DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Remarks
This office action fully acknowledges Applicant’s remarks and amendments filed on 15 September 2025.
Claims 41 and 44-63 are pending.
Claims 1-40 and 42-43 are cancelled.
Claims 60-61 are withdrawn.
Claim 63 is newly added.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 41, 47-48, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Fan et al. (US 2016/0289669 A1), referred to hereinafter as “Fan”, in view of Liu et al. (US 2017/0341078 A1), referred to hereinafter as “Liu”, and as evidenced through Pope et al. (Pope, Stephen B. Turbulent Flows. Cambridge: Cambridge University Press, 2000.), hereinafter “Pope”.
Regarding Claim 41, Fan teaches a cell sorting device comprising: a conduit, which is elongate or oblong, and which has an upstream portion having at least one inlet port for the conduit and a downstream portion having at least one outlet port for the conduit, a microarray of microwells positioned within the conduit between the upstream and downstream portions (See the annotated Fig. 62B below.),
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wherein the microarray is further positioned in the conduit between ports or apertures of a first set of branching channels and ports or apertures of a second set of branching channels (Fig. 12 shows that the microarray is positioned within the conduit between the inlet and outlet. Thus Fig. 62b, having a commensurate microarray structure with that of Fig. 12 but with a branched inlet assembly instead of a linear inlet, and in consideration of the [0292] recitation teaching of an embodiment where “…one or more outlet ports for delivery of fluids to a sample collection point or a waste reservoir…” can be implemented to “…facilitate uniform distribution of cells and beads across the plurality of microwells…” -- Fig. 17 and Fig. 85 show multiple outlet ports/apertures converging to form a branched channel structure, as opposed to the single outlet port shown in Fig. 62B annotated above.), the microarray of Fan is thus positioned between ports or apertures of a first set of branching channels and ports or apertures of a second set of branching channels.),
wherein the microwells are arranged in parallel arrays of microwells or in rows of microwells, which parallel arrays or rows are separated by parallel partitions or spaces, which parallel arrays or rows are positioned longitudinally between the ports or apertures of the first set of branching channels and the ports or apertures of the second set of branching channels (Fig. 12 shows the microwell array wherein the microwells are arranged in parallel rows, wells of the array are separated by parallel spaces, and parallel rows are arranged longitudinally (in as much as is understood by the claim).),
wherein the first and second sets of branching channels are not contained within the conduit, but are in fluid communication with the conduit's interior via ports or apertures in the conduit (See the annotated Fig. 62B above. Arrows flowing from the branching inlet channels (first set of branching channels) through their ports/apertures connecting them to the conduit, and to the conduit represent fluid communication between the branching inlet channels and the conduit. The same is expected of the branching outlet channels given that Fig. 17 and Fig. 85 shows that they have a structural arrangement and ports/apertures commensurate with that of the branching inlet channels shown by Fig. 62B.), as in Claim 41.
Further regarding Claim 41, Fan does not specifically teach the cell sorting device discussed above wherein the first set of branching channels are in fluid communication with a second inlet port and the second set of branching channels are in fluid communication with a second outlet port, the second inlet port and second outlet port not contained within the conduit and distinct from the at least one inlet port and at least one outlet port in the conduit, wherein the cell sorting device is configured to produce a flow between the at least one inlet port and the at least one outlet port in the conduit, which flow is in a direction different than a flow direction between the second inlet port and the second outlet port, as in Claim 41.
However, Liu teaches a respective microfluidic sorting device comprising a first microfluidic channel 107 for flowing through cells or beads comprises a first inlet port and a first outlet port, as well as a second microfluidic channel 108 comprising a second inlet and a second outlet in fluid communication with the first microfluidic channel 107 via the intersection between the channels 107 and 108, wherein a flow between the first inlet/outlet of channel 107 is perpendicular to a flow between the second inlet/outlet of the channel 108, thereby flowing in a direction different than a flow direction between the second inlet port and the second outlet port, this arrangement providing a sufficient structure for deflecting cells via a buffer flow through the second microfluidic channel 108 to sort said cells (Fig. 16 and [0112]: “The second micro-fluidic channel 108 may be positioned perpendicular to the first micro-fluidic channel 107. The impact of the generated jet flow perpendicular on the propagation path of a cell in the first micro-fluidic channel is thereby maximal. For example, power usage may be reduced.”). – Herein, it is further noted that the reference of Liu is not relied upon for providing the limitation of branching channels, wherein this limitation is provided by Fan.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the device of Fan such that the first set of branching channels are in fluid communication with a second inlet port and the second set of branching channels are in fluid communication with a second outlet port, the second inlet port and second outlet port not contained within the conduit and distinct from the at least one inlet port and at least one outlet port in the conduit, wherein a flow between the at least one inlet port and the at least one outlet port in the conduit is in a direction different than a flow direction between the second inlet port and the second outlet port, such as suggested by Liu, so as to provide a sufficient structure for deflecting cells via a buffer flow through the second microfluidic channel to sort said cells, while also minimizing the power required to do so; and would have a reasonable expectation of success therein.
Further regarding Claim 41, Fan does not specifically teach the cell sorting device discussed above wherein a space greater than 100 um separates the microarray of microwells from the first set of branching channels and a space of greater than 100 um separates the microarray of microwells from the second set of branching channels, as in Claim 41.
However, as the spreading, mixing, and kinetic energy of particles in a solution are properties that can be modified by adjusting the distance between a pipe opening and a target area within a larger tank, as evidenced through Pope (p. 97-99), the precise separation distance between the branching channels and the microarray would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. In Fan, one skilled in the art would be motivated to optimize the separation distance to ensure the wells are sufficiently and evenly filled (As discussed in para. [0017].), thereby avoiding always-empty wells residing between or beyond adjacent branching channel apertures, and improving distribution among wells. As such, without showing unexpected results, the precise separation distance between the branching channels and the microarray cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the precise separation distance between the branching channels and the microarray so as to maximally obtain the desired properties of particle spreading, mixing, and kinetic energy as they spread across the microarray (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
See further MPEP 2144.04(IV)(A): Mere change in size (where the only difference between the prior art and the claims is a recitation of relative dimensions of the claimed device and a device having the claimed relative dimensions would not perform differently than the prior art device) absent evidence to criticality, non-obviousness, or unexpected results associated with the claimed size is an obvious matter of design choice.
Regarding Claim 47, the prior art meets the limitations of Claim 41 as discussed above. Further, Fan teaches the cell sorting device discussed above wherein the microarray is a microwell array plate that, at its edge, is aligned between the first and second sets of branching channels and between two opposing fluid conduit ports (Fig. 22B shows the microwell array plate 2207 which positions the microwell array between the inlet and outlet of fluidic layer 2205. Thus, in a branched embodiment shown by Fig. 17 and Fig. 85, the microwell array is between the first and second sets of branching channels and between two opposing fluid conduit ports.), as in Claim 47.
Regarding Claim 48, the prior art meets the limitations of Claim 41 as discussed above. Further, Fan teaches the cell sorting device discussed above wherein an optical tweezer is positioned for use with the device ([0391] states, “In some embodiments, optical tweezers may be used to extract selected cells or beads from microwells and move them…”).
While Fan does not specifically teach said optical tweezer as “positioned under a plane or bottom of the microarray” as in Claim 48, the device having the claimed relative arrangement of parts would not perform differently than the prior art device, absent evidence of criticality, non-obviousness, or unexpected results associated with the position of said optical tweezers – see MPEP 2144.04 (VI)(C).
Further, one of ordinary skill in the art would find it an obvious design choice to position the optical tweezers at the top or bottom plane of the device to afford the largest two-dimensional area for targeting beads, as well as to avoid unnecessary refraction/dispersion caused by the laser being directed from the side where it would encounter structures of the device. Examiner further notes that the present recitation “…positioned under the microarray’s plane or bottom” is not particularly limited herein as the claim does not particularly establish the relative geometry of the microarray nor its plane so as to particularly set forth the desired arrangement/orientation; wherein the present recitation broadly provides for various arrangements/orientations to meet this.
Regarding Claim 62, Fan teaches a cell sorting device comprising a microarray of microwells (Fig. 2A shows a microarray of microwells.), an elongate or oblong conduit (See the annotated Fig. 62B above.), the microwell microarray being comprised in the elongate or oblong conduit (Fig. 58A shows the microwell array positioned in the elongate conduit.), and channels (Fig. 62B shows channels.),
wherein the microwell array is positioned between
at one side the upstream part of the conduit with at least one inlet port of the conduit and
at a second side the downstream part of the conduit with at least one outlet port of the conduit
and wherein the microwell microarray is positioned between the ports or apertures of
a first set of branching channels and
ii) a second set of branching channels,
(Fig. 12 shows that the microarray is positioned within the conduit between the inlet and outlet. Thus Fig. 62b, having a commensurate microarray structure with that of Fig. 12 but with a branched inlet assembly instead of a linear inlet, and in consideration of the [0292] recitation teaching of an embodiment where “…one or more outlet ports for delivery of fluids to a sample collection point or a waste reservoir…” can be implemented to “…facilitate uniform distribution of cells and beads across the plurality of microwells…” (Fig. 17 and Fig. 85 show multiple outlet ports/apertures converging to form a branched channel structure, as opposed to the single outlet port shown in Fig. 62B annotated above.), the microarray of Fan is thus positioned between ports or apertures of a first set of branching channels and ports or apertures of a second set of branching channels.)
wherein the first and second sets of branching channels are outside the conduit but connect with or engage with the conduit via ports or apertures in the conduit (See the annotated Fig. 62B above.);
and wherein the microwells are organized in parallel arrays of microwells or rows of microwells that are arrays or rows separated with parallel partitions or spaces and which are positioned longitudinally between ports or apertures of the first set of branching channels and ports or apertures of the second set of branching channels (Fig. 12 shows the microwell array wherein the microwells are arranged in parallel rows, wells of the array are separated by parallel spaces, and parallel rows are arranged longitudinally (in as much as is understood by the claim). The microwell array is positioned between the first and second sets of branching channels, as discussed above.), as in Claim 62.
Further regarding Claim 62, Fan does not specifically teach the cell sorting device discussed above wherein the first set of branching channels is in fluid communication with a second inlet port and the second set of branching channels is in fluid communication with a second outlet port, the second inlet port and second outlet port not contained within the conduit and distinct from the at least one inlet port and at least one outlet port in the conduit, wherein the cell sorting device is configured to produce a flow between the at least one inlet port and the at least one outlet port in the conduit, which flow is in a direction different than a flow direction between the second inlet port and the second outlet port, as in Claim 62.
However, Liu teaches a respective microfluidic sorting device comprising a first microfluidic channel 107 for flowing through cells or beads comprises a first inlet port and a first outlet port, as well as a second microfluidic channel 108 comprising a second inlet and a second outlet in fluid communication with the first microfluidic channel 107 via the intersection between the channels 107 and 108, wherein a flow between the first inlet/outlet of channel 107 is perpendicular to a flow between the second inlet/outlet of the channel 108, thereby flowing in a direction different than a flow direction between the second inlet port and the second outlet port, this arrangement providing a sufficient structure for deflecting cells via a buffer flow through the second microfluidic channel 108 to sort said cells (Fig. 16 and [0112]: “The second micro-fluidic channel 108 may be positioned perpendicular to the first micro-fluidic channel 107. The impact of the generated jet flow perpendicular on the propagation path of a cell in the first micro-fluidic channel is thereby maximal. For example, power usage may be reduced.”). – Herein, it is further noted that the reference of Liu is not relied upon for providing the limitation of branching channels, wherein this limitation is provided by Fan.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the device of Fan such that the first set of branching channels are in fluid communication with a second inlet port and the second set of branching channels are in fluid communication with a second outlet port, the second inlet port and second outlet port not contained within the conduit and distinct from the at least one inlet port and at least one outlet port in the conduit, wherein a flow between the at least one inlet port and the at least one outlet port in the conduit is in a direction different than a flow direction between the second inlet port and the second outlet port, such as suggested by Liu, so as to provide a sufficient structure for deflecting cells via a buffer flow through the second microfluidic channel to sort said cells, while also minimizing the power required to do so; and would have a reasonable expectation of success therein.
Further regarding Claim 62, Fan does not specifically teach the cell sorting device discussed above wherein a space greater than 100 um separates the microarray of microwells from the first set of branching channels and a space of greater than 100 um separates the microarray of microwells from the second set of branching channels, as in Claim 41.
However, as the spreading, mixing, and kinetic energy of particles in a solution are a properties that can be modified by adjusting the distance between a pipe opening and a target area within a larger tank, as evidenced through Pope (p. 97-99), the precise separation distance between the branching channels and the microarray would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. In fan, one skilled in the art would be motivated to optimize the separation distance to ensure the wells are sufficiently and evenly filled (As discussed in para. [0017].), thereby avoiding always-empty wells residing between or beyond adjacent branching channel apertures, and improving distribution among wells. As such, without showing unexpected results, the precise separation distance between the branching channels and the microarray cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the precise separation distance between the branching channels and the microarray so as to maximally obtain the desired properties of particle spreading, mixing, and kinetic energy as they spread across the microarray (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
See further MPEP 2144.04(IV)(A): Mere change in size (where the only difference between the prior art and the claims is a recitation of relative dimensions of the claimed device and a device having the claimed relative dimensions would not perform differently than the prior art device) absent evidence to criticality, non-obviousness, or unexpected results associated with the claimed size is an obvious matter of design choice.
Claim 63 is rejected under 35 U.S.C. 103 as being unpatentable over Fan Liu, as applied to Claims 41, 47-48, and 62 above, and as evidenced through Hudson et al. (Hudson, S.D. Poiseuille flow and drop circulation in microchannels. Rheol Acta 49, 237–243 (2010).), hereinafter “Hudson”.
Regarding Claim 63, the prior art meets the limitations of Claim 41 as discussed above. Further, Fan does not specifically teach the device discussed above wherein the sum of cross-sections of the ports or apertures in the conduit are 10 to 30 times smaller than a cross-section of the conduit above the microarray of microwells, as in Claim 63.
However, as the pressure of the fluid passing through the apertures and kinetic energy of particles therein is a property that can be modified by adjusting the size of the apertures relative to the conduit/reservoir, as evidenced through Hudson, the aperture size would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed aperture size of having summed cross sections 10x to 30x smaller than the conduit cannot be considered critical or unexpected.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the aperture size so as to maximally obtain the desired pressure of fluid and kinetic energy of particles passing therethrough (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Mere change in size (where the only difference between the prior art and the claims is a recitation of relative dimensions of the claimed device and a device having the claimed relative dimensions would not perform differently than the prior art device) absent evidence to criticality, non-obviousness, or unexpected results associated with the claimed size is an obvious matter of design choice – see MPEP 2144.04(IV)(A).
Claims 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Fan in view of Liu, as applied to Claims 41, 47-48, and 62 above, and in further view of Gilbert et al. (US 2005/0123450 A1), referred to hereinafter as “Gilbert”.
Regarding Claim 44, the prior art meets the limitations of Claim 41 as discussed above. Further, Fan/Liu does not teach the cell sorting device discussed above wherein the upstream portion comprises a first fluid inlet port distal from the microarray and a second fluid inlet port relatively more proximate to the microarray, wherein the first fluid inlet port is in fluid communication with two fluid channels which each extend laterally and longitudinally with a space and open proximate the space so as to create, when operational, a lateral flow of a sheath fluid that sandwiches a core fluid, and wherein the second fluid inlet port opens more in the upstream portion's core so that, when operational, a core fluid stream is created directed towards the microarray, as in Claim 44.
However, Gilbert teaches a comparable microfluidic device for laboratory use, including for handling living cells ([0005]), wherein an upstream portion comprises a first fluid inlet port more distal from the microarray (Gilbert Fig. 6 shows sheath fluid inlet port 11A more distal from an open region 7. In view of Fan, this region 7 holds the microwell array.),
and a second fluid inlet port relatively more proximate to the microarray (Gilbert Fig. 6 shows sheath sample inlet port 15 more distal from the open region 7.),
wherein the first fluid inlet port is in fluid communication with two fluid channels which each extend laterally and longitudinally with a space and open proximate the space so as to create, when operational, a lateral flow of a sheath fluid that sandwiches a core fluid (Fig. 6 shows the sheath fluid inlet port is in fluid communication with the symmetrically laterally and longitudinally diverging (with respect to space 7) sheath flow channels 12. These channels 12 open proximal to the space 7 which they border. Further, [0007] states, “The sample channel provides the injected sample to the accelerating region, such that the particles are confined in the sheath fluid.”)),
and wherein the second fluid inlet port opens more in the upstream portion's core so that, when operational, a core fluid stream is created directed towards the microarray (Fig. 6 shows sample channel 16 as opening in the upstream portion’s core (between the two sheath fluid channels 12) such that the core sample stream is sandwiched by the two sheath streams.), as in Claim 44.
Gilbert teaches the benefit of this hydrodynamic focusing arrangement as providing protection to particles and/or fluids enveloped by the sheath, for example in applications where it is necessary to protect particles from coming into contact with air ([0004]), or preventing cells from contacting the walls of the fluidic system and shearing as a result ([0005]).
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the cell sorting device taught by Fan/Liu with the hydrodynamic focusing/sheathing system taught by gilbert to protect the cells that are being sorted by the device from shear forces caused by contacting the walls of the device, thus minimizing cell death/disturbance and improving accuracy and efficiency.
Examiner further notes that the recitation “…create, when operational, a lateral flow…” is drawn to a conditional process recitation that is both not necessitated by the claim and, as the claims are drawn to a device, such process recitation is not afforded patentable weight. As discussed above, the cited prior art of Fan/Liu/Gilbert provides to commensurately disclose the positively claimed structural arrangement/functionality of the cell sorting device as claimed and is thus fully capable of being utilized in operation with a sheath and core fluid in as much as presently recited and required herein.
Regarding Claim 45, the prior art meets the limitations of Claim 41 as discussed above. Further, Fan/Liu does not teach the cell sorting device discussed above wherein a solid object positioned in the upstream portion of the conduit with a space between the solid object's rim and part of the conduit's wall so as to form channels extending from the first fluid inlet port, and wherein the second fluid inlet port opens in a cavity formed by a recess in an edge of the solid object, which recess faces the microarray so that, when operational, a core fluid stream with cells releases into the cavity and towards the microarray and by lateral flow of a sheath fluid that sandwiches a core fluid directed towards the microarray, as in Claim 45.
However, Gilbert teaches a comparable microfluidic device for laboratory use, including for handling living cells ([0005]), wherein a solid object positioned in the upstream portion of the conduit with a space between the solid object's rim and part of the conduit's wall so as to form channels extending from the first fluid inlet port (Fig. 2A shows solid plate 50 positioned at the upstream portion of space 7 (labeled in Fig. 6) where space between the plate 50 and the walls of space 7 form the channels 12 extending from the first fluid port 11.),
and wherein the second fluid inlet port opens in a cavity formed by a recess in an edge of the solid object, which recess faces the microarray so that, when operational, a core fluid stream with cells releases into the cavity and towards the microarray and by lateral flow of a sheath fluid that sandwiches a core fluid directed towards the microarray (Fig. 2A shows that sample inlet port 15 (the fluid second inlet port) is formed by a recess in the distal edge of the plate 50 and releases a core fluid stream with cells into the cavity 7 (where the microarray is located in view of Fan). As discussed above regarding Claim 44, this arrangement results in the core fluid sandwiched by the sheath fluid.), as in Claim 45.
Gilbert teaches the benefit of this hydrodynamic focusing arrangement as providing protection to particles and/or fluids enveloped by the sheath, for example in applications where it is necessary to protect particles from coming into contact with air ([0004]), or preventing cells from contacting the walls of the fluidic system and shearing as a result ([0005]).
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the cell sorting device taught by Fan/Liu with the hydrodynamic focusing/sheathing system taught by gilbert to protect the cells that are being sorted by the device from shear forces caused by contacting the walls of the device, thus minimizing cell death/disturbance and improving accuracy and efficiency.
Examiner further notes that the recitation “…when operational, a core fluid stream…” is drawn to a conditional process recitation that it both not necessitated by the claim and, as the claims are drawn to a device, such process recitation is not afforded patentable weight. As discussed above, the cited prior art of Fan/Gilbert provides to commensurately disclose the positively claimed structural arrangement/functionality of the cell sorting device as claimed and is thus fully capable of being utilized in operation with a core fluid stream and sheath fluid in as much as presently recited and required herein.
Regarding Claim 46, the prior art meets the limitations of Claim 45 as discussed above. Further, Fan/Liu/Gilbert as applied to Claims 44 and 45 above teaches solid plate 50 (labeled in Fig. 2A), as shown in Fig. 6 of Gilbert and discussed above regarding Claim 45, as being Y-shaped.
Thereby, it would have been obvious to one of ordinary skill in the art to modify Fan/Liu to utilize a solid object that is a Y-shaped plate, as taught by Gilbert, so as to provide a suitable form to allow for two sheathe fluid channels which diverge from a single inlet port and open to the conduit’s edges such as to provide a sheathe fluid stream from a single inlet port, thus reducing complexity of the device by reducing the number of inlet ports.
Claims 49-53 and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Fan in view of Liu, as applied to Claims 41, 47-48, and 62 above, and in further view of Matsuda et al. ("Surface coating of hydrophilic-hydrophobic block co-polymers on a poly(acrylonitrile) hemodialyzer reduces Platelet adhesion and its transmembrane stimulation", 28 Aug 1994, Biomaterials, Vol. 15, No. 6, pages 417-422), referred to herein as “Matsuda,” and as evidenced through Kasemura et al. ("Surface Molecular Mobility for Copolymers Having Both Hydrophobic and Hydrophilic Side Chains Via Dynamic Contact Angle Measurement", 1997, Polymer, Vol. 38, No. 9, pages 2107-2111), referred to herein as “Kasemura.”
Regarding Claim 49, the prior art meets the limitations of Claim 41 as discussed above. The claim’s statement that “…the microarray is for single cell per microwell trapping and lifting of viable cells…” is an intended use. When an apparatus is claimed, its patentability is based on the structure of the apparatus and not on the function it performs or the field in which it is applied. In the present case, the microwell array taught by Fan is inherently capable of holding a single cell per microwell, as the user could simply place a single cell in each microwell, thus performing the same function.
Further, Fan/Liu teaches the cell sorting device discussed above wherein the microwells are in a matrix having a thiol polymer ([0262] states, “Microwells may be fabricated from any of a number of substrate materials known to those of skill in the art… Examples of suitable materials include…thiol-ene based resins.), as in Claim 49.
Fan does not teach the cell sorting device discussed above with methoxy polyethylene glycol methacrylate chains at the surface. However, Fan does teach, “In some embodiments, the application of surface coatings may be used to render substrate surfaces both non-toxic and non-sticky to cells.” in [0267].
Further, Matsuda teaches a methoxy polyethylene glycol methacrylate (MPEGMA) coating for use with a plate-type dialyzer with a polyacrylonitrile (PAN) membrane, wherein said coating “reduces both transmembrane stimulation and adhesion of platelets,” thus rendering the material non-toxic and non-sticky to the cells. While platelets are not considered full cells, these pieces of cells are expected to behave the same or similar to cells in the context of adhering to the walls of a microfluidic device.
Further, Matsuda does not explicitly teach the MPEGMA chains as having a number average molecular weight or an Mn value in a range of between 1,500 and 2,500 g/mol.
However, as the surface molecular mobility of MPEGMA, a factor that affects cell adhesion to a surface and is tunable for specific cell-types, is a property that can be modified by adjusting the average Mn value of said chains, as evidenced through Kasemura, the precise Mn value would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed range of average Mn values cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the Mn value of the MPEGMA chains to maximally obtain the desired properties of non-stickiness and non-toxicity (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Accordingly, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the cell sorting device taught by Fan/Liu with the MPEGMA coating taught by Matsuda (with the average MPEGMA Mn value optimized through routine experimentation) to render the wells of the cell sorting device non-toxic and non-sticky to the cells at-hand, improving experimental efficiency by avoiding cells stuck to the surface, and reducing error due to disturbed/dead cells.
Regarding Claim 50, the prior art meets the limitations of Claim 49 as discussed above. Further, the combination of Fan/Liu and Matsuda (as discussed above regarding Claim 49) does not explicitly teach the MPEGMA chains as having a number average molecular weight or an Mn value in a range of between 1,900 and 2,100 g/mol.
However, as the surface molecular mobility of MPEGMA, a factor that affects cell adhesion to a surface and is tunable for specific cell-types, is a property that can be modified by adjusting the average Mn value of said chains, as evidenced through Kasemura, the precise Mn value would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed range of average Mn values cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the Mn value of the MPEGMA chains to maximally obtain the desired properties of non-stickiness and non-toxicity for suitably accommodating the cells at-hand within the wells (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Regarding Claim 51, the prior art meets the limitations of Claim 49 as discussed above. Further, the combination of Fan/Liu and Matsuda (as discussed above regarding Claim 49) does not explicitly teach the MPEGMA chains as having a number average molecular weight or an Mn value of 2,000 g/mol.
However, as the surface molecular mobility of MPEGMA, a factor that affects cell adhesion to a surface and is tunable for specific cell-types, is a property that can be modified by adjusting the average Mn value of said chains, as evidenced through Kasemura, the precise Mn value would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed average Mn value cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the Mn value of the MPEGMA chains to maximally obtain the desired properties of non-stickiness and non-toxicity for suitably accommodating the cells at-hand within the wells (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Regarding Claim 52, the prior art meets the limitations of Claim 41 as discussed above. The claim’s statement that “…the microarray is for single cell per microwell trapping and lifting of viable human B cells…” is an intended use. When an apparatus is claimed, its patentability is based on the structure of the apparatus and not on the function it performs or the field in which it is applied. In the present case, the microwell array taught by Fan is inherently capable of holding a single cell per microwell, and said cells may be human B cells, as the user could simply place a single B cell in each microwell, thus performing the same function.
Further, the combination of Fan/Liu and Matsuda (as discussed above regarding Claim 49) does not explicitly teach the MPEGMA chains as having a number average molecular weight or an Mn value in a range of between 1,500 and 2,500 g/mol.
However, as the surface molecular mobility of MPEGMA, a factor that affects cell adhesion to a surface and is tunable for specific cell-types, is a property that can be modified by adjusting the average Mn value of said chains, as evidenced through Kasemura, the precise Mn value would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed range of average Mn values cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the Mn value of the MPEGMA chains to maximally obtain the desired properties of non-stickiness and non-toxicity for suitably accommodating the cells at-hand within the wells (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Regarding Claim 53, the prior art meets the limitations of Claim 52 as discussed above. Further, the combination of Fan/Liu and Matsuda (as discussed above regarding Claim 49) does not explicitly teach the MPEGMA chains as having a number average molecular weight or an Mn value in a range of between 1,900 and 2,100 g/mol.
However, as the surface molecular mobility of MPEGMA, a factor that affects cell adhesion to a surface and is tunable for specific cell-types, is a property that can be modified by adjusting the average Mn value of said chains, as evidenced through Kasemura, the precise Mn value would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed range of average Mn values cannot be considered critical.
Thus, one of ordinary skill in the art would have optimized through routine experimentation the Mn value of the MPEGMA chains to maximally obtain the desired properties of non-stickiness and non-toxicity for suitably accommodating the cells at-hand within the wells (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
Regarding Claim 56, the prior art meets the limitations of Claim 49 as discussed above. Further, Fan/Liu teaches the cell sorting device discussed above wherein the thiol polymer is a thiol/ene polymer ([0262] states, “Microwells may be fabricated from any of a number of substrate materials known to those of skill in the art… Examples of suitable materials include…thiol-ene based resins.), as in Claim 56. Examiner notes that this is with respect to Fan, in which Matsuda has been provided for the aspect discussed above in related dependent claim 49.
Claims 54 and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Fan in view of Liu, as applied to Claims 41, 47-48, and 62 above, and as evidenced through Cano et al. (Autoimmunity: From Bench to Bedside, 18 Jul 2013, El Rosario University Press, Chapter 5: Introduction to T and B lymphocytes), referred to herein as “Cano.”.
Regarding Claim 54, the prior art meets the limitations of Claim 41 as discussed above. Further, Fan/Liu teaches the cell sorting device discussed above wherein the cells sorted into microwells of the microwell array comprise immune cells such as B cells and T cells ([0168] and [0038]). Given that said immune cells are generally 8-10 microns in diameter, as evidenced through Cano, one of ordinary skill in the art would find it an obvious design choice to fabricate the microwells taught by Fan with a diameter of 8-10 microns. As this range overlaps with the instant claimed range of 9-14 microns, a prima facie case of obviousness exists in view of In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990), absent contrary evidence of criticality or non-obviousness of the claimed range.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to select the overlapping portion of the range so as to size the wells appropriately to securely accommodate and immobilize the complementarily-sized cells under assay.
Regarding Claim 55, the prior art meets the limitations of Claim 54 as discussed above. Further, Fan/Liu teaches the cell sorting device discussed above wherein the cells sorted into microwells of the microwell array comprise immune cells such as B cells and T cells ([0168] and [0038]). Given that said immune cells are generally 8-10 microns in diameter, as evidenced through Cano, one of ordinary skill in the art would find it an obvious design choice to fabricate the microwells taught by fan with a diameter of 8-10 microns. As this range overlaps at endpoint with the instant claimed range of 10-13 microns, a prima facie case of obviousness exists in view of In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990), absent contrary evidence of criticality or non-obviousness of the claimed range.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to select the overlapping point of the range so as to size the wells appropriately to securely accommodate and immobilize the complementarily-sized cells under assay.
Claim 57 is rejected under 35 U.S.C. 103 as being unpatentable over Fan in view of Liu and Matsuda, as applied to Claims 49-53 and 56 above, and in further view of Adams et al. (US 2003/0018016 A1), referred to herein as “Adams.”
Regarding Claim 57, the prior art meets the limitations of Claim 41 as discussed above. Further, while Fan/Liu/Matsuda teach the cell sorting device discussed above wherein the microwells are in a matrix having a thiol polymer with methoxy polyethylene glycol methacrylate chains at the surface, Fan/Liu/Matsuda does not teach oxiranyl groups at the surface. However, Fan/Liu/Matsuda does teach, “In some embodiments, the application of surface coatings may be used to render substrate surfaces both non-toxic and non-sticky to cells.” (Fan [0267]).
Further, Adams teaches chemical agents to inhibit, prevent or suppress cell adhesion. Adams specifically teaches 2-(4-(phenylurea)phenyl)oxiranyl, where an oxinaryl group is present for preventing cell adhesion ([0056]).
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the cell sorting device with MPEGMA at the microwell surface taught by Fan/Liu/Matsuda oxinaryl groups taught by Adams to render the wells of the cell sorting device non-sticky to cells, improving experimental efficiency by avoiding cells stuck to the surface.
Claim 58 is rejected under 35 U.S.C. 103 as being unpatentable over Fan in view of Liu, as applied to Claims 41, 43, 47-48, and 62 above, and as evidenced through Saharil et al. ("Superior Dry Bonding of Off-Stoichiometry Thiol-Ene Epoxy (Oste(+)) Polymers for Heterogeneous Material Labs-On-Chip", 1 Nov 2012, 16th International Conference on Miniaturized Systems for Chemistry and Life Sciences, pages 1831-1833), referred to herein as “Saharil,” and KTH Royal Institute of Technology (“Off-Stoichiometry Thiol-Enes (OSTE) - The first polymer system developed for labs-on-chip”, 4 Dec 2019, Micro and Nanosystems), referred to herein as “KTH.”
Regarding Claim 58, the prior art meets the limitations of Claim 41 as discussed above. The instant claim teaches a cell sorting device wherein the microwells are fabricated from a group consisting of thiol-enes polymer and thiol-ene-epoxies polymer (note the 35 USC 112 rejection above and interpretation herein). Fan/Liu teaches an alternative-type recitation of suitable materials for fabricating the cell sorting device discussed above comprising epoxy resins, thiol-ene based resins, and the like.
Given that Fan teaches the use of these resins interchangeably, recognizing their suitability for fabricating a microfluidic chip cell sorting device, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine these materials to achieve the same purpose. It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose absent evidence of criticality, non-obviousness, or unexpected results to the contrary – see MPEP 2144.06(I) and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992).
Further, the use of off-stoichiometry thiol-enes polymer and off-stoichiometry thiol-ene-epoxies polymer is well known in the art of microfluidic chip rapid fabrication as these polymers are UV-curable, have low permeability to gasses, can be bonded at low temperatures without surface treatments, and have tunable mechanical properties and surface chemistry, as evidenced through Saharil and KTH. As such, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to fabricate the microfluidic chip cell sorting device of Fan/Liu from off-stoichiometry thiol-enes polymer and off-stoichiometry thiol-ene-epoxies polymer to achieve the benefits discussed above.
Claim 59 is rejected under 35 U.S.C. 103 as being unpatentable over Fan in view of Liu, as applied to Claims 41, 43, 47-48, and 62 above, and in further view of Tanaka et al. (JP 2009/250855 A), referred to herein as “Tanaka” as seen through the machine-translation available at Google Patents, and as evidenced through Blazquez-Castro, (“Optical Tweezers: Phototoxicity and Thermal Stress in Cells and Biomolecules”, 31 Jul 2019, Micromachines, Vol. 10, No. 8, page 507), referred to herein as “Blazquez-Castro.”
Regarding Claim 59, the prior art meets the limitations of Claim 41 as discussed above. The claim’s statement that the device “…further comprising an apparatus for trapping a single viable human B cell in a well and selectively lifting a single viable human B cell from the well without affecting the cell's viability…” is an intended use. When an apparatus is claimed, its patentability is based on the structure of the apparatus and not on the function it performs or the field in which it is applied.
In the present case, the microwell array taught by Fan/Liu is inherently capable of holding a single cell per microwell, and said cells may be human B cells, as the user could simply place a single B cell in each microwell, thus performing the same function. Further, one of ordinary skill in the art would find it obvious to utilize an apparatus that does not affect a cell’s viability, unless cell death is a desired result.
Further, Fan/Liu does not teach the cell sorting device discussed above as having an apparatus comprising a single beam optical tweezer having a 900 - 1200 nm range wavelength and a laser power of between 400 mW and 600 mW, and further wherein the microarray forms part of the apparatus.
However, Tanaka teaches an apparatus for a microarray where an optical tweezer having a wavelength of 1064 nM and a laser power of 530 mW are used to manipulate microbeads to place individual beads at specific points of the array. As Tanaka's teachings of wavelength and laser power fall completely within the instant claimed ranges of wavelength and laser power, the claimed ranges are anticipated by Tanaka. Near-infrared milliwatt- power optical tweezers are commonly used for the manipulation of cells to avoid phototoxity, damage to the cell’s internal components that leads to undesired cell malfunctioning/death, as evidenced through Blazquez-Castro. Further, Tanaka Fig. 8 shows that the microarray forms part of the apparatus.
Given that the optical tweezer of Tanaka is commensurately employed for the positional manipulation of single cells, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the optical tweezers of the cell sorting device taught by Fan/Liu with the of specific power and wavelength taught by Tanaka to enable the positional manipulation of single cells, while being of sufficiently low energy to avoid unwanted phototoxicity.
Response to Arguments
35 USC 103
Applicant’s arguments are on the grounds allegedly that Fan in view of Liu does no