of about 200 µm2 to 250 µm2, absent a showing of unexpected results and configure the pillars in the micropillar array in the second end to have a suitable height and width that provides for passage of healthy cells in a fluid sample perfused through the length of the at least one microchannel but occludes cells with impaired deformability for purposes of filtering/separating desired cellular materials, including a height and width that provides a cross-sectional areas of about 40 µm2 to 50 µm2, absent a showing of unexpected results. Note, changes in size are obvious unless they perform differently and changes in shape are obvious unless shapes are significant. (MPEP 2104.04 (IV)(A), (IV)(B))
The use of eight micropillar arrays would have been obvious for purposes of filtering/separating progressively smaller cellular components. Note, the duplication of elements is deemed obvious unexpected results. (MPEP 2144.04 (VI)(B))
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 11 obvious.
XI.) Regarding applicant’s claim 13, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 13 depends.
Claim 13 recites that the fluid sample includes blood cells.
It is noted that the fluid sample is not a structural part of the claimed device, and as such is not attributed patentable weight in a claim to a device.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 13 obvious.
XII.) Regarding applicant’s claim 14, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 13 obvious from which claim 14 depends.
Claim 14 recites that the cells are red blood cells.
It is noted that the fluid sample is not a structural part of the claimed device, and as such is not attributed patentable weight in a claim to a device.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 14 obvious.
XIII.) Regarding applicant’s claim 18, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 18 depends.
Claim 18 recites the microchannel including a substantially planar transparent wall that defines the upper surface or lower surface of the microchannel.
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. is silent on the use of a transparent material for constructing the microfluidic device.
It would have been obvious to one of ordinary skill in the art to provide the microchannel of Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. with a substantially planar transparent wall that defines the upper surface or lower surface of the microchannel for purposes of being able to visually monitor flow through the device during use.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 18 obvious.
XIV.) Regarding applicant’s claim 19, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 18 obvious from which claim 19 depends
Claim 19 recites that the substantially planar transparent wall permits observation into the microfluidic channel by microscopy.
As noted above, it would have been obvious to one of ordinary skill in the art to provide the microchannel of Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. with a substantially planar transparent wall that defines the upper surface or lower surface of the microchannel for purposes of being able to visually monitor flow through the device during use. Such a transparent wall would “permit” observation into the microfluid channel by microscopy.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 19 obvious.
XV.) Regarding applicant’s claim 52, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 52 depends.
Claim 52 recites that the outer passage have widths in a range of 25 µm to 100 µm.
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. do not teach the widths of the bypass channels.
It would have been obvious to one of ordinary skill in the art to conduct routine engineering optimization experimentation an provide the bypass channels with widths in the range of 25 µm to 100 µm based upon particle/cell sizes of interest to prevent occlusion and/or obstruction.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 52 obvious.
2. Claims 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. as applied to claim 1 above and further in view of Ingber et al.
I.) Regarding applicant’s claim 20, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 20 depends.
Claim 20 recites a micro-gas exchanger for controlling the oxygen content of the blood prior to and/or after delivering the blood to the at least one microchannel.
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. does not teach a micro-gas exchanger for controlling oxygen content prior to or after delivering blood to the microchannel.
Ingber et al. teaches a microfluidic device having a microchannel and a membrane 208 (“gas exchanger”) for purposes of monitoring cell behavior and/or passage of gases, chemicals, molecules, particulates and cells are monitored. [0077]
It would have been obvious to one of ordinary skill in the art to modify Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. to include a membrane (gas exchanger) to control the oxygen content of blood samples for purposes of using the device of Ram et al. to sort blood for analysis purposes.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Ingber et al. renders claim 20 obvious.
II.) Regarding applicant’s claim 21, as noted above Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Ingber et al. renders claim 20 obvious from which claim 21 depends.
Claim 21 recite that the micro-gas exchanger providing hypoxic blood to the at least one microchannel.
As noted above, it would have been obvious to one of ordinary skill in the art to modify Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. to include a membrane (gas exchanger) to control the oxygen content of blood samples for using the device of Ram et al. to sort blood for analysis purposes.
Controlling the level of blood to be hypoxic would have been obvious for purposes of separating and analyzing the effects of low oxygen levels on blood
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Ingber et al. renders claim 21 obvious.
3. Claims 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. as applied to claim 1 above and further in view of Gurkan et al.
I.) Regarding applicant’s claim 22, as noted above, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 1 obvious from which claim 22 depends.
Claim 22 recites 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.
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. does not teach a capturing agent that is immobilized on a surface of the microchannel.
Gurkan et al. teaches a biochip having microchannels in which FN (fibronectin) and LN (laminin) are immobilized microchannels.” [0037]
Gurkan et al. further teaches using GMBS to covalently FN and LN to the glass slide that forms the biochip. [0036] and [0167]
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to modify Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. to include either or both of FN or LN linked to a side wall portion of the microchannel using GMBS as taught by Gurkan et al. for purposes of capturing cells of interest for further analysis.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Gurkan et al. renders claim 22 obvious.
II.) Regarding applicant’s claim 23, as noted above, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Gurkan et al. renders claim 22 obvious from which claim 23 depends.
Claim 23 recites that the at least one capturing agent comprising at least one of laminin, fibronectin, E-Selectin, P-Selectin, L- selectin, intracellular adhesion molecule 1 (ICAM-1), or vascular cellular adhesion molecule 1 (VCAM-1).
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. does not teach least one capturing agent comprising at least one of laminin, fibronectin, E-Selectin, P-Selectin, L- selectin, intracellular adhesion molecule 1 (ICAM-1), or vascular cellular adhesion molecule 1 (VCAM-1) that is immobilized on a surface of the microchannel
As noted above, Gurkan et al. teaches a biochip having microchannels in which FN (fibronectin) and LN (laminin) are immobilized microchannels.” [0037]
Gurkan et al. further teaches using GMBS to covalently FN and LN to the glass slide that forms the biochip. [0036] and [0167]
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to modify Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. to include either or both of FN or LN linked to a side wall portion of the microchannel using GMBS as taught by Gurkan et al. for purposes of capturing cells of interest for further analysis.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Gurkan et al. renders claim 23 obvious.
III.) Regarding applicant’s claim 24, as noted above, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Gurkan et al. renders claim 22 obvious from which claim 24 depends.
Claim 24 recites that capturing agent being covalently immobilized to at least one surface of the at least one microchannel with a cross-linker.
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. does not teach that capturing agent being covalently immobilized to at least one surface of the at least one microchannel with a cross-linker.
As noted above, Gurkan et al. teaches a biochip having microchannels in which FN (fibronectin) and LN (laminin) are immobilized microchannels.” [0037]
Gurkan et al. further teaches using GMBS to covalently FN and LN to the glass slide that forms the biochip. [0036] and [0167]
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to modify Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. to include either or both of FN or LN linked to a side wall portion of the microchannel using GMBS as taught by Gurkan et al. for purposes of capturing cells of interest for further analysis.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Gurkan et al. renders claim 24 obvious.
IV.) Regarding applicant’s claim 25, as noted above, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Gurkan et al. renders claim 24 obvious from which claim 25 depends.
Claim 25 recites that the cross-linker is GMBS.
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. does not teach that the cross-linker is GMBS.
As noted above, Gurkan et al. teaches a biochip having microchannels in which FN (fibronectin) and LN (laminin) are immobilized microchannels.” [0037]
Gurkan et al. further teaches using GMBS to covalently FN and LN to the glass slide that forms the biochip. [0036] and [0167]
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to modify Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. to include either or both of FN or LN linked to a side wall portion of the microchannel using GMBS as taught by Gurkan et al. for purposes of capturing cells of interest for further analysis.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Gurkan et al. renders claim 25 obvious.
4. Claims 53 and 54 are rejected under 35 USC 103 as being unpatentable over Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al.
Ram et al. 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 as shown in Fig. 3A.
The microchannel includes a plurality of micropillar arrays 440a, 440a, 450, 460, 470, etc. shown in Fig. 3a [0051]. The spaces between which micropillars are interpreted as being microcapillaries.
Ram et al. teaches that “as you move from the inlet to the outlet of the micro-pillar array assembly, includes arrays with smaller distances between the pillars.” [0054].
Ram et al. does not teach the width and/or cross sectional area 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.
Faustino et al. teaches microfluidic devices for detecting deformability changes in cells that includes micropillars, including the micropillar arrays having pillars that are spaced apart that permit passage of healthy cells in a fluid sample perfused through the microchannel but occludes cells with impaired deformability.(Fig. 2 and paragraph bridging pages 4-5) As such, Faustino et al. teaches that cells with impaired deformability would be occluded or retained “in” microcapillaries formed between the micropillar arrays in the same manner as applicant discloses.
It would have been obvious to one of ordinary skill in the art to modify Ram et al. to include micropillars that permit passage of healthy cells in a fluid sample perfused through the microchannel but occlude cells with impaired deformability as taught by Faustino et al. for purposes of sorting deformable cells as taught by Faustino et al.
Ram et al. in view of Faustino et al, does not teach that the plurality of micropillars are arranged in rows extending perpendicular to fluid flow through the at least one microchannel.
Lopez et al. teaches that the row of pillars extend perpendicular to the fluid flow direction.
It would have been obvious to one of ordinary skill in the art to modify Ram et al. in view of Faustino et al. to arrange the micropillars to extend perpendicular to the fluid flow directed as taught by Lopez et al. for purposes of separating particles as taught by Lopez et al.
Ram et al. in view of Faustino et al. and Lopez et al. does not teach two parallel outer passages on opposite sides of the inner portion of the microchannel that extend the length of the at least one microchannel, the outer passages being in fluid communication with the plurality of microcapillaries defined by the plurality of micropillar arrays, and the outer passages have cross sectional areas that permit cells in the fluid sample to flow through the length of the at least one microchannel without being occluded and/or obstructed.
Huang et al. teaches the use of a bypass channel shown in Fig. 9 along the side of an array of obstacles that is provided so that large particles, e.g., cells, that could cause clogging downstream are deflected first, and these deflected particles need to bypass the downstream stages to avoid clogging. [0107]
It would have been obvious to one of ordinary skill in the art to modify Ram et al. in view of Faustino et al. and Lopez et al. to include bypass channels along the sides of the micropillar arrays as taught by Huang et al. to allow cells to flow through the micropillar arrays without being occluded and/or obstructed.
I.) Regarding applicant’s claim 53, as noted above Ram et al. in view of Faustino et al., Lopez et al. and Huang et al. teaches all the limitations of claim 53.
Therefore, Ram et al. in view of Faustino et al., Lopez et al. and Huang et al. renders claim 53 obvious.
II.) Regarding applicant’s claim 54, as noted above Ram et al. in view of Faustino et al., Lopez et al. and Huang et al. renders claim 53 obvious from which claim 54 depends.
Claim 54 recites that the outer passage have widths in a range of 25 µm to 100 µm.
Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. do not teach the widths of the bypass channels.
It would have been obvious to one of ordinary skill in the art to conduct routine engineering optimization experimentation an provide the bypass channels with widths in the range of 25 µm to 100 µm based upon particle/cell sizes of interest to prevent occlusion and/or obstruction.
Therefore, Ram et al. in view of Faustino et al., Lopez et al., Kim et al. and Huang et al. renders claim 54 obvious.
Response to Arguments
Applicant's arguments filed 01/19/2026 have been fully considered but they are not persuasive.
On page 13 of applicant’s reply applicant argues that Ram et al. do not teach that the cells with impaired deformability are retained with microcapillaries as in the present invention or to design the microchannel to include outer passages that extend along the length of the microchannel where the cells are not occluded and/or obstructed because then the cells could not be separated or captured by the micro-pillar array.
Ram et al. has noted been relied upon as teaching that the cells with impaired deformability are retained with microcapillaries.
Faustino et al. has been relied upon as teaching that micropillar arrays can be configured to occlude cells with impaired deformability.
Also on page 13 of applicant’s reply applicant argues that Faustino et al. teach a cross-flow microfluidic device where the rows of pillars are provided in different levels in an outer portion of the microchannel, as seen in Fig. 1(a).
Faustino et al. has only been relied upon as teaching that that micropillar arrays can be configured to occlude cells with impaired deformability and for teaching spacings between pillars in micropillar arrays.
On page 14 of applicant’s response applicant argues that Faustino et al. notes that one of the benefits of cross-flow pillars is that it avoids cell clogging and jamming, pg. 2, which would mean that the cells with impaired deformability continue flowing through the microchannel and are not retained in microcapillaries in the present invention.
Faustino et al. as not been relied upon as teaching cross-flow pillars, only for configuring pillars in micropillar arrays for occluding cells with impaired deformability.
On page 15 of applicant’s response applicant argues that Faustino et al. do not teach that the plurality micropillar arrays are in an inner portion that extends the length of the microchannel or that a plurality of micropillars of each micropillar array define microcapillaries that have a decreasing width/cross sectional area in a direction of fluid flow through the at least one microchannel, and that Faustino et al. do not provide any indication that a microfluidic device having micropillars defining capillaries having decreasing width/cross sectional area in the direction of fluid flow in an inner portion extending through the length of the microchannel could be used to occlude cells with impaired deformability while permitting healthy cells to pass through or that the cells with impaired deformability are retained in microcapillaries in the present invention.
As noted above, Ram et al. teaches a gradual decrease in the distance between pillars in subsequent arrays.
Further, As noted above, Faustino et al. teaches configuring pillars in micropillar arrays to occlude cells with impaired deformability while permitting health cells to pass.
Also on page 15 of applicant’s reply applicant argues that Faustino et al. do not teach that the at least one microchannel includes two parallel outer passages on opposite sides of the inner portion that extend the length of the microchannel and have a cross sectional areas that permit cells in a fluid sample to flow through the length of the at least one microchannel without being occluded and/or obstructed.
Faustino et al. has not been relied upon as teaching outer passages.
Huang et al. as been relied upon as teaching the use of outer passages adjacent post arrays in a microfluidic channels which allow cells to bypass the post arrays and pass through the outer passages.
On pages 16-17 of applicant’s reply applicant argues that the bypass channels in Huang et al. serve to collect deflected cells and that Huang et al. do not teach two parallel outer passages on opposite sides of the inner portion of the microchannel that extend the length of the microchannel, that the outer passages are in fluid communication with the plurality of microcapillaries, or have cross sectional areas that permit cells in the fluid sample to flow through the length of the at least one microchannel without being occluded and/or obstructed.
Huang et al. has been relied upon as modifying Ram et al. in view of Faustino et al. and Lopez et al. to include bypass channels along the sides of the micropillar arrays as taught by Huang et al. to allow cells to flow through the micropillar arrays without being occluded and/or obstructed, based on the spacing between pillars in the micropillar arrays.
On pages 17-18 of applicant’s response applicant argues that the bypass channels in Huang et al. are not on opposite sides of the inner portion of the microchannel and are either on one side as seen in Figs. 17-18, 20, or as a central bypass channel flanked by two channels as shown in Fig. 19, and that since the bypass channel is used to remove and collect cells that have been deflected in an array, the bypass channel does not extend the length of the microchannel nor does it allow cells to flow through the length of the microchannel without being occluded and/or obstructed, and that as Huang et al. use lateral displacement to separate the cells, Huang et al. would not use a second bypass channel on the opposite side of the microchannel because no cells would be displacement in that direction.
Huang et al. as been relied upon as teaching the use of outer passages adjacent post arrays in a microfluidic channels which allow cells to bypass the post arrays and pass through the outer passages.
Huang et al. has not been relied upon as teaching the cross-flow situation in Huang et al.
In Ram et al. in view of Faustino et al. and Lopez et al. it would have been obvious to include bypass channels along both sides of the micropillar arrays and along the length of the microfluid channel to allow cells to bypass the micropillar arrays that are obstructed or thought which cells cannot pass.
Conclusion
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/MICHAEL STANLEY GZYBOWSKI/Examiner, Art Unit 1798
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