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 7 is objected to because of the following informalities: It is suggested to recite “wherein The branch flow path comprises the greater than…” as “wherein the branch flow path comprises greater than…”. Appropriate correction is required.
Claim 23 is objected to because of the following informalities: It is suggested to recite “the inlet of the specimen of the main flow path” in line 5 as “the inlet into which the specimen is supplied”. Alternatively, it is suggested to recite “an inlet” as “a specimen inlet” throughout the claims. 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.
Claims 17 and 23 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.
Regarding claim 17, claim 17 recites “wherein the liquid removal rate is a ratio of a flow into the branch flow path at one of branches” in lines 3-4. The description of the liquid removal rate is unclear since it only describes one parameter of the ratio (i.e. “flow into the branch flow path at one of branches”) and does not provide what is the “flow into the branch flow path at one of branches” in relation to.
Regarding claim 23, claim 23 recites “liquid” in line 6. Since “specimen and sheath liquid” is established in line 4, it is unclear if “liquid” of line 6 is the same or different from the “specimen and sheath liquid” of line 4. It is suggested to recite “liquid” as “the specimen and the sheath liquid” or “the sheath liquid”.
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 1-4, 6-12, 16-19, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (LI XIANG ET AL:"Continuous-flow microfluidic blood cell sorting for unprocessed whole blood using surface-micromachined microfiltration membranes", LAB ON A CHIP, vol. 14, no. 14, 6 May 2014 (2014-05-06), - May 6, 2014, pages 2565-2575; cited in the IDS filed 02/25/2025) in view of Urakabe et al. (JP 2011013208 A1; see machine translation) and VanDelinder et al. (VanDelinder et al., “Separation of Plasma from Whole Human Blood in a Continuous Cross-Flow in a Molded Microfluidic Device”, Anal. Chem. (2006) 78 (11): 3765–3771).
Regarding claim 1, Li teaches a particle separation chip (abstract; Fig. 1) that separates particles contained in a specimen based on particle size (Fig. 1 teaches cell sorting based on size using the filter membrane), comprising:
a substrate (Fig. 1, top layer and bottom layer) comprising a micro flow path inside of the substrate (Fig. 1 teaches microfluidic channels in the top and bottom layers); and
a perforated sheet comprising holes (Fig. 1 teaches a filter membrane including pores), wherein the micro flow path comprises:
a main flow path (Fig. 1, microfluidic channel of the top layer) comprising:
an inlet arranged at upstream side (Fig. 1, upstream inlet of the blood sample in the top layer), into which a specimen comprising a first particle, and a second particle that is smaller than the first particle is supplied (Fig. 1 teaches a blood sample including white blood cells, i.e. first particle, and red blood cells, i.e. second particle, are supplied into the inlet in the top layer, wherein the red blood cells are smaller than the white blood cells); and
a first outlet arranged at downstream side (Fig. 1, downstream top outlet), from which a specimen comprising the first particle is discharged (Fig. 1 teaches white blood cells are discharged from the top outlet); and
a branch flow path (Fig. 1, bottom channel of the bottom layer) connected to the main flow path along a flow direction of the main flow path (Fig. 1 teaches the bottom channel is fluidly connected to the top channel of the top layer along the flow direction via the filtration membrane), the branch flow path comprising a second outlet (Fig. 1, bottom outlet) from which a specimen comprising the second particle is discharged at downstream side (Fig. 1 teaches a solution comprising the red blood cells are discharged from the bottom outlet downstream),
the main flow path and the branch flow path are connected via the holes of the perforated sheet (Fig. 1).
Li fails to teach: a branch flow path connected to the main flow path at branches along a flow direction of the main flow path; the main flow path and the branch flow path are connected via the holes of the perforated sheet at the branches; the branch flow path comprises: flow paths arranged non-parallel to the main flow path in plan view, each of the flow paths connecting to the main flow path at each of the branches; and a relay flow path connecting the flow paths to the second outlet, and a length of one of the flow paths that is connected to the main flow path at one of the branches of the upstream side of the main flow path is longer than a length of another of the flow paths that is connected to the main flow path at another of the branches of the downstream side of the main flow path, or a cross-sectional area of the flow paths that is connected to the main flow path at one of the branches of the upstream side of the main flow path is smaller than a cross-sectional area of another of the flow paths that is connected to the main flow path at another of the branches of the downstream side of the main flow path.
Li teaches the crossflow filtration principle in conjunction with the high-porosity PMM could be adapted for separation of other blood components useful for blood-based clinical analysis and diagnosis, such as platelets and blood plasma, by varying the pore size of the PMM (section “Conclusion”, second paragraph).
Urakabe teaches a biological manipulation system to manipulate bodily fluid solutions using microfluidic channels for discriminating and separating spheres of a specific size ([0001]). Urakabe teaches the invention makes it possible to separate cells of similar size, such as nucleated red blood cells and white blood cell ([0009], third paragraph). Urakabe teaches in a combination of branch channels connected to the main channel, blood is driven laminarly to flow red blood cells into the branch channels, leaving only blood cells the size of white blood cells in the main channel ([0009], fourth paragraph). Urakabe teaches the invention allows separation of particle groups with extremely fine differences of several micrometers ([0012]). Urakabe teaches a branch flow path (Fig. 2, paths 14a) connected to a main flow path (12) at branches along a flow direction of the main flow path (Fig. 2, interpreted as the intersection or branch points of main flow path 12 and paths 14a); the main flow path (12) and the branch flow path (paths 14a); the branch flow path comprises: flow paths (Fig. 2, paths 14a) arranged non-parallel to the main flow path in plan view (Fig. 2 shows paths 14a are non-parallel to main flow path 12 in plan view), each of the flow paths connecting to the main flow path at each of the branches (Fig. 2); and a relay flow path (14a1) connecting the flow paths to a second outlet (14a2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the particle separation chip of Li to incorporate Li’s teachings of crossflow filtration to separate blood components based on pore size of a membrane (section “Conclusion”, second paragraph) and Urakabe’s teachings of separation of blood components based on size of the components ([0001], [0009], [0012]; Fig. 2) and a plurality of non-parallel flow paths connected to a main flow path at branches with a relay flow path to connect the flow paths to a second outlet (Fig. 2) to provide: a branch flow path connected to the main flow path at branches along a flow direction of the main flow path; the main flow path and the branch flow path are connected via the holes of the perforated sheet at the branches; the branch flow path comprises: flow paths arranged non-parallel to the main flow path in plan view, each of the flow paths connecting to the main flow path at each of the branches; and a relay flow path connecting the flow paths to the second outlet. Doing so would have a reasonable expectation of successfully improving separation of particle groups with extremely fine differences, therefore improving separation of particles contained in a specimen.
Modified Li fails to teach: a length of one of the flow paths that is connected to the main flow path at one of the branches of the upstream side of the main flow path is longer than a length of another of the flow paths that is connected to the main flow path at another of the branches of the downstream side of the main flow path, or a cross-sectional area of the flow paths that is connected to the main flow path at one of the branches of the upstream side of the main flow path is smaller than a cross-sectional area of another of the flow paths that is connected to the main flow path at another of the branches of the downstream side of the main flow path.
VanDelinder teaches a particle separation chip (Fig. 1; abstract) that separates particles contained in a specimen based on particle size (interpreted as a functional limitation, see MPEP 2114; abstract teaches the device separates plasma from whole human blood by size exclusion in a cross-flow; therefore, the device is capable of performing the functional limitation of separating particles based on particle size), comprising: a substrate (Fig. 1, PDMS and cover glass of microfluidic device) comprising a micro flow path inside of the substrate (Fig. 1 teaches microfluidic channels A, C, D, E inside of the microfluidic device) and a filter regions including holes (Fig. 1 teaches B channels as filters). VanDelinder teaches the device is for separating plasma from whole blood in a continuous cross-flow (page 3766, left column, first full paragraph). VanDelinder teaches the chip (Fig. 1) comprise a main flow path (A), an upstream inlet (A), a first outlet downstream (2), a branch flow path (C and D channels) along the flow direction of the main flow path (Fig. 1), a second outlet (3), the main flow path and branch flow paths are connected via holes of the filter regions (Fig. 1 shows A channel is connected to C and D channels via B channels). VanDelinder teaches the branch flow path (C and D channels) includes flow paths (D channels) arranged non-parallel to the main flow path in plan view (Fig. 1), each of the flow paths connecting to the main flow path at each of the branches (Fig. 1 shows D channels connected to A channel at branches at B channels); and a relay flow path (E) connecting the branch flow path to the second outlet (3). VanDelinder teaches a length of one of the flow paths (Fig. 1, one of the upstream D channels) that is connected to the main flow path at one of the branches of the upstream side of the main flow path is longer than a length of another of the flow paths that is connected to the main flow path at another of the branches of the downstream side of the main flow path (Fig. 1 teaches the length of the D channels upstream are longer than the length of the downstream D channels, i.e. the length of the D channel decrease from the upstream to downstream side of the main flow path A channel). VanDelinder teaches the device was designed with the aim of having equal flow rates through all B channels and D channels (page 3767, right column, second paragraph); therefore, to ensure the same flow rate in all B channels, the cumulative resistance and hence the length of the D channels was varied proportionally to the local pressure in the A channel; therefore, D channels at the end of the filter region were 1/3 as long as those at the beginning (page 3767, right column, last paragraph). VanDelinder teaches the reduction of channel resistance under pressure can lead to redistribution of pressures and flow rates, uneven and excessive draining of plasma, and nonlinear operation of the device (page 3768, left column, first paragraph). VanDelinder teaches the design of the device provided size exclusion of red blood cells; and stable resistance for flow of plasma between the A and E channels, ensuring reliable operation of the device over a wide range of driving pressures (section, “Conclusions”, first paragraph). VanDelinder teaches the device is easy to combine with other microchannel elements (page 3770, left column, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the flow paths of the branch flow path of modified Li to incorporate VanDelinder’s teachings of a particle separation chip for separating blood in a continuous cross-flow (abstract; Fig. 1; page 3766, left column, first full paragraph), the chip including branch flow paths that have longer lengths upstream and shorter lengths downstream of the main flow path (Fig. 1) to provide: a length of one of the flow paths that is connected to the main flow path at one of the branches of the upstream side of the main flow path is longer than a length of another of the flow paths that is connected to the main flow path at another of the branches of the downstream side of the main flow path, or a cross-sectional area of the flow paths that is connected to the main flow path at one of the branches of the upstream side of the main flow path is smaller than a cross-sectional area of another of the flow paths that is connected to the main flow path at another of the branches of the downstream side of the main flow path. Doing so would have a reasonable expectation of successfully improving control of equal flow rates in the flow paths to ensure reliable operation of the device over a wide range of driving pressures by adjusting the length or cross-sectional area of the flow paths from the upstream to downstream side of the main channel (VanDelinder, page 3767, right column, second paragraph; page 3767, right column, last paragraph; page 3768, left column, first paragraph; section, “Conclusions”, first paragraph).
Regarding claim 2, Li further teaches wherein the main flow path (Fig. 1, microfluidic channel of the top layer) and the branch flow path (Fig. 1, bottom channel of the bottom layer) are configured such that a partial specimen supplied from the inlet flows into the branch flow path (Fig. 1 teaches at least partial of the blood sample flows from the inlet into the bottom channel) and a remaining specimen flows into the main flow path (Fig. 1 teaches at least a remaining portion of the blood sample, such as the white blood cells, flows into the main flow path), so that the first particle is discharged from the first outlet (Fig. 1 teaches white blood cells are discharged from the top outlet) and the second particle is discharged from the second outlet (Fig. 1 teaches the red blood cells are discharged from the bottom outlet).
Regarding claim 3, Li further teaches wherein a flow path width of the main flow path is greater than or equal to 100 um and less than or equal to 50 mm (page 15, Fig. 1 teaches the width of the top channel is 500 um).
Regarding claim 4, Li further teaches wherein a flow path width of the main flow path is greater than or equal to 500 um and less than or equal to 50 mm (page 15, Fig. 1 teaches the width of the top channel is 500 um).
Regarding claim 6, modified Li fails to teach: wherein the flow paths connecting with the main flow path are arranged to intersect the main flow path in plan view at each of the branches, and the specimen comprising the second particle flows to both sides of the main flow path.
Urakabe teaches flow paths (14a,14b) that intersect the main flow path (12) in a plan view at each of the branches (Fig. 2), wherein the flow paths (14a,14b) are for separating red blood cells to both sides of the main flow path (Fig. 2; [0042]).
VanDelinder teaches flow paths (Fig. 1, C and D channels) intersect the main flow path (A) in a plan view at each of the branches (Fig. 2), wherein the flow paths (C and D channels) are on both sides of the main flow path (Fig. 1); wherein the flow paths on each side of the main flow path are connected to the second outlet (3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the flow paths of modified Li to incorporate Urakabe’s teachings of flow paths that intersect and are on both sides of a main flow path (Fig. 2; [0042]) and VanDelinder’s teachings of flow paths that intersect and are on both sides of a main flow path (Fig. 1) to provide: wherein the flow paths connecting with the main flow path are arranged to intersect the main flow path in plan view at each of the branches, and the specimen comprising the second particle flows to both sides of the main flow path. Doing so would have a reasonable expectation of successfully improving throughput of separation of the second particle from the main flow path.
Regarding claim 7, modified Li fails to teach: wherein The branch flow path comprises the greater than or equal to 2 and less than or equal to 15,000 flow paths that are connected to the main flow path at each of the branches.
Urakabe teaches a biological manipulation system to manipulate bodily fluid solutions using microfluidic channels for discriminating and separating spheres of a specific size ([0001]). Urakabe teaches the invention makes it possible to separate cells of similar size, such as nucleated red blood cells and white blood cell ([0009], third paragraph). Urakabe teaches in a combination of branch channels connected to the main channel, blood is driven laminarly to flow red blood cells into the branch channels, leaving only blood cells the size of white blood cells in the main channel ([0009], fourth paragraph). Urakabe teaches the invention allows separation of particle groups with extremely fine differences of several micrometers ([0012]). Urakabe teaches because the number of red blood cells is very large, a large number of pathways are formed ([0043]). Urakabe teaches greater than or equal to 2 and less than or equal to 15,000 flow paths that are connected to the main flow path at each of the branches (Fig. 2 shows at least 2 and less than 15000 flow paths 13a, 13b, 14a, 14b, 15a, 15b connected to the main flow path 12 at branch sections for paths 13a, 13b, 14a, 14b, 15a, 15b).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the branch flow path of modified Li to incorporate Urakabe’s teachings of multiple flow paths connected to the main flow path at each branch (Fig. 2) to provide: wherein The branch flow path comprises the greater than or equal to 2 and less than or equal to 15,000 flow paths that are connected to the main flow path at each of the branches. Doing so would have a reasonable expectation of successfully improving throughput of separation of particle groups with extremely fine differences, therefore improving separation of large number of particles as taught by Urakabe ([0009],[0012],[0043]; Fig. 2).
Regarding claim 8, Li further teaches wherein the branch flow path (Fig. 1, bottom channel of the bottom layer) is arranged below the main flow path when the particle separation chip is in use (Fig. 1, teaches the bottom channel of the bottom layer is below the microfluidic channel of the top layer during use).
Regarding claim 9, modified Li further teaches wherein the main flow path (Li, Fig. 1, microfluidic channel of the top layer) further comprises a sheath liquid inlet arranged at the upstream side from the branches (Li, Fig. 1 teaches a sheath flow inlet in the top layer upstream of the bottom channel of the bottom layer; therefore, the sheath flow inlet is arranged upstream of the branches of modified Li which includes the “branches” at the bottom channel of the bottom layer).
Regarding claim 10, Li further teaches the particle separation chip according to claim 9, wherein the sheath liquid inlet (Fig. 1 teaches a sheath flow inlet in the top layer) supplies sheath liquid from upper side of the specimen flowing in the main flow path (Fig. 1 teaches a sheath flow inlet in the top layer is capable of supplying sheath liquid from an upper side of the blood sample in the microfluidic channel of the top layer).
Regarding claim 11, modified Li fails to teach the particle separation chip according to claim 9, wherein the sheath liquid inlet supplies sheath liquid from both sides of the specimen flowing in the main flow path.
Urakabe teaches an embodiment (Fig. 22) wherein a sheath liquid inlet (2202) supplies sheath liquid from both sides of a specimen flowing in a main path (Fig. 22 and [0100] teaches buffer is introduced from both sides of a specimen 2201 that flows into a main path 2204); therefore, allowing a sample flow (2203) to converge in the center of the main flow path (2204) to allow for detection of cells using laser light ([0100]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the particle separation chip of modified Li to incorporate Urakabe’s teachings of supplying sheath liquid from both sides of a sample to allow for detection of particles (Fig. 22; [0100]) to provide: the particle separation chip according to claim 9, wherein the sheath liquid inlet supplies sheath liquid from both sides of the specimen flowing in the main flow path. Doing so would have a reasonable expectation of successfully allowing for desired direction of the sample flow to regions of the main flow path for improved analysis and detection of particles as taught by Urakabe ([0100]).
Regarding claim 12, modified Li fails to teach: wherein a fluid resistance from one of the branches of the upstream side of the main flow path to the second outlet is greater than a fluid resistance from another of the branches of the downstream side of the main flow path to the second outlet.
VanDelinder teaches a length of one of the flow paths (Fig. 1, one of the upstream D channels) that is connected to the main flow path at one of the branches of the upstream side of the main flow path is longer than a length of another of the flow paths that is connected to the main flow path at another of the branches of the downstream side of the main flow path (Fig. 1 teaches the length of the D channels upstream are longer than the length of the downstream D channels, i.e. the length of the D channel decrease from the upstream to downstream side of the main flow path A channel). VanDelinder teaches the device was designed with the aim of having equal flow rates through all B channels and D channels (page 3767, right column, second paragraph); therefore, to ensure the same flow rate in all B channels, the cumulative resistance and hence the length of the D channels was varied proportionally to the local pressure in the A channel; therefore, D channels at the end of the filter region were 1/3 as long as those at the beginning (page 3767, right column, last paragraph). VanDelinder teaches the reduction of channel resistance under pressure can lead to redistribution of pressures and flow rates, uneven and excessive draining of plasma, and nonlinear operation of the device (page 3768, left column, first paragraph). VanDelinder teaches the design of the device provided size exclusion of red blood cells; and stable resistance for flow of plasma between the A and E channels, ensuring reliable operation of the device over a wide range of driving pressures (section, “Conclusions”, first paragraph). VanDelinder teaches the device is easy to combine with other microchannel elements (page 3770, left column, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the flow paths of the branch flow path of modified Li to incorporate VanDelinder’s teachings of a particle separation chip for separating blood in a continuous cross-flow (abstract; Fig. 1; page 3766, left column, first full paragraph), the chip including branch flow paths that have longer lengths upstream and shorter lengths downstream of the main flow path (Fig. 1), and reduction of channel resistances under pressure (page 3768, left column, first paragraph) to provide: wherein a fluid resistance from one of the branches of the upstream side of the main flow path to the second outlet is greater than a fluid resistance from another of the branches of the downstream side of the main flow path to the second outlet. Doing so would have a reasonable expectation of successfully improving control of equal flow rates in the flow paths to ensure reliable operation of the device over a wide range of driving pressures by adjusting the length or cross-sectional area of the flow paths from the upstream to downstream side of the main channel due to the decreasing fluid resistances of flow paths from an upstream side to a downstream side (VanDelinder, page 3767, right column, second paragraph; page 3767, right column, last paragraph; page 3768, left column, first paragraph; section, “Conclusions”, first paragraph).
Regarding claim 16, modified Li fails to teach: wherein the micro flow path is configured to have a liquid removal rate that is substantially the same ratio at each of the branches, wherein the liquid removal rate is a ratio of a flow rate into the branch flow path at one of branches.
VanDelinder teaches a length of one of the flow paths (Fig. 1, one of the upstream D channels) that is connected to the main flow path at one of the branches of the upstream side of the main flow path is longer than a length of another of the flow paths that is connected to the main flow path at another of the branches of the downstream side of the main flow path (Fig. 1 teaches the length of the D channels upstream are longer than the length of the downstream D channels, i.e. the length of the D channel decrease from the upstream to downstream side of the main flow path A channel). VanDelinder teaches the device was designed with the aim of having equal flow rates through all B channels and D channels (page 3767, right column, second paragraph); therefore, to ensure the same flow rate in all B channels, the cumulative resistance and hence the length of the D channels was varied proportionally to the local pressure in the A channel; therefore, D channels at the end of the filter region were 1/3 as long as those at the beginning (page 3767, right column, last paragraph). VanDelinder teaches the reduction of channel resistance under pressure can lead to redistribution of pressures and flow rates, uneven and excessive draining of plasma, and nonlinear operation of the device (page 3768, left column, first paragraph). VanDelinder teaches the design of the device provided size exclusion of red blood cells; and stable resistance for flow of plasma between the A and E channels, ensuring reliable operation of the device over a wide range of driving pressures (section, “Conclusions”, first paragraph). VanDelinder teaches the device is easy to combine with other microchannel elements (page 3770, left column, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the branch flow path of modified Li to incorporate VanDelinder’s teachings of a particle separation chip for separating blood in a continuous cross-flow (abstract; Fig. 1; page 3766, left column, first full paragraph), the chip including branch flow paths that have longer lengths upstream and shorter lengths downstream of the main flow path (Fig. 1), and reduction of channel resistances under pressure (page 3768, left column, first paragraph) to provide: wherein the micro flow path is configured to have a liquid removal rate that is substantially the same ratio at each of the branches, wherein the liquid removal rate is a ratio of a flow rate into the branch flow path at one of branches. Doing so would have a reasonable expectation of successfully improving control of equal flow rates in the flow paths to ensure reliable operation of the device over a wide range of driving pressures by adjusting the length or cross-sectional area of the flow paths from the upstream to downstream side of the main channel (VanDelinder, page 3767, right column, second paragraph; page 3767, right column, last paragraph; page 3768, left column, first paragraph; section, “Conclusions”, first paragraph).
Regarding claim 17, modified Li further teaches wherein the micro flow path is configured to have a liquid removal rate that is greater than 0% and less than or equal to 50% at each of the branches, wherein the liquid removal rate is a ratio of a flow into the branch flow path at one of branches (interpreted as a functional limitation of the micro flow path, see MPEP 2114; see above claim 1, modified Li teaches the claimed particle separation chip; therefore, the particle separation chip of modified Li is identical to the presently claimed particle separation chip including the micro flow path and therefore, would have the ability to perform the function, i.e. to have the claimed removal rate, recited in the claim, See MPEP 2112.01 (I)).
In an alternative interpretation, if it is determined that modified Li fails to teach: wherein the micro flow path is configured to have a liquid removal rate that is greater than 0% and less than or equal to 50% at each of the branches, wherein the liquid removal rate is a ratio of a flow into the branch flow path at one of branches,
Urakabe teaches in a combination of branch channels connected to the main channel, blood is driven laminarly to flow red blood cells into the branch channels, leaving only blood cells the size of white blood cells in the main channel ([0009], fourth paragraph). Urakabe teaches the invention allows separation of particle groups with extremely fine differences of several micrometers ([0012]). Urakabe teaches the ratio of flow rates the flow traveling straight through the main channel and the flow absorbed into the branch channels is precisely determined by the ratio of the resistance values of each channel ([0010], fourth paragraph). Urakabe teaches controlling behavior of particles in a fluid system by designing the flow resistance ratio between the main flow path and branch flow path ([0103], first paragraph).
VanDelinder teaches the device was designed with the aim of having equal flow rates through all B channels and D channels (page 3767, right column, second paragraph); therefore, to ensure the same flow rate in all B channels, the cumulative resistance and hence the length of the D channels was varied proportionally to the local pressure in the A channel; therefore, D channels at the end of the filter region were 1/3 as long as those at the beginning (page 3767, right column, last paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the micro flow path and the branches of modified Li to incorporate Urakabe’s teachings of controlling behavior of particles by designing the flow resistance ratio between the main flow path and branch flow path ([0010], fourth paragraph; [0103], first paragraph) and VanDelinder’s teachings of having equal flow rates of each branch channel (page 3767, right column, second paragraph-last paragraph) to provide: wherein the micro flow path is configured to have a liquid removal rate that is greater than 0% and less than or equal to 50% at each of the branches, wherein the liquid removal rate is a ratio of a flow into the branch flow path at one of branches. Doing so would have a reasonable expectation of successfully improving control and optimization of the flow rates of each of the branches in relation to the main flow path to improve separation of desired particles.
Regarding claim 18, modified Li further teaches wherein the perforated sheet (Li, Fig. 1, filtration membrane) is configured to have an opening ratio such that the first particle of a predetermined size is collected from the first outlet at a predetermined collection rate (Li, Fig. 1 teaches the filtration membrane having an array of through holes at an opening ratio, such that white blood cells are capable of being collected at the top outlet, which is implied to be at a predetermined collection rate; Fig. 5 teaches recovery rate, i.e. predetermined collection rate, of white blood cells at the top outlet), wherein the opening ratio is a ratio of an area of the holes in the perforated sheet to an area of an opening in an intersection surface of the main flow path and the branch flow path (Li, Fig. 1 teaches the filtration membrane having an array of through holes; therefore, the filtration would have an opening ratio as claimed).
Regarding claim 19, Li further teaches wherein a diameter of the holes in the perforated sheet is greater than or equal to 30 nm and less than or equal to 100 um (Fig. 1D teaches the filtration membrane includes 4 um diameter pores).
Regarding claim 21, Li further teaches wherein a diameter of the first particle is greater than or equal to 30 nm and less than or equal to 100 um (note that “first particle” is not positively recited structurally; the device of modified Li is structurally capable of being used with the claimed first particle with the claimed diameter; however, page 7, last paragraph teaches white blood cells have a diameter of 7-10 um).
Regarding claim 23, Li further teaches a particle separation apparatus (Fig. 1; abstract) comprising:
the particle separation chip according to claim 1 (see above claim 1; modified Li teaches the particle separation chip according to claim 1);
a setting part on which the particle separation chip is placed (Li, Fig. 1 teaches a PDMS microfluidic device in use, wherein it is inherent that the device is placed on a surface or support, i.e. setting part, in order to be stable during use and imaging);
a liquid pumping section (Li, Fig. 1 and page 6, section “Separation of microbeads”, interpreted as the syringe pumps) that supplies the specimen and sheath liquid into each of the inlet of the specimen of the main flow path and an inlet of the sheath liquid of the main flow path in the particle separation chip and pumps liquid in the micro flow path (interpreted as a functional limitation, see MPEP 2114; Li, Fig. 1 and page 6, section “Separation of microbeads” teaches syringe pumps that supplies blood sample and sheath flow into each of the inlet of the blood sample and the inlet of the sheath flow and therefore pumps liquid into the microchannel of the top layer);
a first collection section for the first particle that is connected to the first outlet (Li, Fig. 1 and page 6, section “Separation of microbeads” teaches a first vial connected to the top outlet for collecting a sample with the white blood cells); and
a second collection section for the second particle connected to the second outlet (Li, Fig. 1 and page 6, section “Separation of microbeads” teaches a second vial connected to the bottom outlet for collecting a sample with the red blood cells).
If it is determined that modified Li fails to teach: a setting part on which the particle separation chip is placed, Urakabe teaches a setting part (Fig. 15, stage 1503) on which a particle separation chip is placed (1502). Urakabe teaches an automated system including a stage for installing the microchannel chip and a liquid feeding device ([0090]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the particle separation apparatus of modified Li to provide: a setting part on which the particle separation chip is placed. Doing so would have a reasonable expectation of successfully improving support and installation of the particle separation chip during use as taught by Urakabe ([0090]; Fig. 15).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Li in view of Urakabe and VanDelinder as applied to claim 1 above, and further in view of Kanabara et al. (US 20150111293 A1).
Regarding claim 20, modified Li fails to teach: wherein the perforated sheet is configured to have an opening ratio that is greater than 0% and less than or equal to 50% at the branches, wherein the opening ratio is a ratio of an area of holes in the perforated sheet to an area of an opening in an intersection surface of the main flow path and the branch flow path.
Kanabara teaches a cancer cell trapping metal filter, the filter including a sheet with through-holes, and improving the opening ratio of the filter (abstract). Kanabara teaches the filter is provided between an inlet channel and outlet channel such that liquid to be tested flows through the through-hole (Fig. 8; [0019]). Kanabara teaches the filter allows red blood cells, blood platelets, and white blood cells of a metastatic cancer patient to pass therethrough and which traps a circulating tumor cell ([0056]). Kanabara teaches when the opening ratio exceeds 50%, there is a possibility that a decrease in strength of the filter, a decrease in yield ratio due to difficulty in processing, and the like may occur; and when the opening ration is less than 10%, clogging tends to occur, and thus a concentration performance of the filter may deteriorate ([0073]). Kanabara teaches it is preferable to have the opening ratio of the filter to be 10-50% ([0083]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the perforated sheet of modified Li to incorporate Kanabara’s teachings of a filter for separating particles in blood and the filter having a preferable opening ratio of 10-50% to provide: wherein the perforated sheet is configured to have an opening ratio that is greater than 0% and less than or equal to 50% at the branches, wherein the opening ratio is a ratio of an area of holes in the perforated sheet to an area of an opening in an intersection surface of the main flow path and the branch flow path. Doing so would have a reasonable expectation of successfully optimizing strength of the perforated sheet and reduce clogging of the perforated sheet as taught by Kanabara ([0073],[0083]).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Li in view of Urakabe and VanDelinder as applied to claim 1 above, and further in view of Cheng et al. (US 20210170409 A1).
Regarding claim 22, Li further teaches wherein the specimen supplied from the inlet comprises a blood specimen (Fig. 1), the second particle comprises a red blood cell (Fig. 1).
Modified Li fails to teach: the first particle comprises a circulating tumor cell, and the second particle comprises a white blood cell, a red blood cell, and a platelet.
Li teaches the crossflow filtration principle in conjunction with the high-porosity PMM could be adapted for separation of other blood components useful for blood-based clinical analysis and diagnosis, such as platelets and blood plasma, by varying the pore size of the PMM (section “Conclusion”, second paragraph).
Urakabe teaches a biological manipulation system to manipulate bodily fluid solutions using microfluidic channels for discriminating and separating spheres of a specific size ([0001]). Urakabe teaches the invention makes it possible to separate cells of similar size, such as nucleated red blood cells and white blood cell ([0009], third paragraph). Urakabe teaches classifying particle groups containing tumor cells classified by particle sizes ([0096]).
Cheng teaches a microfluidic chip for circulating tumor cell separation (abstract; Figs. 1-2) including a perforated sheet (2) separating a main flow path (4) and branch flow path (5). Cheng teaches capture and detection of circulating tumor cells are of great significance in the diagnosis of early-stage cancer, prognosis analysis, personalized medicine, or single-cell sequencing of tumors ([0002]). Cheng teaches providing a microfluidic chip and method for separating and counting circulating tumor cells that have advantages including high throughput, high efficiency, and ease to operate and promote ([0004]). Cheng teaches the chip allows a blood sample containing circulating tumor cells to flow in the channel on one side and to be filtered through a filter membrane, upon which, blood cells having a smaller volume will pass through the filter membrane and enter into the channel on the other side, along which channel they flow and then be discharged, while circulating tumor cells having a larger volume cannot pass through the filter membrane and will flow with the blood sample in the original channel and then be collected ([0017]). Cheng teaches the filter pore diameter is 8-10 um ([0015]). Cheng teaches circulating tumor cells in the blood are usually larger than blood cells (red blood cells, white blood cells, etc.) ([0016]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the particle separation chip of modified Li to incorporate Li’s teachings of separating blood components for blood-based clinical analysis and diagnosis (section “Conclusion”, second paragraph), Urakabe’s teachings of separating blood components and classifying groups containing tumor cells ([0009], third paragraph; [0096]), and Cheng’s teachings of a great significance of capturing and detection of circulating tumor cells ([0002]) and a microfluidic chip to filter and separate circulating tumor cells from other smaller blood components (Figs. 1-2; [0004];[0016],[0017]) to provide: the first particle comprises a circulating tumor cell, and the second particle comprises a white blood cell, a red blood cell, and a platelet. Doing so would have a reasonable expectation of successfully improving separation of desired particles, such as circulating tumor cells from other blood components, and therefore improving clinical analysis and diagnosis of blood.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Suresh et al. (US 20170232439 A1) teaches an apparatus for sorting and separating cells (abstract). Suresh teaches separation of cancer cells from white blood cells and additional experiments show that a 45% flow fraction into the collection stream yielded a purity of ˜98% and a recovery rate of ˜20% ([0097]).
Kartalov et al. (US 20120085648 A1) teaches a microfluidic separator for separating target components of a fluid by filtration (abstract; Figs. 1-8) including an input (295) and multiple outputs (250, 260, 270, 280) for separate components such as WBCs, RBCs, platelets, and plasma (Fig. 8).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HENRY H NGUYEN whose telephone number is (571)272-2338. The examiner can normally be reached M-F 7:30A-5:00P.
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/HENRY H NGUYEN/Primary Examiner, Art Unit 1758
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