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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 17 March 2026 has been entered.
Response to Amendment
This is an office action in response to Applicant’s arguments and remarks filed on 17 March 2026. Claims 1 and 3-10 are pending in the application. Claim 2 has been previously cancelled. Claims 1 and 3-10 are being examined herein.
Status of Objections and Rejections
The interpretation of claim 9 under 35 U.S.C. § 112(f) is maintained.
The rejections of claims 1, 3, 9, and 10 under 35 U.S.C. § 103 in view of Dale, et. al. (US 20090317874 A1) in view of Nakajima, et. al. (US 20060094004 A1) and Chuang, et. al. ("LMP1 gene detection using a capped gold nanowire array surface plasmon resonance sensor in a microfluidic chip”) are withdrawn in view of amendments.
The rejections of claims 4 and 5 under 35 U.S.C. § 103 in view of Dale, et. al. (US 20090317874 A1) in view of Nakajima, et. al. (US 20060094004 A1) and Chuang, et. al. (LMP1 gene detection using a capped gold nanowire array surface plasmon resonance sensor in a microfluidic chip”) in further view of Montgomery, et. al. (“Influence of PCR Reagents on DNA Polymerase Extension Rates Measured on Real-Time PCR Instruments”) are withdrawn in view of amendments.
The rejection of claim 6 under 35 U.S.C. § 103 in view of Dale, et. al. (US 20090317874 A1) in view of Nakajima, et. al. (US 20060094004 A1) and Chuang, et. al. (LMP1 gene detection using a capped gold nanowire array surface plasmon resonance sensor in a microfluidic chip”) in further view of Klunder, et. al. (US 20110086361 A1) are withdrawn in view of amendments.
The rejections of claims 7 and 8 under 35 U.S.C. § 103 in view of Dale, et. al. (US 20090317874 A1) in view of Nakajima, et. al. (US 20060094004 A1) and Chuang, et. al. (LMP1 gene detection using a capped gold nanowire array surface plasmon resonance sensor in a microfluidic chip”) in further view of Davalieva, et. al. (“Influence of Salts and PCR Inhibitors on the Amplification Capacity of Three Thermostable DNA Polymerases’”) are withdrawn in view of amendments.
Response to Arguments
Applicant’s arguments, see Remarks, pages 5-9, filed 17 March 2026, with respect to the rejection(s) of claim(s) 1 and 9 under 35 U.S.C. § 103 in view of Dale, et. al. (US 20090317874 A1) in view of Nakajima, et. al. (US 20060094004 A1) and Chuang, et. al. ("LMP1 gene detection using a capped gold nanowire array surface plasmon resonance sensor in a microfluidic chip”) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Dale, et. al. (US 20090317874 A1) in view of Cui, et. al. (CN 114367321 A) and Amarie, et. al. (Microfluidic Devices Integrating Microcavity Surface-Plasmon-Resonance Sensors: Glucose Oxidase Binding-Activity Detection, citations made with respect to attached copy).
Examiner notes the continued use of Dale (US 20090317874 A1) as prior art in regard to the thermocycling configuration as no arguments were provided against the thermocycling components.
Applicant does provide an argument about the lack of multiple outlets and connection ports for biological sensor chips (Remarks, pg. 7, par. 05) and the modification for continuous flow (Remarks, pg. 8, par. 03) in Dale and how in view of Nakajima (Remarks, pg. 7, par. 06 - pg. 8, par. 01) and Chuang (Remarks, pg. 8, par. 02) do not remedy these deficiencies. Examiner is now presenting new art to remedy these deficiencies, more details below.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are:
“A flow control unit for controlling the flow rate...” in Claim 9, line 15. The “flow control unit” is interpreted to be a micropump or equivalents thereof as per specification paragraph 0042 of the instant application.
“A temperature control unit...” in Claim 9, line 17. The “temperature control unit” are interpreted as any sensors and controlled electronically controlled and connected to thermal units and equivalents thereof as per specification paragraph 0038 and 0043 and Figure 3 of the instant application.
“A detection unit for detecting the biological chip...” in Claim 9, line 20. The “detection unit” is interpreted to be what is needed based on the selected detection chip, including but not limited to objective lens, polarizer, lend, and/or optical fiber as per specification paragraph 0044 of the instant application. For example, with a surface plasmon resonance chip, an optical fiber via fiber lens is the detection unit (par. 0056).
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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 1, 3, 9, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Dale, et. al. (US 20090317874 A1) + Cui, et. al. (CN 114367321 A) in view of Amarie, et. al. (Microfluidic Devices Integrating Microcavity Surface-Plasmon-Resonance Sensors: Glucose Oxidase Binding-Activity Detection, citations made with respect to attached copy).
Regarding claim 1, Dale teaches a microfluidic chip used for thermocyclic processes (Abstract) such as amplifying nucleic acids in a real-time PCR system (par. 0002) (a PCR detection device). Dale teaches a microfluidic chip 200 comprising a winding microchannel 202 (Fig. 1, 4; par. 0045, 0047) (a microfluidic substrate comprising a microchannel, wherein the microchannel is configured in the microfluidic substrate with a plurality of isometric parallel back-and-forth cycles). Dale teaches thermal elements 208 with 206 and 210 with 204 that are on opposite sides of microchannel 202 with a gap separating the two, with each element heating a different part of the microchannel 202 (Fig. 2; par. 0056-0060) (a heating unit comprising a first heating plate and a second heating plate, wherein the first heating plate and the second heating plate are arranged to be parallel and juxtaposed with a spacing d) (wherein the microfluidic substrate is mounted on the heating unit, and contacts with the first heating plate to form a first heating zone and contacts with the second heating plate to form a second heating zone). Dale teaches thermal elements 208/206 and 210/204 create three distinct temperature zones (Fig. 4; par. 0061) (wherein the first heating plate applies a first temperature T1 to heat the first heating zone, and the second heating plate applies a second temperature T2 to heat the second heating zone) (wherein when T1 is different from T2, the region above the spacing d in the microfluidic substrate forms a third heating zone, and a third temperature T3 formed in the third heating zone is between T1 and T2).
Dale teaches the winding motion of microchannel 202 passes back and forth through each of the three thermal zones multiple times (Fig. 4, 6A-D; par. 0057, 0060-0061) (wherein each isometric parallel back-and-forth cycle in the microfluidic substrate passes through the first heating zone, the second heating zone and the third heating zone). Dale teaches the system comprises an optical imaging system 112 for real-time monitoring of the PCR reaction (Fig. 1; par. 0052), and Dale additionally suggests a post-PCR analyzer 116 fluidically connected to the microchannel for a multitude of analytical techniques (Fig. 1; par. 0055) (at the end of the microchannel of the microfluidic substrate in a fluid- communicable manner). Dale teaches an inlet side (near label 117 of Fig. 1) 202 and an outlet side (near label 116 of Fig. 1) of the microchannel (par. 0057) (the microchannel of the microfluidic substrate comprises one inlet port).
Dale is silent to a plurality of outlet ports and a plurality of biological detection chips loaded on respective chip microchannel connection ports at the end of the microchannel of the microfluidic substrate in a fluid-communicable manner, wherein each of the biological detection chips is respectively disposed at a corresponding one of the outlet ports.
Cui teaches a microfluidic detection device (par. n0001) for detecting a plurality of biomolecules such as nucleic acids (par. n0004) through pairing the microfluidic device with solid state chips (par. n0004-n0005). Cui teaches the device comprises a microfluidic device that is a mixer with microchannels on a PDMS and glass substrate (par. n0008) wherein the microfluidic device includes at least one inlet, a serpentine microchannel, and 8-12 branched outlets at the end of the microchannel (Fig. 3; par. n0011) (a plurality of outlet ports). The outlets further being connected to different detector chips (par. n0011, n0040) (a plurality of biological detection chips) all parts being fluidically connected (par. n0038) (a plurality of biological detection chips…at the end of the microchannel of the microfluidic substrate in a fluid-communicable manner, wherein each of the biological detection chips is respectively disposed at a corresponding one of the outlet ports). Cui teaches the mixing and detecting device is assembled on bases to fix the microfluidic mixer and detector together (par. n0015). Cui teaches the use of chips for detection are low-cost, fast and easy to use, and suitable for point-of-care devices (par. n0004) with this specific device further improving detection speed and having the ability to be reuse (par. n0006, n0009).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention modify the microfluidic outlet and post-PCR analysis system of Dale to include a plurality of biological detection chips…at the end of the microchannel of the microfluidic substrate in a fluid-communicable manner, wherein each of the biological detection chips is respectively disposed at a corresponding one of the outlet ports as taught by Cui because pairing microfluidics with detections chips creates a low-cost, fast and easy to use point-of-care device with improved detection speed (Cui, par. n0004, n0006) with reasonable expectation of success. MPEP 2143(I)(G). Further, one of ordinary skill in the art before the effective filing date of the invention would be motivated to substitute the singular outlet of Dale with the plurality of outlets as taught by Cui because it allows for parallel testing as indicated by the use of multiple, unique detection chips at each outlet (Cui, par. n0040), and the simple substitution on one known element (singular outlet, Dale) for another known element (multiple outlets, Cui) is likely to be obvious when predictable results (multiple detector/detection options) are achieved. MPEP 2143(I)(B).
Modified Dale is still silent to the plurality of biological detection chips (being) loaded on respective chip microchannel connection ports.
Amarie teaches a microcavity surface-plasmon-resonance (MSPR) sensors integrated with microfluidics (Abstract). Amarie teaches an integrated device comprising microchannels fabricated a PDMS substrate with at least one inlet leading to a main chamber (pg. 345, "Channel Fabrication" Section) and multiple MSPR sensors attached to the microfluidic main chamber (pg. 345, "Chip Assembly" Section) (the plurality of biological detection chips loaded on respective chip microchannel connection ports). Amarie teaches the MSPR sensors are ideal for use as biosensors because of their label-free detection and ability to be easily integrated into a microfluidic device (pg. 344, col. 1, par. 02), and when integrated, allows for a detection system and method with extensive analysis time with minimal reagent volume and improved accuracy and precision (pg. 344, col. 2, par. 01).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention modify the post-PCR analysis system using detection chips of modified Dale to have MSPR sensor detection chips themselves integrated within the microfluidic chip as taught by Amarie because it provides label-free detection, minimal reagent volumes, and improving accuracy and precision (Amarie, pg. 344, col. 2, par. 01) with reasonable expectation of success. MPEP 2143(I)(G).
Regarding claim 3, modified Dale teaches the microfluidic chip 200 that hold the microchannel 202 has a preferable width of 20 mm long by 20 mm wide (Dale, Fig. 4; par. 0056), meaning the full width of microchannel 202 including zone 1, 2 (space), and 3 is 20 mm total.
Modified Dale is silent to the spacing d is in the range of 1 to 10 mm.
Dale teaches the thermal distribution element and heat plate combination can vary in location and size. The size (width) of each thermal distribution element 224/226, 234/236, 244,246, 254/256 directly impacts the spacing (forming the third zone) 222, 232, 242, 252 and thus impacts the dwell time within each temperature zone (Fig. 6A-D; par. 0065). The configurations as seen in Figures 6A-D, illustrate that depending on the temperature requirements of the PCR, the dwell time in each temperature zone can be altered (par. 0066-0070) based on needs of the sample and solutions used in the sample such as PCR primers, dNTPs, polymerase enzymes, salts, buffers, surface- passivating agents, and the like (par. 0044). Dale teaches the width modification of the temperature zones allows for optimization of the PCR process which relies on distinct thermal zones (par. 0022).
Further, Dale teaches wherein the dwell times and thermal zones is a result effective variable. Specifically, Dale teaches the spacing/sizing of the thermal zones directly impacts the dwell times of the sample/solution in the microchannel and therefore directly impacts the thermocyclic reaction occurring within the microchannel. Since this particular parameter is recognized as result-effective variable, i.e., a variable which achieves a recognized result, the determination of the optimum or workable ranges of said variable can be characterized as routine experimentation. MPEP § 2144.05(II)(A)- (B). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to modify space between the two heated elements to be in the range of 1 to 10 mm with a reasonable expectation of success of creating a dwell time to allow for a reaction to completely occur.
It would have been obvious to one skilled in the art before the effective filing date of the invention to modify the total width of the microchannel as provided by Dale to include the spacing d is in the range of 1 to 10 mm between the two heating elements in order to optimize the thermocyclic reactions of PCR. Because Dale teaches that the width of the microchannel and therefore the spacing between the heating elements attached to the microchannel can be modified based on heating requirements as taught by Dale, modifying the spacing to be within a certain range (1 to 10 mm), provides likewise sought functionality with reasonable expectation of success. MPEP 2143 (I)(G).
Regarding claim 9, Dale teaches a microfluidic chip used for thermocyclic processes (Abstract) such as amplifying nucleic acids in a real-time PCR system (par. 0002). Dale teaches a microfluidic chip 200 comprising a winding microchannel 202 in which a fluid is pumped through microchannel 202 by pump mechanism 106 (Fig. 1, 4; par. 0045, 0047-0048) (a microfluidic substrate comprising a microchannel, wherein the microchannel is configured in the microfluidic substrate with a plurality of isometric parallel back-and-forth cycles) (a flow control unit for controlling the flow rate of liquid in the microfluidic substrate). Dale thermal elements 208 with 206 and 210 with 204 that are on opposite sides of microchannel 202 with a gap separating the two, with each element heating a different part of the microchannel 202 (Fig. 2; par. 0056-0060) (a heating unit comprising a first heating plate and a second heating plate, wherein the first heating plate and the second heating plate are arranged to be parallel and juxtaposed with a spacing d) (wherein the microfluidic substrate is mounted on the heating unit and contacts with the first heating plate to form a first heating zone and contacts with the second heating plate to form a second heating zone).
Dale teaches thermal elements 208/206 and 210/204 create three distinct temperature zones (Fig. 4; par. 0061) (wherein the first heating plate applies a first temperature T1 to heat the first heating zone, and the second heating plate applies a second temperature T2 to heat the second heating zone) (wherein when T7 is greater than T2, the region above the spacing d in the microfluidic substrate forms a third heating zone, and a third temperature T3 formed in the third heating zone is between T1 and T2). Dale teaches a temperature control system 107 to control and monitor the temperatures of heaters 208/206 and 210/204 through a temperature controller 111 (Fig. 1; par. 0049-0050; 0059) (a temperature control unit, which is electrically connected to the heating unit and respectively controls the heating temperatures of the first heating plate and the second heating plate).
Dale teaches the system comprises an optical imaging system 112 for real-time monitoring of the PCR reaction (Fig. 1; par. 0052) (a detection unit), and Dale additionally suggests a post-PCR analyzer 116 for a multitude of analytical techniques (Fig. 1; par. 0055) (at the end of the microchannel of the microfluidic substrate in a fluid-communicable manner). Dale is silent to a biological detection chip (loaded at the end of the microchannel of the microfluidic substrate in a fluid-communicable manner) and a detection unit for detecting the biological detection chip. Dale teaches an inlet side (near label 117 of Fig. 1) 202 and an outlet side (near label 116 of Fig. 1) of the microchannel (par. 0057) (the microchannel of the microfluidic substrate comprises one inlet port)
Dale is silent to a plurality of outlet ports and a plurality of biological detection chips loaded on respective chip microchannel connection ports at the end of the microchannel of the microfluidic substrate in a fluid-communicable manner, wherein each of the biological detection chips is respectively disposed at a corresponding one of the outlet ports.
Cui teaches a microfluidic detection device (par. n0001) for detecting a plurality of biomolecules such as nucleic acids (par. n0004) through pairing the microfluidic device with solid state chips (par. n0004-n0005). Cui teaches the device comprises a microfluidic device that is a mixer with microchannels on a PDMS and glass substrate (par. n0008) wherein the microfluidic device includes at least one inlet, a serpentine microchannel, and 8-12 branched outlets at the end of the microchannel (Fig. 3; par. n0011) (a plurality of outlet ports). The outlets further being connected to different detector chips (par. n0011, n0040) (a plurality of biological detection chips) all parts being fluidically connected (par. n0038) (a plurality of biological detection chips…at the end of the microchannel of the microfluidic substrate in a fluid-communicable manner, wherein each of the biological detection chips is respectively disposed at a corresponding one of the outlet ports). Cui teaches the mixing and detecting device is assembled on bases to fix the microfluidic mixer and detector together (par. n0015). Cui teaches the use of chips for detection are low-cost, fast and easy to use, and suitable for point-of-care devices (par. n0004) with this specific device further improving detection speed and having the ability to be reuse (par. n0006, n0009).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention modify the microfluidic outlet and post-PCR analysis system of Dale to include a plurality of biological detection chips…at the end of the microchannel of the microfluidic substrate in a fluid-communicable manner, wherein each of the biological detection chips is respectively disposed at a corresponding one of the outlet ports as taught by Cui because pairing microfluidics with detections chips creates a low-cost, fast and easy to use point-of-care device with improved detection speed (Cui, par. n0004, n0006) with reasonable expectation of success. MPEP 2143(I)(G). Further, one of ordinary skill in the art before the effective filing date of the invention would be motivated to substitute the singular outlet of Dale with the plurality of outlets as taught by Cui because it allows for parallel testing as indicated by the use of multiple, unique detection chips at each outlet (Cui, par. n0040), and the simple substitution on one known element (singular outlet, Dale) for another known element (multiple outlets, Cui) is likely to be obvious when predictable results (multiple detector/detection options) are achieved. MPEP 2143(I)(B).
Modified Dale is still silent to the plurality of biological detection chips (being) loaded on respective chip microchannel connection ports at the end of the microchannel of the microfluidic substrate.
Amarie teaches a microcavity surface-plasmon-resonance (MSPR) sensors integrated with microfluidics (Abstract). Amarie teaches an integrated device comprising microchannels fabricated a PDMS substrate with at least one inlet leading to a main chamber (pg. 345, "Channel Fabrication" Section) and multiple MSPR sensors attached to the microfluidic main chamber (pg. 345, "Chip Assembly" Section) (the plurality of biological detection chips loaded on respective chip microchannel connection ports). Amarie teaches the MSPR sensors are ideal for use as biosensors because of their label-free detection and ability to be easily integrated into a microfluidic device (pg. 344, col. 1, par. 02), and when integrated, allows for a detection system and method with extensive analysis time with minimal reagent volume and improved accuracy and precision (pg. 344, col. 2, par. 01).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention modify the post-PCR analysis system using detection chips of modified Dale to have MSPR sensor detection chips themselves integrated within the microfluidic chip as taught by Amarie because it provides label-free detection, minimal reagent volumes, and improving accuracy and precision (Amarie, pg. 344, col. 2, par. 01) with reasonable expectation of success. MPEP 2143(I)(G).
Regarding claim 10, modified Dale in view of Amarie teaches the integrated detection chips are specifically multiple MSPR sensors attached to the microfluidic main chamber (Amarie, pg. 345, "Chip Assembly" Section) (wherein the biological detection chips are surface plasmon resonance chips).
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Dale, et. al. (US 20090317874 A1) in view of Cui, et. al. (CN 114367321 A) and Amarie, et. al. (Microfluidic Devices Integrating Microcavity Surface-Plasmon-Resonance Sensors: Glucose Oxidase Binding-Activity Detection, citations made with respect to attached copy) as applied to claim 1 above, and further in view of Montgomery, et. al. (“Influence of PCR Reagents on DNA Polymerase Extension Rates Measured on Real-Time PCR Instruments”) (citations made with respect to copy provided with OA dated 29 July 2025).
Regarding claim 4, modified Dale teaches the microfluidic chip 200 that hold the microchannel 202 has a preferable width of 20 mm long by 20 mm wide (Dale, Fig. 4; par. 0056), meaning the full width of microchannel 202 including zone 1, 2 (space), and 3 is 20 mm total. Dale additionally teaches that real-time PCR reagent mixtures may or may not include salts (Dale, par. 0044).
Modified Dale is silent to the spacing d is in the range of 1 to 6 mm for a salt-free sample.
Dale teaches the thermal distribution element and heat plate combination can vary in location and size. The size (width) of each thermal distribution element 224/226, 234/236, 244,246, 254/256 directly impacts the spacing (forming the third zone) 222, 232, 242, 252 and thus impacts the dwell time within each temperature zone (Fig. 6A-D; par. 0065). The configurations as seen in Figures 6A-D, illustrate that depending on the temperature requirements of the PCR, the dwell time in each temperature zone can be altered (par. 0066-0070) based on needs of the sample and solutions used in the sample such as PCR primers, dNTPs, polymerase enzymes, salts, buffers, surface- passivating agents, and the like (par. 0044). Dale teaches the width modification of the temperature zones allows for optimization of the PCR process which relies on distinct thermal zones (par. 0022). Montgomery teaches that salts, specifically the cations from salts, can decrease the extension rate of common PCR enzymes when present in the PCR solution (Fig. 2; pg. 336, col. 2, par. 01). This information can be interpreted to mean that the presence of salts in a PCR solution inhibit optimum performance of the PCR process resulting in the need for extended PCR cycle times as comparted to PCR solutions with no salt concentration (Fig. 5).
Further, Dale teaches wherein the dwell times and thermal zones is a result effective variable. Specifically, Dale teaches the spacing/sizing of the thermal zones directly impacts the dwell times of the sample/solution in the microchannel and therefore directly impacts the thermocyclic reaction occurring within the microchannel. Montgomery teaches salt-free solutions perform more quickly as comparted to salt- containing sample and therefore will need less dwell time. Since this particular parameter is recognized as result-effective variable, i.e., a variable which achieves a recognized result, the determination of the optimum or workable ranges of said variable can be characterized as routine experimentation. MPEP § 2144.05(II)(A)-(B). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to modify space between the two heated elements to be in the range of 1 to 10 mm with a reasonable expectation of success of creating a dwell time to allow for a reaction to completely occur.
It would have been obvious to one skilled in the art before the effective filing date of the invention to modify the total width of the microchannel as provided by Dale to include the spacing d is in the range of 1 to 6 mm for a salt-free sample between the two heating elements in order to optimize the thermocyclic reactions of PCR in a salt free sample. Because Dale teaches that the width of the microchannel and therefore the spacing between the heating elements attached to the microchannel can be modified based on heating requirements as taught by Dale and Montgomery teaches salt-free samples undergo the reaction more quickly, modifying the spacing to be within a certain range based on the absence of salt (1 to 6 mm), provides likewise sought functionality with reasonable expectation of success. MPEP 2143 (I)(G).
Regarding claim 5, modified Dale teaches the microfluidic chip 200 that hold the microchannel 202 has a preferable width of 20 mm long by 20 mm wide (Dale, Fig. 4; par. 0056), meaning the full width of microchannel 202 including zone 1, 2 (space), and 3 is 20 mm total. Dale additionally teaches that real-time PCR reagent mixtures may or may not include salts (Dale, par. 0044).
Modified Dale is silent to the spacing d is in the range of 6 to 10 mm for a salt- containing sample.
Dale teaches the thermal distribution element and heat plate combination can vary in location and size. The size (width) of each thermal distribution element 224/226, 234/236, 244,246, 254/256 directly impacts the spacing (forming the third zone) 222, 232, 242, 252 and thus impacts the dwell time within each temperature zone (Fig. 6A-D; par. 0065). The configurations as seen in Figures 6A-D, illustrate that depending on the temperature requirements of the PCR, the dwell time in each temperature zone can be altered (par. 0066-0070) based on needs of the sample and solutions used in the sample such as PCR primers, dNTPs, polymerase enzymes, salts, buffers, surface- passivating agents, and the like (par. 0044). Dale teaches the width modification of the temperature zones allows for optimization of the PCR process which relies on distinct thermal zones (par. 0022). Montgomery teaches that salts, specifically the cations from salts, can decrease the extension rate of common PCR enzymes when present in the PCR solution (Fig. 2; pg. 336, col. 2, par. 01). This information can be interpreted to mean that the presence of salts in a PCR solution inhibit optimum performance of the PCR process resulting in the need for extended PCR cycle times as comparted to PCR solutions with no salt concentration (Fig. 5).
Further, Dale teaches wherein the dwell times and thermal zones is a result effective variable. Specifically, Dale teaches the spacing/sizing of the thermal zones directly impacts the dwell times of the sample/solution in the microchannel and therefore directly impacts the thermocyclic reaction occurring within the microchannel. Montgomery teaches salt-containing solutions perform more less efficiently as comparted to salt-containing sample and therefore will need additional dwell time. Since this particular parameter is recognized as result-effective variable, i.e., a variable which achieves a recognized result, the determination of the optimum or workable ranges of said variable can be characterized as routine experimentation. MPEP § 2144.05(II)(A)- (B). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to modify space between the two heated elements to be in the range of 1 to 10 mm with a reasonable expectation of success of creating a dwell time to allow for a reaction to completely occur.
It would have been obvious to one skilled in the art before the effective filing date of the invention to modify the total width of the microchannel as provided by Dale to include the spacing d is in the range of 6 to 10 mm for a salt-containing sample between the two heating elements in order to optimize the thermocyclic reactions of PCR in a salt-containing sample. Because Dale teaches that the width of the microchannel and therefore the spacing between the heating elements attached to the microchannel can be modified based on heating requirements as taught by Dale and Montgomery teaches salt-containing samples undergo decreased extension rates, modifying the spacing to be within a certain range based on the presence of salt (6 to 10 mm), provides likewise sought functionality with reasonable expectation of success. MPEP 2143 (I)(G).
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Dale, et. al. (US 20090317874 A1) in view of Cui, et. al. (CN 114367321 A) and Amarie, et. al. (Microfluidic Devices Integrating Microcavity Surface-Plasmon-Resonance Sensors: Glucose Oxidase Binding-Activity Detection, citations made with respect to attached copy) as applied to claim 1 above, and further in view of Klunder, et. al. (US 20110086361 A1).
Regarding claim 6, modified Dale teaches a first temperature range (Dale, at Zone 1, Fig. 4) from 85°C to 100°C (the temperature of the first heating plate is controlled in the range of 80 °C to 100 °C) and a second temperature range (Dale, at Zone 2, Fig. 4) from 20°C to 70°C (77 is greater than T2) (Dale, par. 0049).
Modified Dale is silent to the temperature of the second heating plate is controlled in the range of 55 °C to 65 °C.
Klunder teaches a temperature range of 85°C to 100°C of the first denaturation zone and a temperature range of 60°C to 75°C in the second elongation zone (Fig. 1; par. 0014). Klunder gives the specific temperature suggestions at 95°C for the first zone and 65°C for the second zone (Fig. 1) (the temperature of the second heating plate is controlled in the range of 55 °C to 65 °C). Klunder teaches each temperature zone is unique and set based on the amplification and detection of specific nucleic acid sequences (par. 0005).
It would have been obvious to one skilled in the art before the effective filing date of the invention to try a narrower range or specific temperature as taught by Klunder out of the wider range as taught by Dale in order to perform the reaction based on specific nucleic acid targets and enzymes used. Because both microfluidic devices use cycling through distinct temperature zones to, it would have been obvious to try a narrower range of temperatures, or a specific/finite temperature as provided by Klunder with reasonable expectation of success. MPEP 2143(I)(E).
Claims 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Dale, et. al. (US 20090317874 A1) in view of Cui, et. al. (CN 114367321 A) and Amarie, et. al. (Microfluidic Devices Integrating Microcavity Surface-Plasmon-Resonance Sensors: Glucose Oxidase Binding-Activity Detection, citations made with respect to attached copy) as applied to claim 1 above, and further in view of Klunder, et. al. (US 20110086361 A1) and Davalieva, et. al. (“Influence of Salts and PCR Inhibitors on the Amplification Capacity of Three Thermostable DNA Polymerases’”) (citations made with respect to copy provided with OA dated 29 July 2025).
Regarding claim 7, modified Dale teaches a first temperature range (Dale, at Zone 1, Fig. 4) from 85°C to 100°C (the temperature of the first heating plate is controlled in the range of 80 °C to 90 °C) and a second temperature range (Dale, at Zone 2, Fig. 4) from 20°C to 70°C (the second heating plate is controlled in the range of 55 °C to 65 °C) (Dale, par. 0049).
Modified Dale is silent to the temperature of the first heating plate is controlled in the range of 80 °C to 90 °C and the temperature of the second heating plate is controlled in the temperature of the second heating plate is controlled in the range of 55 °C to 65 °C for a salt-free sample.
Klunder teaches a temperature range of 85°C to 100°C of the first denaturation zone and a temperature range of 60°C to 75°C in the second elongation zone (Klunder, Fig. 1; par. 0014). Klunder teaches each temperature zone is unique and set based on the amplification and detection of specific nucleic acid sequences and enzymes used (Klunder, par. 0005). Klunder additionally teaches salts may or may not be present in the reaction solution and can therefore impact the rate and efficiency the reaction (Klunder, par. 0192, 0209). Davalieva teaches salt is a known inhibitor in PCR (Davalieva, pg. 58, col. 1, par. 01). Davalieva teaches at increasing ion concentrations decreases the performance of different thermostable DNA polymerase enzymes (Davalieva, Table 3). Therefore, the enzymes with increased thermostability perform better in the presence of salt ions as compared to less thermostable enzymes for PCR processes (Davalieva, pg. 61, “Conclusion” section).
Further, Klunder teaches wherein the thermal zones and constituents of the reaction solution are result effective variables. Specifically, Klunder teaches the temperature of the thermal zones directly impacts the reaction activity of the sample/solution in the microchannel and therefore directly impacts the thermocyclic reaction occurring within the microchannel. Davalieva teaches salt-containing solutions perform less efficiently as compared to salt-free sample and show improved performance with more thermostable enzymes. Since this particular parameter is recognized as result-effective variable, i.e., a variable which achieves a recognized result, the determination of the optimum or workable ranges of said variable can be characterized as routine experimentation. MPEP § 2144.05(II)(A)-(B). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to modify the temperature of the first heating plate is controlled in the range of 80 °C to 90 °C and the temperature of the second heating plate is controlled in the temperature of the second heating plate is controlled in the range of 55 °C to 65 °C for a salt-free sample with a reasonable expectation of success of creating a temperature range to allow for a reaction to completely occur.
It would have been obvious to one skilled in the art before the effective filing date of the invention to try a narrower range or specific temperature as taught by Klunder out of the wider range as taught by Dale in order to perform the reaction based on specific nucleic acid targets and enzymes used in the absence of salt. Further, because salt is absent, using the better performing more thermostable enzymes is not necessary as taught by Davalieva. Because both microfluidic devices use cycling through distinct temperature zones to, it would have been obvious to try a narrower range of temperatures, or a specific/finite temperature in a salt-free sample as provided by Klunder in view of Davalieva with reasonable expectation of success. MPEP 2143(I)(E).
Regarding claim 8, modified Dale teaches a first temperature range (Dale, at Zone 1, Fig. 4) from 85°C to 100°C (the temperature of the first heating plate is controlled in the range of 90 °C to 100 °C) and a second temperature range (Dale, at Zone 2, Fig. 4) from 20°C to 70°C (the second heating plate is controlled in the range of 55 °C to 65 °C) (Dale, par. 0049).
Modified Dale is silent to the temperature of the first heating plate is controlled in the range of 90 °C to 100 °C and the temperature of the second heating plate is controlled in the range of 55 °C to 65 °C for a salt-containing sample.
Klunder teaches a temperature range of 85°C to 100°C of the first denaturation zone and a temperature range of 60°C to 75°C in the second elongation zone (Klunder, Fig. 1; par. 0014). Klunder teaches each temperature zone is unique and set based on the amplification and detection of specific nucleic acid sequences and enzymes used (Klunder, par. 0005). Klunder additionally teaches salts may or may not be present in the reaction solution and can therefore impact the rate and efficiency the reaction (Klunder, par. 0192, 0209). Davalieva teaches salt is a known inhibitor in PCR (Davalieva, pg. 58, col. 1, par. 01). Davalieva teaches at increasing ion concentrations decreases the performance of different thermostable DNA polymerase enzymes (Davalieva, Table 3). Therefore, the enzymes with increased thermostability perform better in the presence of salt ions as compared to less thermostable enzymes for PCR processes (Davalieva, pg. 61, “Conclusion” section).
Further, Klunder teaches wherein the thermal zones and constituents of the reaction solution are result effective variables. Specifically, Klunder teaches the temperature of the thermal zones directly impacts the reaction activity of the sample/solution in the microchannel and therefore directly impacts the thermocyclic reaction occurring within the microchannel. Davalieva teaches salt-containing solutions perform less efficiently as compared to salt-free sample and show improved performance with more thermostable enzymes. Since this particular parameter is recognized as result-effective variable, i.e., a variable which achieves a recognized result, the determination of the optimum or workable ranges of said variable can be characterized as routine experimentation. MPEP § 2144.05(II)(A)-(B). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to modify the temperature of the first heating plate is controlled in the range of 90 °C to 100 °C and the temperature of the second heating plate is controlled in the range of 55 °C to 65 °C for a salt-containing sample with a reasonable expectation of success of creating a temperature range to allow for a reaction to completely occur.
It would have been obvious to one skilled in the art before the effective filing date of the invention to try a narrower range or specific temperature as taught by Klunder out of the wider range as taught by Dale in order to perform the reaction based on specific nucleic acid targets and enzymes used in the absence of salt. Further, because salt is present, using the better performing more thermostable enzymes increased performance as taught by Davalieva. Because both microfluidic devices use cycling through distinct temperature zones to, it would have been obvious to try a narrower range of temperatures, or a specific/finite temperature in a salt-containing sample as provided by Klunder in view of Davalieva with reasonable expectation of success. MPEP 2143(1)(E).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Gobyadinov (US 20210322974 A1) a microfluidic device comprising a series of serpentine-like loops with designated heating regions (Abstract).
Lahoud, et. al. (US 20220002823 A1) teaches a PCR detection device (Abstract) with a serpentine heating arrangement wherein a sample alternately passes through different temperature regions (Fig. 31).
Trauba (US 20200055049 A1) teaches a PCR device comprising a heating assembly with different zones so that a reaction mixture is continuously passing through the different heating zones.
Samuel, et. al. (US 20180093273 A1) teaches a microfluidic device comprising a serpentine pathway that passes through a plurality of temperature zones (Abstract).
Nootchanat, Supeera, et. al. (Fabrication of Miniature Surface Plasmon Resonance Sensor Chips by Using Confined Sessile Drop Technique) teaches a method of integrating a surface plasmon resonance sensor chip onto a microfluidic device (Abstract).
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/M.T.H./Examiner, Art Unit 1758
/HENRY H NGUYEN/Primary Examiner, Art Unit 1758
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