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 10 June 2026.
Claims 272-273, 275, 278, 280-285, 287-288, and 290-300 are pending.
Claims 1-271, 274, 276-277, 279, 286, and 289 are cancelled.
No claims are withdrawn.
Claim 300 is newly added.
No claims are amended.
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 272-276, 280, 282, 288, 291, and 300 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US 2003/0175947 A1), hereinafter “Liu”, in view of Gilbert et al. (US 2017/0128938 A9), hereinafter “Gilbert”, and Battrell et al. (US PAT 9,895,692 B2), hereinafter “Battrell”.
Regarding Claim 272, Liu teaches a method for detecting at least one target material in a sample liquid ([0013]: “The present invention provides methods and microfluidic devices for mixing a sample within microfluidic cavity and for detecting a target analyte within the sample.”), the method comprising:
introducing the sample liquid into a microfluidic channel 30 of a microfluidic network within a microfluidic device 24 (Fig. 3 and [0013]: “…the sample has been introduced to the microfluidic cavity…” – see also para. [0066].),
the microfluidic network comprising a gas bladder at a distal terminus of and in gaseous communication with the microfluidic channel 30, the microfluidic channel and the gas bladder containing a gas 26 therein, such that the sample liquid contacts the gas 26, thereby forming a sample liquid-gas interface therebetween ([0013]: “The microfluidic cavity has at least one gas pocket…After the sample has been introduced to the microfluidic cavity, the volume of said gas pocket is altered to mix said sample such that said target analyte binds to said biological binding molecule.”); wherein the sample liquid-gas interface is oriented generally perpendicular to a longitudinal axis of the microchannel (Fig. 3 shows the gas pocket 26 and its interface with the analyte 32 containing liquid being “generally perpendicular” to a longitudinal axis of the microchannel – the microchannel having longitudinal axes extending along each of its curved lengths.),
moving the sample liquid and the sample liquid-gas interface toward the gas bladder along the longitudinal axis of the microchannel and into a first zone (reaction module) thereof so that the sample liquid contacts a first reagent disposed within the first zone (Fig. 3 and [0066]: “Preferably, microfluidic channel 30 has array of biological binding molecules 32 contained therein.”) decreasing a pressure of the gas (As discussed in para. [0066] the device oscillated pressure of the gas pocket 26 to move the fluid within the device. Thus, it may be said that when the pressure is reduced, the sample enters a first zone and when the pressure is restored, the sample leaves the first zone. Herein it is noted that applicant has not provided any particular structure so as to limit the first zone, wherein this nominal descriptor may thus be any region of the device.), and
mixing the sample liquid with the first reagent oscillating the pressure of the gas at the one or more acoustic frequencies ([0278]: “Referring to FIGS. 9-12 again, a large amount of gross liquid motion was observed upon application of the acoustic waves.”) and forming a first mixture comprising the sample liquid and the first reagent ([0065]: “Expansion and contraction of the gas pocket or gas therein (for example and not by way of limitation, by heating and cooling of the gas therein) causes the fluid to oscillate back and forth within the microfluidic channel…”);
wherein oscillating the pressure of the gas is performed:
concurrently with (As discussed above, the reduction in pressure is concurrent with the oscillation of the pressure, given that oscillation of the pressure involves reduction of the pressure.), and/OR after decreasing the pressure of the gas, and, during the method, the first and second inner walls of the gas bladder are spaced apart distally along the longitudinal axis of the microchannel from the sample liquid and the sample liquid-gas interface (Fig. 3 shows the sample liquid molecules 32 spaced apart from the walls of the gas bladder 26, showing that the liquid carrying the sample molecules 32 is spaced apart from the gas bladder 26. In as much as is claimed, the walls of the gas bladder are shown as being spaced apart distally along the longitudinal axis of the microchannel.),
as in Claim 272.
Further regarding Claim 272, Liu does not specifically teach the method discussed above wherein control over the pressure of the gas is performed through increasing and decreasing a spacing between inner walls of the gas bladder, wherein the steps of increasing the internal spacing between the first and second inner walls and oscillating the internal spacing between the first and second inner walls are performed by contacting an external surface of the gas bladder with an actuation system comprising an actuation foot that contacts a contact portion of an outer surface of the bladder zone that is aligned with at least a portion of the first inner wall, such that the actuation foot is spaced apart distally from the sample liquid- gas interface whereby effects of the oscillations of the actuation foot are transmitted to the liquid-gas interface of the sample liquid indirectly via the gas occupying the gas bladder and other distal portions of the microchannel, as in Claim 272.
However, Gilbert teaches a respective microfluidic system wherein a gas bubble is actuated by increasing and decreasing the spacing between inner walls 20/40 of a gas bladder 70 via an actuation foot 50 contacting an outer surface of the gas bladder, and wherein the actuation foot is spaced apart distally from the sample liquid- gas interface such that actuation of the actuation foot causes movement of the sample-gas interface and, consequently, allows or prevents movement of fluid within the microfluidic system (Fig. 2 and [0048]: “...the stacked first plate 20, second plate 30 and third plate 40 define a closed, gas filled gas reservoir 70, which can be actuated with a displacement actuator 50.” – [0049]: “The actuator 50 deflects the upper wall of the reservoir, defined by plate 40, which decreases the volume of the reservoir 70... The decreased volume consequently increases the pressure of the reservoir 70 and causes the meniscus 80 to deflect into the channel interior to create a constriction in the channel, thereby impeding fluid flow or pushing fluid away from the meniscus.”). Therein, this arrangement represents an obvious alternative to the heater (and/or diaphragm pump) arrangement of Liu, achieving the identical function of actuating a fluid/gas interface.
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 Liu wherein control over the pressure of the gas is performed through increasing and decreasing a spacing between inner walls of the gas bladder, wherein the steps of increasing the internal spacing between the first and second inner walls and oscillating the internal spacing between the first and second inner walls are performed by contacting an external surface of the gas bladder with an actuation system comprising an actuation foot that contacts a contact portion of an outer surface of the bladder zone that is aligned with at least a portion of the first inner wall, such that the actuation foot is spaced apart distally from the sample liquid- gas interface whereby effects of the oscillations of the actuation foot are transmitted to the liquid-gas interface of the sample liquid indirectly via the gas occupying the gas bladder and other distal portions of the microchannel, such as suggested by Gilbert, because it is obvious to substitute one known element for another to achieve the same function, where such alternatives are recognized in the art as interchangeable and yield predictable results. When two or more known techniques perform substantially the same function in substantially the same way to achieve substantially the same result, the selection of one over the other is considered a matter of design choice absent a showing of unexpected results or criticality. The motivation to make such a substitution may arise from routine optimization, cost considerations, material availability, or ease of manufacturing.
Further regarding Claim 272, Liu does not specifically teach the method discussed above wherein the reagent is a dry reagent, as in Claim 272.
However, Battrell teaches a respective microfluidic device comprising dried reagent housed in chambers wherein a diaphragm introduces a sample liquid to the reagent-containing chambers and mixes the sample liquid with the reagent using oscillation of the sample liquid ([col. 24, line 1]: “the fluid can be oscillated when contacting solid phase absorbent 409 (FIG. 4) so as to efficiently take up adsorbed nucleic acids”), thereby providing pre-loadable cartridges having reagents ready to use for a particular assay ([col. 5, line 3]: “Dry reagents are printed or “spotted” in channels or chambers and are rehydrated at the time of use. The liquid reagents function as buffers, diluents, solvents, eluants, wash reagents, and as rehydrating reagents.”).
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 method of Liu wherein the reagent is a dry reagent, such as suggested by Battrell, so as to provide a ready-to-use device capable of being pre-loaded with reduced risk of degradation, and would have a reasonable expectation of success therein.
Further regarding Claim 272, as Liu’s teaching of range 1000 – 6000 Hz (para. [0059]) overlaps with the instant claimed step (c) range of at least about 250 Hz, 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 maximally achieve the sought mixing benefits while avoiding degradation of delicate samples such as DNA which are sensitive to mechanical forces. This seen for the above reasons as well as in the absence of a showing of a criticality or unexpected results arising otherwise.
Further regarding Claim 272, Liu/Battrell does not specifically teach the method discussed above wherein the step (b) of moving the liquid-gas interface is by at least about 4 mm, as in Claim 272.
However, it would have been obvious to one of ordinary skill in the art at the time of the invention to configure the prior art device such that the sample liquid moves about at least 4 mm to contact the dry reagent, because precise travel distance of the liquid is a result-effective variable governed by the arrangement of fluidic structures and reagent location. Optimization of such a variable to ensure fluid-reagent contact would have amounted to no more than routine experimentation. No criticality for the claimed minimum distance is apparent from the claim, nor has Applicant shown that 4 mm produces any unexpected result.
Further regarding Claim 272, Liu/Battrell does not specifically teach the method discussed above wherein inner walls of the gas bladder are spaced apart from the sample liquid-gas interface by at least about 1 cm, as in Claim 272.
However, similarly as above, it would have been obvious to one of ordinary skill in the art at the time of the invention to configure the prior art device such that the sample liquid-gas interface is spaced apart from the gas bladder by at least about 1 cm as this amounts to no more than choosing a workable distance of the particular cartridge, such spacing representing a variable that can be optimized depending on the dimensions of the cartridge. No criticality for the claimed minimum distance is apparent from the claim, nor has Applicant shown that 1 cm produces any unexpected result.
Regarding Claim 273, the prior art meets the limitations of Claim 272 as discussed above. Further, as Liu’s teaching of range 1000 – 6000 Hz (para. [0059]) overlaps with the instant claimed range of about 250 Hz to about 1500 Hz, 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 maximally achieve the sought mixing benefits while avoiding degradation of delicate samples such as DNA which are sensitive to mechanical forces. This seen for the above reasons as well as in the absence of a showing of a criticality or unexpected results arising otherwise.
Regarding Claim 274, the prior art meets the limitations of Claim 272 as discussed above. Further, as Liu’s teaching of range 1000 – 6000 Hz (para. [0059]) overlaps with the instant claimed range of about 2000 Hz or less, 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 maximally achieve the sought mixing benefits while avoiding degradation of delicate samples such as DNA which are sensitive to mechanical forces.
Regarding Claim 275, the prior art meets the limitations of Claim 272 as discussed above. Further, Liu teaches the fluid control method discussed above wherein the first reagent comprises a lysing reagent, a binding reagent, and/OR an optical label, (Fig. 3 and [0066]: “Preferably, microfluidic channel 30 has array of biological binding molecules 32 contained therein.”), as in Claim 275.
Regarding Claim 276, the prior art meets the limitations of Claim 272 as discussed above. Further, Liu does not specifically teach the fluid control method discussed above wherein decreasing the pressure of the gas comprises increasing an internal spacing between a first inner wall and a second inner wall of a bladder zone located at a distal portion of the microfluidic device, wherein the bladder zone, the first inner wall, and the second inner wall are in direct contact with the gas and are in gaseous communication with the sample liquid-gas interface and the microfluidic channel, as in Claim 276.
However, Gilbert teaches a respective microfluidic system wherein a gas bubble is actuated by increasing and decreasing the spacing between inner walls 20/40 of a gas bladder 70 via an actuation foot 50 contacting an outer surface of the gas bladder, and wherein the actuation foot is spaced apart distally from the sample liquid- gas interface such that actuation of the actuation foot causes movement of the sample-gas interface and, consequently, allows or prevents movement of fluid within the microfluidic system (Fig. 2 and [0048]: “...the stacked first plate 20, second plate 30 and third plate 40 define a closed, gas filled gas reservoir 70, which can be actuated with a displacement actuator 50.” – [0049]: “The actuator 50 deflects the upper wall of the reservoir, defined by plate 40, which decreases the volume of the reservoir 70... The decreased volume consequently increases the pressure of the reservoir 70 and causes the meniscus 80 to deflect into the channel interior to create a constriction in the channel, thereby impeding fluid flow or pushing fluid away from the meniscus.”). Therein, this arrangement represents an obvious alternative to the heater (and/or diaphragm pump) arrangement of Liu, achieving the identical function of actuating a fluid/gas interface.
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 fluid control device of Liu wherein decreasing the pressure of the gas comprises increasing an internal spacing between a first inner wall and a second inner wall of a bladder zone located at a distal portion of the microfluidic device, wherein the bladder zone, the first inner wall, and the second inner wall are in direct contact with the gas and are in gaseous communication with the sample liquid-gas interface and the microfluidic channel, such as suggested by Gilbert, so as to provide a sufficient structure for oscillating a gas and fluid to give a mixing effect; and would have a reasonable expectation of success therein as a simple substitution.
Regarding Claim 280, the prior art meets the limitations of Claim 272 as discussed above. Further, Liu teaches the fluid control method discussed above further comprising:
moving the first mixture and the sample-liquid gas interface further toward the gas bladder along the microchannel from the first zone and into a second zone of the microchannel so that the sample liquid contacts a second reagent disposed within the second zone by again decreasing the pressure of the gas, the second zone containing a second reagent disposed therein (As discussed in para. [0066] the device oscillated pressure of the gas pocket 26 to move the fluid within the device. Thus, it may be said that when the pressure is reduced, the sample enters a second zone and when the pressure is restored, the sample leaves the second zone. Herein it is noted that applicant has not provided any particular structure so as to limit the first zone, wherein this nominal descriptor may thus be any region of the device. Further, as Liu teaches multiple different reagents contained therein ([0181]), the second zone is said to have a second reagent.); and
mixing the first mixture with the second reagent by again oscillating the pressure of the gas at one or more acoustic frequencies ([0065]: “Expansion and contraction of the gas pocket or gas therein (for example and not by way of limitation, by heating and cooling of the gas therein) causes the fluid to oscillate back and forth within the microfluidic channel…”);
wherein oscillating the pressure of the gas again is performed concurrent with (As discussed above, the reduction in pressure is concurrent with the oscillation of the pressure, given that oscillation of the pressure involves reduction of the pressure.), and/OR after decreasing the pressure of the gas again,
as in Claim 280.
Further regarding Claim 280, Liu does not specifically teach the method discussed above wherein control over the pressure of the gas is performed through increasing and decreasing a spacing between inner walls of the gas bladder, as in Claim 280.
However, Gilbert teaches a respective microfluidic system wherein a gas bubble is actuated by increasing and decreasing the spacing between inner walls 20/40 of a gas bladder 70 via an actuation foot 50 contacting an outer surface of the gas bladder, and wherein the actuation foot is spaced apart distally from the sample liquid- gas interface such that actuation of the actuation foot causes movement of the sample-gas interface and, consequently, allows or prevents movement of fluid within the microfluidic system (Fig. 2 and [0048]: “...the stacked first plate 20, second plate 30 and third plate 40 define a closed, gas filled gas reservoir 70, which can be actuated with a displacement actuator 50.” – [0049]: “The actuator 50 deflects the upper wall of the reservoir, defined by plate 40, which decreases the volume of the reservoir 70... The decreased volume consequently increases the pressure of the reservoir 70 and causes the meniscus 80 to deflect into the channel interior to create a constriction in the channel, thereby impeding fluid flow or pushing fluid away from the meniscus.”). Therein, this arrangement represents an obvious alternative to the heater (and/or diaphragm pump) arrangement of Liu, achieving the identical function of actuating a fluid/gas interface.
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 fluid control device of Liu wherein decreasing the pressure of the gas comprises increasing an internal spacing between a first inner wall and a second inner wall of a gas bladder, such as suggested by Gilbert, so as to provide a sufficient structure for oscillating a gas and fluid to give a mixing effect; and would have a reasonable expectation of success therein as a simple substitution.
Regarding Claim 281, the prior art meets the limitations of Claim 280 as discussed above. Further, Liu teaches the fluid control method discussed above further comprising:
moving the second mixture and the sample-liquid gas interface further toward the gas bladder along the microchannel from the second zone and into a third zone by yet again decreasing the pressure of the gas, the third zone of the microchannel so that the sample liquid contacts a third reagent disposed within the third zone by yet again increasing the internal spacing between the first and second walls thereby yet again decreasing the pressure of the gas (As discussed in para. [0066] the device oscillated pressure of the gas pocket 26 to move the fluid within the device. Thus, it may be said that when the pressure is reduced, the sample enters a third zone and when the pressure is restored, the sample leaves the third zone. Herein it is noted that applicant has not provided any particular structure so as to limit the first zone, wherein this nominal descriptor may thus be any region of the device. Further, as Liu teaches multiple different reagents contained therein ([0181]), the second zone is said to have a second reagent.); and
mixing the second mixture with the third reagent by yet again oscillating the pressure of the gas at one or more acoustic frequencies, and forming a third mixture ([0065]: “Expansion and contraction of the gas pocket or gas therein (for example and not by way of limitation, by heating and cooling of the gas therein) causes the fluid to oscillate back and forth within the microfluidic channel…”); wherein oscillating the pressure of the gas yet again is performed concurrently with (As discussed above, the reduction in pressure is concurrent with the oscillation of the pressure, given that oscillation of the pressure involves reduction of the pressure.), and/OR after decreasing the pressure of the gas yet again,
as in Claim 281.
Further regarding Claim 281, Liu does not specifically teach the method discussed above wherein control over the pressure of the gas is performed through increasing and decreasing a spacing between inner walls of the gas bladder, as in Claim 281.
However, Gilbert teaches a respective microfluidic system wherein a gas bubble is actuated by increasing and decreasing the spacing between inner walls 20/40 of a gas bladder 70 via an actuation foot 50 contacting an outer surface of the gas bladder, and wherein the actuation foot is spaced apart distally from the sample liquid- gas interface such that actuation of the actuation foot causes movement of the sample-gas interface and, consequently, allows or prevents movement of fluid within the microfluidic system (Fig. 2 and [0048]: “...the stacked first plate 20, second plate 30 and third plate 40 define a closed, gas filled gas reservoir 70, which can be actuated with a displacement actuator 50.” – [0049]: “The actuator 50 deflects the upper wall of the reservoir, defined by plate 40, which decreases the volume of the reservoir 70... The decreased volume consequently increases the pressure of the reservoir 70 and causes the meniscus 80 to deflect into the channel interior to create a constriction in the channel, thereby impeding fluid flow or pushing fluid away from the meniscus.”). Therein, this arrangement represents an obvious alternative to the heater (and/or diaphragm pump) arrangement of Liu, achieving the identical function of actuating a fluid/gas interface.
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 fluid control device of Liu wherein decreasing the pressure of the gas comprises increasing an internal spacing between a first inner wall and a second inner wall of a gas bladder, such as suggested by Gilbert, so as to provide a sufficient structure for oscillating a gas and fluid to give a mixing effect; and would have a reasonable expectation of success therein as a simple substitution.
Further regarding Claims 280 and 281, as these method steps are mere repetition of the step of mixing the sample with an additional reagent and oscillating the sample and reagent to mix them together, one of ordinary skill in the art would find it obvious to repeat this step as many times as necessary so as to combine the sample with all of the necessary reagents for an assay. As such, the mere repetition of these steps cannot be considered critical without a showing of criticality or unexpected results.
Regarding Claim 282, the prior art meets the limitations of Claim 281 as discussed above. Further, Liu teaches the fluid control method discussed above further comprising actuating a magnetic field generator so as to move the target material towards an inner wall of the microfluidic channel ([0266]), wherein the target material is bound to a magnetic particle ([0263]), as in Claim 282.
Regarding Claim 288, the prior art meets the limitations of Claim 272 as discussed above. Further, as Liu’s teaching of range 1000 – 6000 Hz (para. [0059]) overlaps with the instant claimed range of about 250 Hz to about 1500 Hz, 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 maximally achieve the sought mixing benefits while avoiding degradation of delicate samples such as DNA which are sensitive to mechanical forces.
Regarding Claim 291, the prior art meets the limitations of Claim 272 as discussed above. Further, 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).
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to provide the device of Liu/Gilbert with the total contact area of Claim 291 so as to suitably attach the attach the actuation foot to the contact area; and would have a reasonable expectation of success therein.
Regarding Claim 300, Liu teaches the method discussed above wherein the oscillating in step c) repeatedly displaces the sample liquid-gas interface along the longitudinal axis of the microchannel to mix the sample liquid with the first reagent ([0178]: “the reaction module may contain the necessary reagents” – See also [0006] incorporating Anderson et al. by reference discussing reagent coated on the channel walls and shearing off into solution upon mixing.) while the gas remains within the gas bladder and one or more distal portions of the microchannel ([0066]: “Gas pocket 26 is fluidly connected to microfluidic channel 30. Heating resistive heater 28 causes expansion within gas cavity 26, thereby causing the liquid sample within microfluidic channel 30 to move away from gas pocket 26. Turning off resistive heater 28, thereby cooling the gas within gas pocket 26, results in the fluid within microfluidic channel 30 moving towards gas pocket 26.”), as in Claim 300.
Further regarding Claim 300, Liu does not specifically teach the method discussed above wherein the reagent is a dry reagent, as in Claim 300.
However, Battrell teaches a respective microfluidic device comprising dried reagent housed in chambers wherein a diaphragm introduces a sample liquid to the reagent-containing chambers and mixes the sample liquid with the reagent using oscillation of the sample liquid ([col. 24, line 1]: “the fluid can be oscillated when contacting solid phase absorbent 409 (FIG. 4) so as to efficiently take up adsorbed nucleic acids”), thereby providing pre-loadable cartridges having reagents ready to use for a particular assay ([col. 5, line 3]: “Dry reagents are printed or “spotted” in channels or chambers and are rehydrated at the time of use. The liquid reagents function as buffers, diluents, solvents, eluants, wash reagents, and as rehydrating reagents.”).
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 method of Liu wherein the reagent is a dry reagent, such as suggested by Battrell, so as to provide a ready-to-use device capable of being pre-loaded with reduced risk of degradation, and would have a reasonable expectation of success therein.
Claims 278, 290, and 296-299 are rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Gilbert and Battrell, as applied to Claims 272-276, 280,282, 288-289, and 291 above, and as evidenced through Vishwanathan et al. (Vishwanathan, G., Juarez, G. Generation and application of sub-kilohertz oscillatory flows in microchannels. Microfluid Nanofluid 24, 69 (2020).), hereinafter “Vishwanathan”.
Regarding Claim 278, the prior art meets the limitations of Claim 272 as discussed above. Further, Liu/Gilbert does not explicitly teach the oscillation of the space between the first chamber wall and the second chamber wall as having the total peak-to-peak distances of about 75 um or less and about 2 um or more. However, as the mixing speed is a variable that can be modified by adjusting the peak-to-peak distance over which the first plate oscillates, the precise peak-to-peak distance would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made, as evidenced through Vishwanathan. As such, without showing unexpected results, the peak-to-peak distance over which the first plate oscillates cannot be considered critical. Thus, one of ordinary skill in the art would have optimized through routine experimentation the peak-to-peak distance to maximally obtain the desired mixing time (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 290, the prior art meets the limitations of Claim 272 as discussed above. Further, Liu/Gilbert does not explicitly teach the portion of the first inner wall as spaced apart distally from the sample-liquid gas interface by distances of at least about 0.75 cm. However, as the mixing speed is a variable that can be modified by adjusting the gas volume (dependent on the wall-spacing distance from the interface) which the first plate oscillates, the precise wall-interface distance would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made, as evidenced through Vishwanathan. (When the oscillation range of the wall is kept the same but the volume of the gas is increased (i.e. when there is a greater spacing between the wall and the gas-liquid interface), the oscillation of the gas is decreased proportional with Boyle’s law.) As such, without showing unexpected results, the claimed wall interface distances cannot be considered critical. Thus, one of ordinary skill in the art would have optimized through routine wall-interface distance to maximally obtain the desired mixing time (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).
Further regarding Claim 290, 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).
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to provide the device of Liu/Gilbert with the wall-interface spacing distances of Claim 290 so as to provide a suitable gas volume for providing the sought oscillations.
Regarding Claim 296, the prior art meets the limitations of Claim 272 as discussed above. Further, Liu/Gilbert does not explicitly teach the speed of sample movement at least about 400 um/s and about 2000 um/s or less as in Claim 296. However, as the mixing speed is a variable that can be modified by adjusting the speed at which the sample-gas interface moves, the precise speed would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made, as evidenced through Vishwanathan. As such, without showing unexpected results, the speed/rate of movement of the gas-liquid interface as in Claim 296 cannot be considered critical. Thus, one of ordinary skill in the art would have optimized through routine experimentation the speed to maximally obtain the desired mixing time (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 297, the prior art meets the limitations of Claim 272 as discussed above. Further, Liu/Gilbert does not explicitly teach the specific volume of gas of at least 0.03 mm2 and about 0.08 mm2 or less actuated as in Claim 297. However, as the mixing speed is a variable that can be modified by adjusting the volume of gas actuated (When the oscillation range of the wall is kept the same but the volume of the gas is increased (i.e. when there is a greater spacing between the wall and the gas-liquid interface), the oscillation of the gas is decreased proportional with Boyle’s law.), the precise volume would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made, as evidenced through Vishwanathan. As such, without showing unexpected results, the volume of gas actuated as in Claim 296 cannot be considered critical. Thus, one of ordinary skill in the art would have optimized through routine experimentation the volume to maximally obtain the desired mixing time (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 298, the prior art meets the limitations of Claim 272 as discussed above. Further, Liu/Gilbert does not explicitly teach the specific gas/liquid interface area as in Claim 298. However, as the mixing speed is a variable that can be modified by adjusting the area of the gas/liquid interface (When a greater area of liquid is actuated by the gas, a greater displacement of said liquid occurs.), the precise gas/liquid interface area would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made, as evidenced through Vishwanathan. As such, without showing unexpected results, the areas as in Claim 296 cannot be considered critical. Thus, one of ordinary skill in the art would have optimized through routine experimentation the gas/liquid interface area to maximally obtain the desired mixing time (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).
Further regarding Claim 298, 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).
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 Liu/Gilbert so as to include the gas/liquid interface areas such as in Claim 298 so as to maximally achieve the desired oscillation and sample mixing effects.
Regarding Claim 299, the prior art meets the limitations of Claim 272 as discussed above. Further, Liu/Gilbert does not explicitly teach the specific gas/liquid interface area ratio as in Claim 299. However, as the mixing speed is a variable that can be modified by adjusting the area of the gas/liquid interface ratio (When a greater area of liquid is actuated by the gas, a greater displacement of said liquid occurs.), the precise gas/liquid interface ratio would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made, as evidenced through Vishwanathan. As such, without showing unexpected results, the ratio range as in Claim 296 cannot be considered critical. Thus, one of ordinary skill in the art would have optimized through routine experimentation the gas/liquid interface ratio to maximally obtain the desired mixing time (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).
Further regarding Claim 299, 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).
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 Liu/Gilbert so as to include the gas/liquid interface ratio such as in Claim 299 so as to maximally achieve the desired oscillation and sample mixing effects.
Claims 283-285 are rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Gilbert and Battrell, as applied to Claims 272-276, 280,282, 288-289, and 291 above, and in further view of Galen at al. (US 2018/0067101 A1), hereinafter “Galen”.
Regarding Claim 283, the prior art meets the limitations of Claim 282 as discussed above. Further, Liu teaches the fluid control method discussed above further comprising:
concurrently with increasing the pressure of the gas, oscillating the pressure of the gas at the one or more acoustic frequencies (As discussed above, the reduction in pressure is concurrent with the oscillation of the pressure, given that oscillation of the pressure involves reduction of the pressure.),
as in Claim 283.
Further regarding Claim 283, Liu does not specifically teach the fluid control method discussed above further comprising:
moving the third mixture not bound to any magnetic particle and the sample- liquid gas interface proximally out of from the third zone to by increasing the pressure of the gas, wherein the target material bound to the magnetic particle remains within the third zone,
as in Claim 283.
However, Galen teaches a respective microfluidic method wherein magnetic particles are separated from a sample mixture prior to detection such that only sample molecules containing non-magnetic particles are analyzed ([0040, 0053]).
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 Liu such that the magnetic particles are separated out from the sample by way of activating an actuatable magnet of the third zone and moving the sample to the first zone, such as suggested by Galen, so as to isolate the analyte of interest, thereby improving the accuracy and precision of measurement results; and would have a reasonable expectation of success therein.
Further regarding Claim 283, Liu does not specifically teach the method discussed above wherein control over the pressure of the gas is performed through increasing and decreasing a spacing between inner walls of the gas bladder, as in Claim 283.
However, Gilbert teaches a respective microfluidic mixing device comprising acoustic mixing pumps (LCATs) comprising a piezoelectric buzzer causing vibrations of an ultrasound gel spacer, thereby causing the spacing between the inner walls surrounding the ultrasound gel to increase and decrease and in turn oscillating a gas volume (“trapped air bubble”) so as to oscillate a fluid/gas interface, thereby oscillating the fluid to cause mixing of the fluid (Figs. 1 and 2, and Abstract). Therein, this structure taught by Gilbert represents a mere obvious alternative “oscillation pump”, wherein Liu makes clear in para. [0066] openness of the device for use with a variety of different pumps, not limited to the thermal expansion pump shown in Fig. 1.
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 fluid control device of Liu wherein decreasing the pressure of the gas comprises increasing an internal spacing between a first inner wall and a second inner wall of a gas bladder, such as suggested by Gilbert, so as to provide a sufficient structure for oscillating a gas and fluid to give a mixing effect; and would have a reasonable expectation of success therein.
Regarding Claim 284, the prior art meets the limitations of Claim 1 as discussed above. Further, Liu teaches the fluid control method discussed above further comprising:
irradiating the third zone with a light, thereby causing an optical label to emit a signal ([0086]); and
detecting the signal via an optical detector, thereby indicating the presence of the target material in the sample liquid ([0086]: “After binding, a variety of techniques allow for the detection of radiation emitted by the above labels. These techniques include using fiber optic sensors with nucleic acid probes in solution or attached to the fiber optic. Fluorescence is monitored using a photomultiplier tube or other light detection instrument attached to the fiber optic.”),
as in Claim 284.
Thus, when combined with the third magnetized zone and separation technique of Galen, the detected signal will be only from non-magnetic particles not attached to magnetic probes.
Regarding Claim 285, the prior art meets the limitations of Claim 284 as discussed above. Further, Liu teaches the fluid control method discussed above wherein the optical label is a fluorescence label ([0086]: “Fluorescence is monitored…”), as in Claim 285.
Claim 287 is rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Gilbert, Battrell, and Galen, as applied to Claims 283-286 above, and as evidenced through Vishwanathan.
Regarding Claim 287, the prior art meets the limitations of Claim 280 as discussed above. Further, Liu/Gilbert does not explicitly teach the oscillation of the space between the first chamber wall and the second chamber wall as having the total peak-to-peak distances of about 75 um or less and at least about 2 um as in Claim 287. However, as the mixing speed is a variable that can be modified by adjusting the peak-to-peak distance over which the first plate oscillates, the precise peak-to-peak distance would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made, as evidenced through Vishwanathan. As such, without showing unexpected results, the claimed range of peak-to-peak distance over which the first plate oscillates cannot be considered critical. Thus, one of ordinary skill in the art would have optimized through routine experimentation the peak-to-peak distance to maximally obtain the desired mixing time (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).
Claims 292 and 295 are rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Gilbert and Battrell, as applied to Claims 272-276, 280,282, 288-289, and 291 above, and in further view of Thielsch at al. (US 2017/0343518 A1), referred to hereinafter as “Thielsch”.
Regarding Claim 292, the prior art meets the limitations of Claim 272 as discussed above. Further, Liu/Gilbert does not specifically teach the fluid control method discussed above wherein the method further comprises compressing the internal spacing prior to introducing the sample liquid to the microfluidic channel, and maintaining the compression of the internal spacing while introducing the sample liquid to the microfluidic channel, as in Claim 292.
However, Thielsch teaches a respective microfluidic device wherein sample injection into the device is facilitated by the compression of a piston prior to sample injection, followed by subsequent decompression of the piston so as to draw the sample into the device ([0048]).
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 method of Liu/Gilbert to include compressing the internal spacing prior to introducing the sample liquid to the microfluidic channel, and maintaining the compression of the internal spacing while introducing the sample liquid to the microfluidic channel, such as suggested by Thielsch, so as to provide a sufficient structure for facilitating injection of the sample into the device; and would have a reasonable expectation of success therein.
Regarding Claim 295, the prior art meets the limitations of Claim 292 as discussed above. Further, Liu/Gilbert does not specifically teach a total internal height of the gas bladder defined by a distance between the first inner wall and the second inner wall, as measured along an axis that is perpendicular to a plane defined by the microfluidic device prior to compression, is between about 50 and 200 μm, as in Claim 295.
However, 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).
Herein, one of ordinary skill in the art would find it obvious to provide the device of Liu/Gilbert with a total internal height of the bladder zone defined by a distance between the first inner wall and the second inner wall, as measured along an axis that is perpendicular to a plane defined by the microfluidic device, is from about 50 and 200 μm prior to the step of compressing, so as to provide a suitable volume for accommodating the gas/liquid interface and oscillating said interface; and would have a reasonable expectation of success therein.
Claims 293 and 294 are rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Gilbert, Battrell and Thielsch, as applied to Claims 292 and 295 above, and as evidenced through Vishwanathan.
Regarding Claims 293 and 294, the prior art meets the limitations of Claim 292 as discussed above. Further, Liu/Gilbert does not explicitly teach the oscillation of the space between the first chamber wall and the second chamber wall as having the total percent compression or compression distances as in Claims 293 and 294. However, as the mixing speed is a variable that can be modified by adjusting the distance over which the first plate oscillates, the precise distance would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made, as evidenced through Vishwanathan. As such, without showing unexpected results, the distances as in Claims 293 and 294 cannot be considered critical. Thus, one of ordinary skill in the art would have optimized through routine experimentation the distance to maximally obtain the desired mixing time (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).
Response to Arguments
I. Independent Claim 272
Applicant’s introductory arguments are on the alleged grounds that Battrell, Galen, Thielsch and Vishwanathan are relied upon only for ancillary limitations, such that the oscillatory mixing is provided through Liu and Gilbert, and wherein Gilbert is not drawn to a mixing device but rather a valve arrangement and would thereby fail to produce the oscillations in Liu, and that Liu fails to teach sequential actuation through distinct zones.
Applicant’s arguments are not persuasive because Gilbert is not relied on for providing the oscillatory mixing; Gilbert is merely relied on for providing an alternative push/pull pumping mechanism to that of Liu using an air chamber, wherein the push/pull action is fully accounted for by the compression and relaxation of the air chamber in Gilbert.
Further, regarding the fluid actuation reaching successive reagent zones, Claim 272 only requires one reagent zone, which is expressly accounted for by Liu. Claims 280 and 281 introduce second and third reagent zones; however, as explained above in the body of the action, reducing and increasing the pressure in Liu results in the claimed entrance of various zones, given that Applicant has not particularly defined those zones. The zones may be adjacent such that actuation of the fluid across all three zones, such as in the back-and-forth movement of Liu, satisfies the claim language, nothing that each actuation results in or already has contact with the dry sample in the zone provided by Battrell. Applicant may wish to amend the claims to more specifically require the sequential process of reaching one zone before the next, wherein reaching the first zone excludes the second and third, the second zone excludes...etc. so as to avoid broad interpretation with the particular zone language.
Examiner maintains the rejection of Claim 272, and dependents thereof, under 35 USC 103 as being unpatentable over at least Liu in view of Gilbert and Battrell, as discussed above in the body of the action.
A. Applicant’s arguments are on the alleged grounds that Gilbert’s actuator merely constricts or blocks fluid flow and is therefore not interchangeable with Liu’s heater-driven oscillation pump; that no reason exists to use Gilbert to move or mix a sample to arrive at the method of Claim 272; and that the proposed modification would change the principle of operation of Liu.
Applicant’s arguments are not persuasive because Gilbert is not limited to complete blockage. Gilbert expressly states that its actuator 50 may “inhibit liquid flow or...cause liquid flow” ([0010]), that deflection of the gas chamber walls by the actuator pushes fluid away from the meniscus ([0010-0012]), and that the amplitude, frequency and duration of the displacement of the meniscus are parameters controllable by the actuator ([0052]). Complete blockage is merely the fully actuated state disclosed in para. [0053], not the only manner of operation.
Further, the rejection does not arbitrarily transplant Gilbert’s entire valve into Liu. Rather, the rejection substitutes Gilbert’s known flexible-wall gas-pressure actuator while retaining Liu’s gas pocket, channel, and oscillatory mixing operation. Liu expressly states that heating and cooling are non-limiting examples, and identifies diaphragm pumps as an exemplary known alternative to cause the required pressure oscillations by changes in volume rather than temperature of the enclosed gas (Liu [0065-0067]). As using the particular pump of Gilbert remains as another mere alternative for achieving the sought oscillatory pressure changes in Liu, the principle of operation remains the same: to actuate a gas so as to cause actuation of a liquid in a microfluidic device. Thus, Liu remains operable for its intended mixing purposes.
B. Applicant’s arguments are on the alleged grounds that Gilbert directly actuates an adjacent meniscus rather than a remote, perpendicular interface through an intervening gas column as in the method of Claim 272; that Liu and Gilbert cannot be combined into a coherent structure having the claimed distal wall arrangement; and that the 1 cm and 4 mm dimensions cannot be supplied by routine optimization because the prior art does not expressly identify those exact parameters as result-effective.
Applicant’s arguments are not persuasive because the rejection maintains Liu’s terminal gas-pocket and channel arrangement and applies Gilbert’s manner of mechanically varying the volume and pressure of a gas reservoir so as to actuate a fluid therethrough. Gilbert teaches that an external actuator deflects a reservoir wall, thereby changing gas pressure and moving a liquid-gas meniscus. Thus, the actuator’s effect is transmitted through the gas rather than by direct actuator-liquid contact (Gilbert [0043, 0048-0049]). Gilbert further states that a skilled artisan may select an appropriate channel volume and length ([0043]), and that the meniscus may be located at any appropriate location in the microchannel ([0045]). Accordingly, the combined teachings reasonably suggest placing Gilbert’s actuated wall on Liu’s terminal gas pocket and transmitting its pressure change through the intervening gas to Liu’s interface, thereby forming a coherent structure satisfying the intended mode of operation of Liu.
Further, regarding the “moving the sample liquid and the sample liquid-gas interface by at least about 4 mm” and “the first and second inner walls of the gas bladder are spaced apart distally along the longitudinal axis of the microchannel from the sample liquid and the sample liquid-gas interface by at least about 1 cm”, the prior art need not specifically point out a variable as being result-effective for said variable to be considered a result-effective variably. Herein, one of ordinary skill in the art would readily recognize that the degree of deflection distance of the liquid to directly affect the mixing efficiency as greater distances oscillated by the sample results in more vigorous mixing; and that the spacing of walls in the gas bladder affect how much air/liquid can be actuated in a single deflection, thereby further affecting the mixing efficiency as larger chambers have greater capacity to move the sample a greater distance and, when performed as oscillations, increases the mixing vigor and thereby the speed and effectiveness of the mixing.
C. Applicant’s arguments are on the alleged grounds that Liu merely agitates liquid in place over a fixed array and does not translate a sample bolus at least about 4 mm into a discrete zone containing a dry reagent, as required by Claim 272, while Battrell allegedly uses passive wet-out rather than the claimed distal-bladder movement.
Applicant’s arguments are not persuasive because Liu teaches that cooling moves the sample toward the gas pocket 26, and heating moves the liquid away from the gas pocket 26, and repeated oscillation forces substantially the entire sample across the channel to increase sample-reagent contact ([0065-0067]). Battrell supplies the dried reagent feature by teaching dried reagents spotted in designated channels or chambers to be rehydrated by sample liquid. Battrell further teaches reversing fluid flow to improve mixing and rehydration and expressly states that fluid may be oscillated (cols. 5 and 24).
Thus, the combined method moves/aspirates the sample into the device toward Liu’s gas pocket into a channel region containing Battrell’s dry reagent (or an additional channel region supplied by Battrell), and thereafter oscillates the sample to mix/dissolve and rehydrate the reagent. The particular 4 mm distance merely represents the travel required by the selected channel and reagent layout and would not affect the actual process of a sample liquid contacting with and dissolving a solid sample; the mixing and dissolving would remain the same no matter how far the sample first has to travel to reach the reagent. As such, selection of a workable travel distance, such as 4 mm, would have been a matter of routine optimization, absent evidence of a criticality or unexpected results related thereto.
D. Applicant’s arguments are on the alleged grounds that Battrell’s pneumohydraulic diaphragm and alleged passive reagent wet-out do not disclose the distal bladder, 1 cm spacing, indirect gas transmission, or directed 4 mm movement as required by Claim 272.
Applicant’s arguments are not persuasive because Battrell is not relied on for teaching those disputed limitations. Liu and Gilbert collectively provide the gas pocket, wall actuation, fluid movement, and oscillatory mixing teachings, while Battrell is relied on for dried reagents positioned in microfluidic channels or chambers. Battrell also confirms that flow reversal and oscillation may be used to improve reagent rehydration and mixing. Whether Battrell independently teaches Liu’s particular architecture is therefore not dispositive. A rejection based on combined references cannot be overcome by requiring the reference supplying one feature to teach the limitations supplied by the other references – see MPEP 2145(IV).
In view of the above discussions of the sections I. A-D presented by Applicant, Examiner maintains the rejection of Claim 272, and dependents thereof, under 35 USC 103 as being unpatentable over at least Liu in view of Gilbert and Battrell, as discussed above in the body of the action.
II. Dependent Claims
A. Applicant’s arguments are on the alleged grounds that Liu’s frequency range applies only to resonance of a 0.5-1 mm bubble and is thereby not a free design parameter; that Liu’s approximately 5 kHz example frequency would not lead a skilled artisan to the claimed sub-1.5 kHz frequencies as required by Claims 273 and 288; and that the rejection’s sample degradation rationale is not a teaching of Liu.
Applicant’s arguments are not persuasive because Liu expressly discloses an oscillation frequency range of 1-6 kHz and states that the frequency may be swept through a range ([0059]). This range overlaps with those required by Claims 273 and 288. An overlapping prior art range establishes a prima facie case of obviousness absent evidence of teaching away from the claimed range. As such, Applicant’s assertion that the variable is not optimizable is moot; and Applicant has provided no showing of evidence that one skilled in the art would avoid the lower overlapping portion of the frequency range provided by Liu.
Further, Applicant argues that lower frequencies avoiding sample degradation is Applicant’s own rationale read back into Liu. This is not the case because it is well-known in the biological arts that samples containing long strands of DNA or folded structures such as proteins (both of which being contemplated by Liu – paras. [0032-0033, 0040-0041]) are subject to mechanical damage when mishandled. This is why many proteins are not to be agitated with a vortex mixer and why long-strand DNA samples require a wide-mouth pipette tip to avoid force shearing.
Thus, Examiner maintains the rejection of Claims 273 and 288 under 35 USC 103 as being unpatentable over Liu in view of Gilbert and Battrell, as discussed above in the body of the action.
B. Applicant’s arguments are on the alleged grounds that a skilled artisan would not optimize the variables of Claims 278, 287, 290, 293-294, and 296-299 because Liu and Gilbert fail to disclose the underlying apparatus (such as discussed in the response to arguments section I above), that Vishwanathan does not bridge the gap as it lacks a gas bladder actuator and instead uses a speaker arrangement, and that the prior art does not expressly identify each parameter (oscillation distance, air chamber wall spacing, degree of compression, movement rate, gas volume, interface area, and volume-to-area) as result-effective.
Applicant’s arguments are not persuasive because the Liu/Gilbert/Battrell accounts for the claimed underlying mixing structure (such as discussed in the response to arguments section I above and in the body of the action). Vishwanathan is used as evidence of the recognized relationship between oscillatory displacement and microfluidic flow or mixing, not as the reference supplying the claimed bladder structure. As such, a skilled artisan would not be deterred from recognizing variables in the commensurate structure as being result-effective, as the structure on which the variables are applied is substantially identical as claimed.
Further, the prior art need not expressly identify each parameter as being result-effective. The required relationship may be expressly or implicitly recognized by a person of ordinary skill in the art. See MPEP: 2144.05(II)(B): “The articulated rationale must include an explanation of why it would have been routine optimization to arrive at the claimed invention and why a person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed range.” i.e.: the Examiner must support an implicit recognition of a result-effective variable with articulated technical reasoning, which is satisfied by the respective rejections of Claims 278, 287, 290, 293-294, and 296-299:
Claims 278 and 287: Vishwanathan expressly recognizes amplitude (peak-to-peak distance) as result effective on mixing (Sections 3.1 and 3.3.2).
Claims 290 and 297: Examiner explains “When the oscillation range of the wall is kept the same but the volume of the gas is increased (i.e. when there is a greater spacing between the wall and the gas-liquid interface), the oscillation of the gas is decreased proportional with Boyle’s law.” – When the actuation foot is spaced further as in Claim 290, or when the volume of gas is greater as in Claim 297, the foot/gas has more room to compress to actuate the liquid, and thereby has a greater peak-to-peak distance capacity. And, as supplied by Vishwanathan, when oscillation amplitude (peak-to-peak distance) is increased, mixing efficiency is increased in a result-effective manner (Sections 3.1 and 3.3.2).
Claims 293-294: Vishwanathan expressly recognizes amplitude (peak-to-peak distance) as result effective on mixing (Sections 3.1 and 3.3.2). Examiner explains the degree of compression of the gas bladder is directly proportional to the peak-to-peak distance.
Claim 296: Vishwanathan expressly discloses mixing speed (oscillatory frequency) as affecting mixing speed and efficiency (Fig. 5: mixing index vs frequency) in a result-effective manner (Section 3.3.2).
Claims 298-299: Examiner explains: “When a greater area of liquid is actuated by the gas, a greater displacement of said liquid occurs.” Therein, such amplitude differences are provided by Vishwanathan as being result-effective on mixing speed and efficiency (Section 3.3.2).
Further, the above discussed optimizations would have a reasonable expectation of success in Liu/Gilbert/Battrell as they are achievable by mere modification of the gas bladder size in Liu, and mere modification of the actuator range of Gilbert. As such, optimization of the above discussed parameters represents no more than a predictable use of the device and method of Liu/Gilbert/Battrell and yields the predictable results of changes in mixing amplitude and frequency which directly affect mixing index.
As each of the variables discussed above regarding parameters of the gas bladder are either meant to affect the oscillatory amplitude and/or frequency of the actuated liquid, and Vishwanathan expressly teaches that oscillatory amplitude and frequency of a liquid moving back and forth in a channel are result-effective variables controlling the mixing speed and efficiency, Examiner maintains the rejection of Claims 278, 287, 290, 293-294, and 296-299 as being unpatentable under 35 USC 103 over Liu in view of Gilbert and Battrell, and as evidenced through Vishwanathan, as discussed above in the body of the action.
C. Applicant’s arguments are on the alleged grounds that Galen does not cure the alleged deficiencies of Claim 272, and that the proximal removal of unbound mixture as in Claim 283 demonstrates controlled, reversible translation not performed by Gilbert’s valve.
Applicant’s arguments are not persuasive because no such deficiencies of Liu/Gilbert/Battrell are present regarding Claim 272, as discussed in the response to arguments section I above. Thus, Applicant’s argument is moot as Galen is not relied on for curing the disputed elements of Claim 272.
Regarding Claim 283, Liu expressly teaches movement both forward and away from the gas pocket ([0066]), and Gilbert teaches transient liquid displacement followed by reverse flow upon actuator release ([0070]) and further teaches apposite flow during reservoir pressure relief ([0075-0076]). Thus, decreasing wall spacing to move liquid proximally is the predictable reverse operation of a same variable-volume gas actuator as in Gilbert.
Thus, in view of the discussion above, Examiner maintains the rejection of Claim 272 under 35 USC 103 as being unpatentable over Liu in view of Gilbert and Battrell, and Claim 283 under 35 USC 103 as being unpatentable over Liu in view of Gilbert, Battrell, and Galen, as discussed above in the body of the action.
D. Applicant’s arguments are on the alleged grounds that Thielsch does not cure the alleged deficiencies of Liu/Gilbert/Battrell in Claim 272, that the chromatography piston and valve of Thielsch are structurally different from the claimed gas bladder, and that the claimed pre-compression percentages, distances, and internal heights as in Claims 292-295 describe a bladder geometry absent from the prior art.
Applicant’s arguments are not persuasive because no such deficiencies of Liu/Gilbert/Battrell are present regarding Claim 272, as discussed in the response to arguments section I above. Thus, Applicant’s argument is moot as Thielsch is not relied on for curing the disputed elements of Claim 272.
Regarding Claim 292, Thielsch is relied on only for the known fluid-control technique of establishing a compressed/decompressed state and/or pre-pressurized/depressurized volume via a piston before fluidic coupling or injection so as to draw sample into the device by switching the compressed/decompressed state and/or pre-pressurized/depressurized volume ([0039-0041 and 0049]). Thielsch is not relied upon for accomplishing this task via a gas bladder, wherein this limitation is accounted for by Liu/Gilbert/Battrell. Obviousness does not require transplanting Thielsch’s piston and valve structure into the cartridge of Liu/Gilbert/Battrell. The relevant teaching of Thielsch is the pressure-preloading technique for drawing in a sample which one of ordinary skill in the art would have recognized as applicable to the method of Liu/Gilbert/Battrell which commensurately utilizes a variable volume of gas to actuate a liquid. The gas in Thielsch is merely compressed by a piston, which serves the functionally equivalent purpose and is commensurately drawn to actuating walls to change a gas volume. Thus, the methods rely on structures not so different that one skilled in the art would not find it obvious to combine them, as asserted by applicant; rather, the structures are substantially equivalent and one skilled in the art would recognize their overlapping teachings.
Regarding the variables of Claims 293-295, such variables are fully tunable within the device of Liu/Gilbert/Battrell which commensurately describes an actuator actuating a wall of a gas bladder to actuate a fluid in a channel. In Claims 294-295, one skilled in the art need only change the gas bladder size, in Claim 293, one skilled in the art need only change the compression degree/range of the actuation foot. As discussed above, these variables merely serve to change the oscillatory amplitude of mixing, a property recognized by Vishwanathan as being a result-effective variable, and wherein merely changing the internal height of the gas bladder as in Claim 295 would not affect its operation, the range of the actuation foot remaining the same.
Thus, in view of the discussion above, Examiner maintains the rejection of Claim 272 under 35 USC 103 as being unpatentable over Liu in view of Gilbert and Battrell, and Claims 292-295 under 35 USC 103 as being unpatentable over Liu in view of Gilbert, Battrell, and Thielsch (Claims 293 and 294 being further evidenced through Vishwanathan), as discussed above in the body of the action.
Newly Added Claim 300
New Claim 300 is rejected above in the body of the action under 35 USC 103 as being unpatentable over Liu in view of Gilbert and Battrell, as necessitated by Applicant’s addition of the new claim in the reply to the prior office action.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/B.J.K./Examiner, Art Unit 1798
/P. Kathryn Wright/Primary Examiner, Art Unit 1798
