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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 19, 2026 has been entered.
Status of Claims
Claims 15-20 were pending and examined herein.
Claim Objections
Claim 15 is objected to because of the following informalities:
Claim 15 recites “dissociating disassociating the cleavable tag or aptamer a portion of the second binding member” (last par.), which is a combination of deletions and insertions made on June 10, 2025 - “dissociating the cleavable tag or aptamer .
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Morin (PGPub 2014/0378331) in view of Shen et al. (US 8,637,242), Sivagnanam et al. (Anal Chem. 2009 Aug 1;81(15):6509-15), and Caulum et al. (Anal Chem. 2007 Jul 15;79(14):5249-56), for reasons of record which are reiterated herein below.
Regarding claim 15, Morin teaches a microfluidics nanopore device comprising a nanopore module and at least one nanopore, (i.e., device comprises an upper chamber, a middle chamber, and a lower chamber (i.e., microfluidics modules), wherein the upper chamber is in communication with the middle chamber through a first pore, and the middle chamber is in communication with the lower chamber through a second pore ([0015])).
Fig. 5 shows the upper (Chamber A) and lower chambers (Chamber C) as equivalents for the first and second capillary channels of the instant disclosure, where they intersect at an intersecting region (region between Chambers A and C), and a nanopore (511 or 512) disposed in a nanopore layer (layer between membranes (501) and (502)) disposed between the first and second capillary channels proximate the intersection region (between Chambers A and C), wherein at least the first capillary channel (Chambers A ) is positioned to receive the fluid droplet. Because of their small sizes (see Fig. 5 for comparison to the pore size of 1-100 nm), chambers A and C qualify as capillaries channels.
Additionally, Morin teaches the first transfer position is proximate an interface between the microfluidics module and the nanopore module. Specifically, Morin teaches that a sample is loaded into the upper chamber (Chamber A, Fig. 5) – this position is proximate an interface between the nanopore module and the microfluidics module taught below by Shen.
It is noted that the additional claimed limitation, “wherein at least one of contacting a sample with a first binding member, contacting an analyte with a second binding member, removing second binding member not bound to the analyte bound to the first binding member, and dissociating the cleavable tag or aptamer of the second binding member thereof in the gap between the first and second substrates”, is directed how the system is used or performs. This limitation is interpreted as an intended use for the claimed system and does not further define a new structural limitation in claim 15.
Morin does not teach a microfluidics module comprising an array of electrodes, specific-binding members immobilized on a solid support, the second specific-binding member comprises a cleavable tag or aptamer, and the analyte selected from the group consisting of a protein, a lipid, and a carbohydrate.
Regarding claim 15, Shen teaches apparatuses for performing sequencing using droplet manipulation and performing sample preparation (Abstract).
Shen also teaches a microfluidic module that performs droplet operations comprising a substrate surface with an array of electrowetting electrode control pads wherein a droplet dispensed onto the substrate surface moves along a desired path to the defined one or more channels by the control pad (col. 2, lines 30-39 and col. 8, lines 11-22).
Additionally, Shen teaches a sequencing module comprising the first substrate (a substrate layer, Fig. 1), the second substrate (top of flowcell chamber, Fig. 1), an array of electrodes (in the top of flowcell chamber, Fig. 1). The first substrate and the second substrate are separated by a gap (liquid flow label, Fig. 1).
Shen teaches the microfluidics module includes droplet-based mixers to facilitate the movement of droplets electrically using electrodes to independently control each droplet.
Finally, Shen teaches “the hydrophilic patch comprises one or more primers. Optionally, the nucleic acid molecules are immobilized by hybridizing to the one or more primers” (Col. 8, lines 22-25). As such, the system of the prior art could be used as intended to performs at least contacting a sample with a first binding member.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the system of Morin by employing the microfluidics module as taught by Shen, in order to provide a system with integrated sample preparation (Shen, Col. 4, lines 2-3), as an obvious matter of combining prior art elements according to known methods (both modules are microfluidic in nature) to yield predictable results. The combined system would comprise the microfluidics and the nanopore modules, which would perform the same functions as they do separately: sample manipulation and sample analysis.
Morin and Shen do not teach specific-binding members immobilized on a solid support, the second specific-binding member comprises a cleavable tag or aptamer, and the analyte selected from the group consisting of a protein, a lipid, and a carbohydrate.
Regarding claim 15, Sivagnanam teaches a microfluidic system for on-chip immunoassay (pg. 6510, col. 2, par. 3). Sivagnanam also teaches a first specific-binding member that is immobilized on a solid support and specifically binds to an analyte, and a second specific-binding member that specifically binds to the analyte, wherein the analyte is selected from the group consisting of a protein, a lipid, and a carbohydrate.
Specifically, the reference teaches a sandwich immunoassay using the first specific-binding member immobilized on a solid support - biotin-labeled capture antibody immobilized on streptavidin-coated beads and the second specific-binding member that specifically binds to the analyte - Cy3-labeled detection antibody (Fig. 3). Additionally, the reference teaches mouse IgG as target antigen (Abstract). IgG is a protein. The streptavidin-coated beads meet the definition of the solid support as disclosed in [00178] (an exterior surface of a bead).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the system of Morin and Shen by employing the first and second analyte-specific binding members as taught by Sivagnanam, in order to provide a system for performing immunoassays, as an obvious matter of using of known technique (immunoassay of Sivagnanam) to improve similar devices (microfluidic system of Morin and Shen) in the same way.
Morin, Shen, and Sivagnanam do not teach the second specific-binding member comprises a cleavable tag or aptamer.
Caulum teaches “Detection of cardiac biomarkers using micellar electrokinetic chromatography and a cleavable tag immunoassay” (Title). Caulum also teaches a cleavable tag immunoassay with the second specific-binding member comprising a cleavable tag.
Specifically, Caulum teaches a multianalyte system for disease detection using cleavable immunoassay tags comprising a traditional immunoassay for analyte molecule and a separate from the immunoassay micellar electrokinetic chromatography detection system (Introduction and Fig. 2). The immunoassay system of Caulum has the first specific-binding member immobilized on a solid support specifically binding to an analyte of claim 15 and the micellar electrokinetic chromatography detection system is the nanopore module with its detection circuit.
Additionally, Caulum teaches a fluorescent tag (CTI tag) comprising a disulfide bond cleavable by a reducing agent (TCEP). The CTI tag also comprises a biotin moiety for strong binding to avidin (pg. 5251, col. 1, last par. and Fig. 1). The second specific-binding member is biotinylated and mixed with avidin (pg. 5251, col. 2, last par.). In the course of the assay the CTI tags bind to three remaining binding sites available on the avidin (id.).
During the assay capture beads with immobilized first specific-binding member are mixed with an analyte, the beads are washed, and then mixed with the second specific-binding member (fluorescently-labeled antibody). The disulfide bond is reduced by TCEP and the cleavable tags are removed for analysis by the detection system (pg. 5253, col. 1, par. 2).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the system of Morin, Shen, and Sivagnanam with the second specific-binding member comprising a cleavable tag as taught by Caulum, in order to provide a system with multianalyte immunoassay detection (pg. 5250, col. 2, par. 3). One having ordinary skill in the art would have been motivated to use the cleavable tag of Caulum to provide multianalyte detection in immunoassays, because traditional immunoassays can only detect a few proteins from one sample (pg. 5250, col. 1, par. 2). This combination would have been desirable to those of ordinary skill in the art because multianalyte detection increases assay throughput.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Morin, Shen, and Sivagnanam and Caulum are similarly drawn to immunoassay format, and Caulum has demonstrated that the fluorescent cleavable tags are compatible with immunoassays and TCEP reducing agent.
Regarding claim 16 interpretation, refer to par. [0027] of the instant spec in regards to the nanopore module comprising a first microchannel and a second microchannel, positioned in a first and second substrate (i.e., layers of substrates) of the nanopore. Wherein the nanopore layer is positioned in between the first and second substrates at the location where the first and the second capillary channels intersect.
Regarding claim 17, Morin in view of Shen teaches that the microfluidics pump can be configured to push liquids to the detector (the nanopore of Morin), as well as can be configured to pull liquids away from the detector (Shen, Fig. 6B and Col. 20, lines 52-56). An array of control pads (17) corresponds to a pair of electrodes recited in claim 17. It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to utilize either one of these configurations or both configurations together.
Regarding claim 18, Morin in view of Shen teaches that the microfluidics module connected to the nanopore module (a sequencing apparatus of Shen) connects to waste reservoir (13) (Shen, Col. 20, lines 33-35), meeting the limitation of claim 18 reciting a reservoir proximate one or both ends of the second capillary channel.
Regarding claim 18 interpretation, refer to par. [0030] of the instant spec in regards to the function of the first reservoir and/or the second reservoir. “In certain embodiments, the first reservoir and/or the second reservoir comprises a fluid to be positioned across from the first capillary channel at the intersection which fluid facilitates operation of the nanopore layer to drive current through a nanopore of the nanopore layer.”
Regarding claim 19, Morin teaches electrodes (523) and (521) configured to drive current (I1 and I2, Fig, 5) through the nanopore, where Chambers A and C correspond to the first and second reservoirs respectively.
Regarding claim 20, Applicant fails to describe specific functional benefits of the second capillary channel having two reservoirs. Since Applicant has not disclosed that the specific limitations of the first reservoir and the second reservoir recited in instant claim 20 are for any particular purpose or solve any stated problem and the prior art teaches that one reservoir is sufficient for functionality of a microfluidics-based system (Shen, waste reservoir (13) (Col. 20, lines 33-35), it would have been obvious for one of ordinary skill to operate the microfluidics-based nanopore system of Morin and Shen with one reservoir with a reasonable expectation of success. First, one reservoir is sufficient for collecting assayed fluid droplets. Second, two reservoirs are not required to facilitate operation of the nanopore layer to drive current through the nanopore disposed in the nanopore layer, because the nanopore design illustrated in Fig. 5 (Morin) is already capable of facilitating such operation.
Double patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 15-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 11,022,598 in view of Sivagnanam et al. (Anal Chem. 2009 Aug 1;81(15):6509-15) and Caulum et al. (Anal Chem. 2007 Jul 15;79(14):5249-56), for reasons of record which are reiterated herein below.
Claim 1 of ‘598 recites an integrated digital microfluidics nanopore device comprising: a microfluidics module comprising a first substrate having an array of electrodes disposed in a grid pattern to generate electrical actuation forces on a liquid droplet disposed thereon; and a nanopore module in fluid communication with the microfluidics module and comprising at least one nanopore, wherein the microfluidics module is configured to introduce a liquid droplet to the at least one nanopore.
Claim 4 of ‘598 recites the microfluidics module comprises: a second substrate spaced apart from the first substrate.
With respect to instant claim 15, it is noted that the additional claimed limitation, “wherein at least one of contacting a sample with a first binding member, contacting an analyte with a second binding member, removing second binding member not bound to the analyte bound to the first binding member, and dissociating the cleavable tag or aptamer of the second binding member thereof in the gap between the first and second substrates”, is directed to a sample droplet that is used in the device. This limitation is interpreted under MPEP 2115 and does not further define a new structural limitation in claim 15.
‘598 does not teach specific-binding members immobilized on a solid support, the second specific-binding member comprises a cleavable tag or aptamer, and the analyte selected from the group consisting of a protein, a lipid, and a carbohydrate.
Regarding claim 15, Sivagnanam teaches a microfluidic system for on-chip immunoassay (pg. 6510, col. 2, par. 3). Sivagnanam also teaches first specific-binding member that is immobilized on a solid support and specifically binds to an analyte, and a second specific-binding member that specifically binds to the analyte, wherein the analyte is selected from the group consisting of a protein, a lipid, and a carbohydrate.
Specifically, the reference teaches a sandwich format immunoassay using the first specific-binding member immobilized on a solid support - biotin-labeled capture antibody immobilized on streptavidin-coated beads and the second specific-binding member that specifically binds to the analyte - Cy3-labeled detection antibody (Fig. 3). Additionally, the reference teaches detection of mouse IgG as target antigen (Abstract). IgG is a protein. The streptavidin-coated beads meet the definition of the solid support as disclosed in [00178] (an exterior surface of a bead).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the system of ‘598 by employing the first and second analyte-specific binding members as taught by Sivagnanam, in order to provide a system for performing immunoassays, as an obvious matter of using of known technique (immunoassay of Sivagnanam) to improve similar devices (microfluidic system of Morin and Shen) in the same way.
Sivagnanam do not teach the second specific-binding member comprises a cleavable tag or aptamer.
Caulum teaches “Detection of cardiac biomarkers using micellar electrokinetic chromatography and a cleavable tag immunoassay” (Title). Caulum also teaches a cleavable tag immunoassay with the second specific-binding member comprising a cleavable tag.
Specifically, Caulum teaches a multianalyte system for disease detection using cleavable immunoassay tags comprising a traditional immunoassay for analyte molecule and a separate from the immunoassay micellar electrokinetic chromatography detection system (Introduction and Fig. 2). The immunoassay system of Caulum is the first specific-binding member that is immobilized on a solid support and specifically binds to an analyte of claim 15 and the micellar electrokinetic chromatography detection system is the nanopore module with a detection circuit.
Additionally, Caulum teaches a fluorescent tag (CTI tag) comprising a disulfide bond cleavable by a reducing agent (TCEP). The CTI tag also comprises a biotin moiety for strong binding to avidin (pg. 5251, col. 1, last par. and Fig. 1). The second specific-binding member is biotinylated and allowed to bind to avidin (pg. 5251, col. 2, last par.). In the course of the assay the CTI tags bind to three remaining binding sites available on the avidin (id.).
In the course of the assay capture beads with immobilized first specific-binding member are mixed with an analyte, the beads are washed, and then mixed with the second specific-binding member (fluorescently-labeled antibody). The disulfide bond is reduced by TCEP and the cleavable tags are removed for analysis by the detection system (pg. 5253, col. 1, par. 2).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the system of ‘598 and Sivagnanam with the second specific-binding member comprising a cleavable tag as taught by Caulum, in order to provide a system with multianalyte immunoassay detection (pg. 5250, col. 2, par. 3). One having ordinary skill in the art would have been motivated to use the cleavable tag of Caulum to provide multianalyte detection in immunoassays, because traditional immunoassays can only detect a few proteins from one sample (pg. 5250, col. 1, par. 2). This combination would have been desirable to those of ordinary skill in the art because multianalyte detection increases assay throughput.
Claims 15-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11 of U.S. Patent No. 11,016,053 in view of Sivagnanam et al. (Anal Chem. 2009 Aug 1;81(15):6509-15), for reasons of record which are reiterated herein below.
Claim 1 of ‘053 recites a multi-functional cartridge comprising: a microfluidics module fluidically connected to a nano pore module via an interface comprising a first transfer position and a second transfer position, wherein: the microfluidic module comprises: a first substrate; a second substrate; a gap separating the first substrate from the second substrate; a plurality of electrodes that generate electrical actuation forces on a liquid droplet comprising a tag or an analyte-specific binding member, wherein the plurality of electrodes in the microfluidics module transports a first fluid droplet to the first transfer position and a second fluid droplet to the second transfer position; and the nanopore module comprising: an electrical detection region comprising: a nanopore layer comprising a nanopore.
With respect to instant claim 15, it is noted that the additional claimed limitation, “wherein at least one of contacting a sample with a first binding member, contacting an analyte with a second binding member, removing second binding member not bound to the analyte bound to the first binding member, and dissociating the cleavable tag or aptamer of the second binding member thereof in the gap between the first and second substrates”, is directed to a sample droplet that is used in the device. This limitation is interpreted under MPEP 2115 and does not further define a new structural limitation in claim 15.
Claim 11 of ‘053 recites a the plurality of electrodes in the microfluidics module transports a first fluid droplet to the first transfer position, a microfluidics module fluidically connected to a nanopore module via an interface comprising a first transfer position and a second transfer position, a first capillary channel that intersects with a second capillary channel, wherein the nanopore layer is positioned where the first and the second capillary channels intersect, wherein the first capillary channel extends to the interface and is adjacent to the first transfer position to receive the first fluid droplet.
‘053 does not teach specific-binding members immobilized on a solid support, the second specific-binding member comprises a cleavable tag or aptamer, and the analyte selected from the group consisting of a protein, a lipid, and a carbohydrate.
Regarding claim 15, Sivagnanam teaches a microfluidic system for on-chip immunoassay (pg. 6510, col. 2, par. 3). Sivagnanam also teaches first specific-binding member that is immobilized on a solid support and specifically binds to an analyte, and a second specific-binding member that specifically binds to the analyte, wherein the analyte is selected from the group consisting of a protein, a lipid, and a carbohydrate.
Specifically, the reference teaches a sandwich format immunoassay using the first specific-binding member immobilized on a solid support - biotin-labeled capture antibody immobilized on streptavidin-coated beads and the second specific-binding member that specifically binds to the analyte - Cy3-labeled detection antibody (Fig. 3). Additionally, the reference teaches detection of mouse IgG as target antigen (Abstract). IgG is a protein. The streptavidin-coated beads meet the definition of the solid support as disclosed in [00178] (an exterior surface of a bead).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the system of ‘053 by employing the first and second analyte-specific binding members as taught by Sivagnanam, in order to provide a system for performing immunoassays, as an obvious matter of using of known technique (immunoassay of Sivagnanam) to improve similar devices (microfluidic system of Morin and Shen) in the same way.
Sivagnanam do not teach the second specific-binding member comprises a cleavable tag or aptamer.
Caulum teaches “Detection of cardiac biomarkers using micellar electrokinetic chromatography and a cleavable tag immunoassay” (Title). Caulum also teaches a cleavable tag immunoassay with the second specific-binding member comprising a cleavable tag.
Specifically, Caulum teaches a multianalyte system for disease detection using cleavable immunoassay tags comprising a traditional immunoassay for analyte molecule and a separate from the immunoassay micellar electrokinetic chromatography detection system (Introduction and Fig. 2). The immunoassay system of Caulum is the first specific-binding member that is immobilized on a solid support and specifically binds to an analyte of claim 15 and the micellar electrokinetic chromatography detection system is the nanopore module with a detection circuit.
Additionally, Caulum teaches a fluorescent tag (CTI tag) comprising a disulfide bond cleavable by a reducing agent (TCEP). The CTI tag also comprises a biotin moiety for strong binding to avidin (pg. 5251, col. 1, last par. and Fig. 1). The second specific-binding member is biotinylated and allowed to bind to avidin (pg. 5251, col. 2, last par.). In the course of the assay the CTI tags bind to three remaining binding sites available on the avidin (id.).
In the course of the assay capture beads with immobilized first specific-binding member are mixed with an analyte, the beads are washed, and then mixed with the second specific-binding member (fluorescently-labeled antibody). The disulfide bond is reduced by TCEP and the cleavable tags are removed for analysis by the detection system (pg. 5253, col. 1, par. 2).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the system of ‘053 and Sivagnanam with the second specific-binding member comprising a cleavable tag as taught by Caulum, in order to provide a system with multianalyte immunoassay detection (pg. 5250, col. 2, par. 3). One having ordinary skill in the art would have been motivated to use the cleavable tag of Caulum to provide multianalyte detection in immunoassays, because traditional immunoassays can only detect a few proteins from one sample (pg. 5250, col. 1, par. 2). This combination would have been desirable to those of ordinary skill in the art because multianalyte detection increases assay throughput.
Claims 15-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 17 of copending Application No. 17/540,974 in view of in view of Sivagnanam et al. (Anal Chem. 2009 Aug 1;81(15):6509-15), for reasons of record which are reiterated herein below.
Claim 1 of ‘974 reciting a digital microfluidic device, comprising: a first substrate and a second substrate aligned generally parallel to each other with a gap defined there between inside view, at least one of the first substrate and the second substrate including: a first electrode array, a second electrode array spaced from and in electrical communication with the first electrode array, and a first interstitial area defined between the first electrode array and the second electrode array, at least one of the first electrode array and the second electrode array configured to generate electrical actuation forces within an actuation area to urge at least one droplet within the gap along the at least one of the first substrate and second substrate; and at least one spacer disposed in the first interstitial area to maintain the gap between the first substrate and the second substrate.
Claim 17 of ‘974 reciting at least one of the first substrate and the second substrate comprises at least one of an array of wells and a nanopore layer formed therein.
With respect to instant claim 15, it is noted that the additional claimed limitation, “wherein at least one of contacting a sample with a first binding member, contacting an analyte with a second binding member, removing second binding member not bound to the analyte bound to the first binding member, and dissociating the cleavable tag or aptamer of the second binding member thereof in the gap between the first and second substrates”, is directed to a sample droplet that is used in the device. This limitation is interpreted under MPEP 2115 and does not further define a new structural limitation in claim 15.
‘974 does not teach specific-binding members immobilized on a solid support, the second specific-binding member comprises a cleavable tag or aptamer, and the analyte selected from the group consisting of a protein, a lipid, and a carbohydrate.
Regarding claim 15, Sivagnanam teaches a microfluidic system for on-chip immunoassay (pg. 6510, col. 2, par. 3). Sivagnanam also teaches first specific-binding member that is immobilized on a solid support and specifically binds to an analyte, and a second specific-binding member that specifically binds to the analyte, wherein the analyte is selected from the group consisting of a protein, a lipid, and a carbohydrate.
Specifically, the reference teaches a sandwich format immunoassay using the first specific-binding member immobilized on a solid support - biotin-labeled capture antibody immobilized on streptavidin-coated beads and the second specific-binding member that specifically binds to the analyte - Cy3-labeled detection antibody (Fig. 3). Additionally, the reference teaches detection of mouse IgG as target antigen (Abstract). IgG is a protein. The streptavidin-coated beads meet the definition of the solid support as disclosed in [00178] (an exterior surface of a bead).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the system of ‘974 by employing the first and second analyte-specific binding members as taught by Sivagnanam, in order to provide a system for performing immunoassays, as an obvious matter of using of known technique (immunoassay of Sivagnanam) to improve similar devices (microfluidic system of Morin and Shen) in the same way.
Sivagnanam do not teach the second specific-binding member comprises a cleavable tag or aptamer.
Caulum teaches “Detection of cardiac biomarkers using micellar electrokinetic chromatography and a cleavable tag immunoassay” (Title). Caulum also teaches a cleavable tag immunoassay with the second specific-binding member comprising a cleavable tag.
Specifically, Caulum teaches a multianalyte system for disease detection using cleavable immunoassay tags comprising a traditional immunoassay for analyte molecule and a separate from the immunoassay micellar electrokinetic chromatography detection system (Introduction and Fig. 2). The immunoassay system of Caulum is the first specific-binding member that is immobilized on a solid support and specifically binds to an analyte of claim 15 and the micellar electrokinetic chromatography detection system is the nanopore module with a detection circuit.
Additionally, Caulum teaches a fluorescent tag (CTI tag) comprising a disulfide bond cleavable by a reducing agent (TCEP). The CTI tag also comprises a biotin moiety for strong binding to avidin (pg. 5251, col. 1, last par. and Fig. 1). The second specific-binding member is biotinylated and allowed to bind to avidin (pg. 5251, col. 2, last par.). In the course of the assay the CTI tags bind to three remaining binding sites available on the avidin (id.).
In the course of the assay capture beads with immobilized first specific-binding member are mixed with an analyte, the beads are washed, and then mixed with the second specific-binding member (fluorescently-labeled antibody). The disulfide bond is reduced by TCEP and the cleavable tags are removed for analysis by the detection system (pg. 5253, col. 1, par. 2).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the system of ‘974 and Sivagnanam with the second specific-binding member comprising a cleavable tag as taught by Caulum, in order to provide a system with multianalyte immunoassay detection (pg. 5250, col. 2, par. 3). One having ordinary skill in the art would have been motivated to use the cleavable tag of Caulum to provide multianalyte detection in immunoassays, because traditional immunoassays can only detect a few proteins from one sample (pg. 5250, col. 1, par. 2). This combination would have been desirable to those of ordinary skill in the art because multianalyte detection increases assay throughput.
Response to Arguments
Applicant's arguments filed February 19, 2026 have been fully considered.
Applicant argues that “There must be a reason or guidance in the prior art as to why one of ordinary skill in the art would start with a particular prior art teaching and modify it to arrive at the claimed invention” (pg. 7, par. 3). The argument is unclear because Applicant fails to point out specific problems with the prior art teachings and cite a proper section from MPEP. Citing case law references without providing specific explanations is not a proper way for presenting arguments. The argument is not persuasive.
Applicant is reminded, that the primary reference of Morin teaches relevant art of a microfluidics nanopore device. Specifically, Morin teaches a microfluidics nanopore device comprising a nanopore module and at least one nanopore, (i.e., device comprises an upper chamber, a middle chamber, and a lower chamber (i.e., microfluidics modules), wherein the upper chamber is in communication with the middle chamber through a first pore, and the middle chamber is in communication with the lower chamber through a second pore ([0015])).
Applicant argues that “the skilled artisan would not combine the cleavage tag of Caulum with the nanopore of Morin at least because the cleavable tag would not be detectable through the nanopore” (pg. 7, par. 4). Applicant further adds that Caulum teaches fluorescein-based tag (pg. 8, par. 1) and according to Example 22 of the specification small molecules go through nanopores too fast for detection (pg. 8, par. 2).
The argument is not persuasive because Applicant is arguing limitations which are not claimed. In response to applicant’s argument that the references fail to show certain features of the invention, it is noted that the claim doesn’t include any structural configurations about particular sized molecules going through the nanopore and the size of the labeled molecule is not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Additionally, the reasons for not combining the cleavage tag of Caulum with the nanopore of Morin must be argued in view of the presented prior art, but not in view of the specification. Applicant fails to identify the corresponding teach away information in the prior art references. It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the system of Morin, Shen, and Sivagnanam with the second specific-binding member comprising a cleavable tag as taught by Caulum, in order to provide a system with multianalyte immunoassay detection (pg. 5250, col. 2, par. 3). One having ordinary skill in the art would have been motivated to use the cleavable tag of Caulum to provide multianalyte detection in immunoassays, because traditional immunoassays can only detect a few proteins from one sample (pg. 5250, col. 1, par. 2). One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Morin, Shen, and Sivagnanam and Caulum are similarly drawn to immunoassay format, and Caulum has demonstrated that the fluorescent cleavable tags are compatible with immunoassays and TCEP reducing agent.
Finally, the small size of the label taught by Caulum was not used in the rejection. Caulum was cited of its teaching of a cleavable nature of the tag - “Detection of cardiac biomarkers using micellar electrokinetic chromatography and a cleavable tag immunoassay” (Title).
Applicant’s arguments against nonstatutory obviousness-type double patenting rejections (pg. 9-10) rely on the same small molecule argument addressed above. Therefore, the arguments are not persuasive. The rejections of claims 15-20 under 35 U.S.C. § 103 and nonstatutory obviousness-type double patenting rejections stay.
Conclusion
All claims are identical to, patentably indistinct from, or have unity of invention with the claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/ALEXANDER ALEXANDROVIC VOLKOV/Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677