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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/29/2022 has been considered by the examiner.
Claim Objections
Claims 1 and 3-9 are objected to because of the following informalities:
Claim 1, line 1-2: please amend “of clozapine in a whole blood sample or plasma sample” to – of clozapine in a sample comprising a whole blood sample or a plasma sample —.
Claim 1, line 18-19: please amend “applying varied voltage, fixed voltage, current or impedance” to – applying a varied voltage, a fixed voltage, a current or an impedance —.
Claim 1, line 19: please amend “the working microelectrodes” to –the array of working microelectrodes—for purposes of consistency.
Claim 1, line 21-22: please amend “or the potential” to – or measuring the potential —.
Claim 1, line 23-24: please amend “consisting of plurality of electrochemical signals” to – consisting of a plurality of electrochemical signals —.
Claim 1, line 25-26: please amend “optionally preprocessing the raw data electrochemical signals” to – optionally preprocessing the raw data set
Claim 3, line 1: please amend “A method” to --[[A]]The method --.
Claim 4, line 1: please amend “A method” to --[[A]]The method --.
Claim 4, line 1: please amend “the chip” to “the lab-on-a-chip” for purposes of consistency with claim 3.
Claim 4, line 5: please amend “a microstructure consists of” to—a microstructure of the discrete microstructures consists of—for purposes of consistency.
Claim 4, line 6: please amend “each microstructure” to each microstructure of the discrete microstructures-- for purposes of consistency.
Claim 5, line 1: please amend “A method” to --[[A]]The method --.
Claim 6, line 1: please amend “A method” to --[[A]]The method --.
Claim 7, line 1: please amend “A method” to --[[A]]The method --.
Claim 8, line 1: please amend “A method” to --[[A]]The method --.
Claim 8, line 1: please amend “raw data” to –raw data set—.
Claim 9, line 1: please amend “A method” to --[[A]]The method --.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, claim 1 recites the limitation "the working electrodes" in line 21. There is insufficient antecedent basis for this limitation in the claim. Additionally, line 21 reads “the working electrodes and a counter electrode. It is unclear if the working electrodes are the same as the previously recited working microelectrodes or is a newly recited, additional element. Furthermore, it is unclear if “a counter electrode” is a newly recited, additional counter electrode or the same as the previously recited counter electrode of line 16. Applicant should clarify the relationship between the working electrodes, array of working microelectrodes, and the two recited counter electrodes. Therefore, the scope of claim 1 is indefinite. Claims 2-9 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 1.
Regarding claim 1, claim 1 recites the limitation "the potential" in line 22. There is insufficient antecedent basis for this limitation in the claim. Therefore, the scope of claim 1 is indefinite. Claims 2-9 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 1.
Regarding claim 1, claim 1 recites the limitation "a reference electrode" in line 23. It is unclear if “a reference electrode” is the same as the previously recited reference microelectrode(s) of lines 16-17 or is a newly recited, additional element [e.g., exteneral to the microsensor]. Therefore, the scope of claim 1 is indefinite. Claims 2-9 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 1.
Regarding claim 1, claim 1 recites the limitation "the current flowing or the impedance" in lines 20-21. However, it is unclear if it is the same current and impedance as previously recited in lines 18-19, because an electrochemical method would not, for example, apply impedance and then measure the impedance [the applied variable and the measured variable should be different]. It’s unclear if the applied impedance and current is the same as measuring the current or the impedance, since the claim limitation the impedance and the current gives antecedent basis back to the applied current and impedance. Therefore, the scope of claim 1 is indefinite. Claims 2-9 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 1.
Regarding claim 1, claim 1 recites the limitation "or raw data" in the last two lines of the claim. However, it is unclear which raw data is referred to, if it is the raw data set or the raw data electrochemical signals that were previously recited, or a new and different raw data that is currently recited. Applicant should clarify the claim language. Therefore, the scope of claim 1 is indefinite. Claims 2-9 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 1.
Regarding claim 2, claim 2 recites the limitation “according to claim 2”. It is unclear if claim 2 should depend on claim 1, or is an independent claim, as it cannot depend on itself. Therefore, the scope of claim 2 is indefinite. For purposes of examination, the claim is interpreted to depend on claim 1. The examiner notes if applicant amends the claim to depend on claim 1, the claim should recite “The method according to claim 1”.
Regarding claim 2, claim 2 recites “one or more bare microelectrodes”, “one or more polysaccharide coated microelectrodes”, “one or more platinum-black microelectrodes”, “one or more polysaccharide-coated microelectrodes with conductive additives incorporated into the coating” and “one or more reduced graphene oxide-coated microelectrodes”. It is unclear if these microelectrodes are the same microelectrodes as recited in claim 1 [lines 6-14] or are new, additional electrodes that are in addition to the claimed microelectrodes of claim 1. Therefore, the scope of claim 2 is indefinite. For the purposes of examination, claim 2 is interpreted to be at least any of the previously mentioned options.
Regarding claim 3, claim 3 recites the limitation “the electrochemical microsensor according is in the form”. However, it is unclear what is being referred to, the electrochemical microsensor according to what? Therefore, the scope of claim 3 is indefinite. Claims 4-6 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 3.
Regarding claim 4, claim 4 recites “has a recessed region on its surface, defined by a wall” in lines 2-3. However, it is unclear if the surface of the chip or the surface of the substrate is being referred to, and if the chip or the substrate or the recessed region is defined by a wall. Applicant should clarify the claim language. Therefore, the scope of claim 4 is indefinite. Claims 5-6 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 4.
Regarding claim 4, claim 4 recites “a liquid sample”. However, it is unclear if the liquid sample refers to the whole blood sample or plasma sample of claim 1, or is a newly recited element. Therefore, the scope of claim 4 is indefinite. Claims 5-6 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 4.
Regarding claim 4, claim 4 recites “a microelectrode” in line 7. However, it is unclear if “a microelectrode” is the same as the array of working microelectrodes and/or the one or more reference microelectrodes of claim 1, or if these microelectrodes are a different and newly recited structure. Therefore, the scope of claim 4 is indefinite. Claims 5-6 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 4.
Regarding claim 4, claim 4 recites “each microstructure is encircled by a wall” in lines 6-7. It is unclear if the microstructure which is encircled by a wall is the same wall or a new different wall from the wall recited in line 2 of claim 4. Applicant should clarify the claim language. Therefore, the scope of claim 4 is indefinite. Claims 5-6 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 4.
Regarding claim 7, claim 7 recites the limitation "the electrochemical signal" in line 2. There is insufficient antecedent basis for this limitation in the claim. Furthermore, it is unclear if the electrochemical signal is the same as or part of the “the plurality of the electrochemical signals” as recited in claim 1, or is a newly recited feature. Therefore, the scope of claim 7 is indefinite. Claim 8 is further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 7.
Regarding claim 7, claim 7 recites the limitation "applying variable voltage and measuring current". It is unclear if the “variable voltage” is the same as the “varied voltage” of claim 1 and if “measuring current” is the same as “measuring the current flowing”. Applicant should clarify the relationship between all of these terms. Therefore, the scope of claim 7 is indefinite. Claim 8 is further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 7.
Regarding claim 8, claim 8 recites the limitation "the reduction" in line 2. There is insufficient antecedent basis for this limitation in the claim. Furthermore, it is unclear if the reduction refers to “reduced in dimensions” or if it includes “reduced in dimensions and normalized”. Therefore, the scope of claim 8 is indefinite.
Regarding claim 9, claim 9 recites “comprising applying one or more chemometric method(s) selected from partial least square regression or a trained artificial neural network model (ANN)”. It is unclear if “applying one or more chemometric method(s)” is the same as the “applying chemometric method(s)” of claim 1 or is a newly recited feature. Furthermore, it is unclear from the current language if these chemometric methods are used to process data as it only requires applying one or more of these chemometric method(s) without specifying a function or what these methods should be used for. Therefore, the scope of claim 9 is indefinite.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1 and 3-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ben-Yoav et al. (US20140332410A1) in view of Shukla et al. (A Chitosan–Carbon Nanotube-Modified Microelectrode for In Situ Detection of Blood Levels of the Antipsychotic Clozapine in a Finger-Pricked Sample Volume, 2019, Advanced Healthcare Materials, 8, Pages 1-14) and Ben-Yoav et al. (US20200138344A1), hereby referred to as Ben-Yoav II.
Regarding claim 1, a method of electrochemical detection of clozapine in a whole blood sample or plasma sample (Ben-Yoav teaches a method using an electrochemical lab-on-a-chip device for electrochemical detection of clozapine in a whole blood sample [see e.g., Abstract, Para. 0003, 0021, 0036 and Fig. 3A-C]), the method comprising:
bringing the sample into contact with an electrochemical microsensor comprising an array of working Ben-Yoav teaches introducing a whole blood sample into the electrochemical lab-on-a-chip device 1110 [corresponding to an electrochemical microsensor] comprising an array of working electrodes 1111 a 2, 1111 b 2, 1111 c 2 and 1211 a 2, 1211 b 2, 1211 c 2 and 1311 a 2, 1311 b 2, 1311 c 2 in multiple channels to enable concurrent measurements of multiple parameters [see e.g., Fig. 3A-C and Paras. 0075-0089]):
Ben-Yoav does not explicitly disclose an array of working microelectrodes.
Shukla discloses an electrochemical microsensor for clozapine detection in whole blood for point-of-care monitoring of schizophrenia [Abstract]. The electrochemical microsensor includes an array of working microelectrodes with six electroanalytical microchambers containing three microelectrodes; the center microelectrode was used as the working microelectrode for the in situ electrochemical detection of clozapine in microliters of whole blood [Abstract; Page 2, Col. 2, last paragraph; Page 11, Col. 2, last paragraph and Fig. 7].
Ben-Yoav and Shukla are considered analogous art to the claimed invention because they are in the same field of electrochemical sensors for point-of-care detection and monitoring of antipsychotics [Abstract and Paras. 0003-0005 of Ben-Yoav and Abstract of Shukla]. It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to change the size of the array of working electrodes of Ben-Yoav to be a microelectrode, as taught by Shukla, and thus an array of working microelectrodes, since Shukla teaches this suitable alternative size and configuration of the working microelectrode for the point-of-care electrochemical detection of clozapine [Abstract; Page 2, Col. 2, last paragraph; Page 11, Col. 2, last paragraph and Fig. 7 of Shukla]. Furthermore, the use of a known technique (i.e., an array of working microelectrodes, taught by Shukla) to improve similar methods in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143 [I][C]). Additionally, a change in size is generally recognized as being within the level of one of ordinary skill in the art absent evidence that the change in size results in a difference in performance. See In re Rose, 105 USPQ 237 (CCPA 1955) (see MPEP § 2144.04).
one or more bare microelectrodes (Ben-Yoav teaches at least one electrode set including a working electrode that presents a bare, unmodified surface [Para. 0006, 0011, 0047, 0049, claim 1 of Ben-Yoav] and Modified Ben-Yoav teaches the working electrodes are working microelectrodes [see rejection above]);
Modified Ben-Yoav does not explicitly disclose one or more thin film-coated microelectrodes selected from the group consisting of reduced graphene oxide-coated microelectrode and transition metal chalcogenide-coated microelectrodes;
However, Ben-Yoav discloses the nature of the working electrodes 1111 a 2, 1111 b 2, 1111 c 2 and 1211 a 2, 1211 b 2, 1211 c 2 and 1311 a 2, 1311 b 2, 1311 c 2 may be different from one another and such a testing configuration and protocol provides more accurate sensing performance when fouling of the electrochemical system occurs with human serum as the testing medium [Para. 0089]. Ben-Yoav teaches the electrochemical lab-on-a-chip device 1110 also includes multiple channels to enable concurrent measurements of multiple parameters where the additional channels may also be used to detect the presence of other types of analytes and biomarkers such as drugs, metabolites, vitamins, etc. [Para. 0075 and Fig. 3A-C]. Ben-Yoav further teaches a major challenge in the analysis of biological samples is the electrochemical reactivity and non-specific adsorption of molecules which cause fouling of the electrode. These molecules increase the background signal, decrease the signal-to-noise ratio, and deteriorate the sensitivity of the sensor [Para. 0100].
Ben-Yoav II teaches an electrochemical sensor comprising a counter electrode and an array of multiple working electrodes, preferably made as gold for use as a bare electrode and as the base electrode of the film-coated electrodes (Abstract, Para. 0024, Fig. 3). Ben-Yoav II further teaches an array of non-selective working electrodes that differ from each other by combining film-coated electrodes, bare electrodes and conductive additives-incorporated film coated electrodes, which is beneficial for analyzing samples containing more than one type of redox molecule [such as biofluids, blood “serum”] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information (Para. 0010, 0004, 0006, 0019, Fig. 3). Ben-Yoav II teaches one type of film-forming material can be reduced graphene oxide onto gold electrodes [Para. 0042] and that the thickness of the film coating is in the range of 0.2 μm to 0.3 μm or 0.3 μm to 0.4μm [Para. 0033, examiner notes 0.3 μm is equivalent to 300 nm], which is a thin film as evidenced by the instant specification which defines a thin film as 1 to 3000 nm [Page 4, lines 1-3 of the instant specification], and the film-coated electrode is beneficial for being selective towards detecting an analyte of interest in multicomponent mixtures (blood) relevant to monitoring antipsychotics (Para. 0010).
Modified Ben-Yoav and Ben-Yoav II are considered analogous art to the claimed invention because they are in the same field of electrochemical sensors for analysis of biofluids [Abstract of Ben-Yoav and Abstract of Ben-Yoav II]. Given the teachings of Ben-Yoav above regarding that the nature of the working electrodes may be different from one another and such a testing configuration and protocol provides more accurate sensing performance with human serum and a major challenge in the analysis of biological samples is the electrochemical reactivity and non-specific adsorption of molecules which increase the background signal, decrease the signal-to-noise ratio, and deteriorate the sensitivity of the sensor [see rejection above, Para. 0100, 0089 and 0075 of Ben-Yoav], it would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify one or more of the working microelectrodes in the array of Modified Ben-Yoav to include one or more thin-film coated, reduced graphene oxide film/coating on the microelectrode(s) as taught by Ben-Yoav II, since Ben-Yoav II teaches it would be beneficial to include an array of non-selective working electrodes that differ from each other by combining film-coated electrodes and bare electrodes for analyzing samples containing more than one type of redox molecule [such as biofluids, blood] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information and the film-coated electrode would be beneficial for being selective towards detecting an analyte of interest in multicomponent mixtures (blood) relevant to monitoring antipsychotics (Para. 0010, 0004, 0006, 0019, Fig. 3 of Ben-Yoav II). Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A].
Modified Ben-Yoav does not explicitly disclose one or more thick film-coated microelectrodes, selected from the group consisting of polysaccharide-coated microelectrodes and platinum black-coated microelectrodes.
However, Ben-Yoav teaches one of the electrodes may be modified or coated with a film, selected from the group consisting of a chitosan-coated electrode [chitosan corresponds to a polysaccharide] [Para. 0068, 0065, 0089 of Ben-Yoav]. Ben-Yoav discloses the nature of the working electrodes 1111 a 2, 1111 b 2, 1111 c 2 and 1211 a 2, 1211 b 2, 1211 c 2 and 1311 a 2, 1311 b 2, 1311 c 2 may be different from one another and such a testing configuration and protocol provides more accurate sensing performance when fouling of the electrochemical system occurs with human serum as the testing medium [Para. 0089]. Ben-Yoav teaches the electrochemical lab-on-a-chip device 1110 also includes multiple channels to enable concurrent measurements of multiple parameters where the additional channels may also be used to detect the presence of other types of analytes and biomarkers such as drugs, metabolites, vitamins, etc. [Para. 0075 and Fig. 3A-C]. Ben-Yoav further teaches a major challenge in the analysis of biological samples is the electrochemical reactivity and non-specific adsorption of molecules which cause fouling of the electrode. These molecules increase the background signal, decrease the signal-to-noise ratio, and deteriorate the sensitivity of the sensor [Para. 0100].
Shukla discloses an electrochemical microsensor for clozapine detection in whole blood for point-of-care monitoring of schizophrenia [Abstract]. The electrochemical microsensor includes an array of working microelectrodes with six electroanalytical microchambers containing three microelectrodes; the center microelectrode was used as the working microelectrode for the in situ electrochemical detection of clozapine in microliters of whole blood [Abstract; Page 2, Col. 2, last paragraph; Page 11, Col. 2, last paragraph and Fig. 7]. Shukla further discloses the microelectrode is modified with a micrometer thick biopolymer chitosan encapsulating carbon nanotubes [corresponding to a thick-film coated microelectrode, selected from the group consisting of polysaccharide-coated microelectrode with conductive additive incorporated into the coating] which is beneficial for detecting clozapine oxidation current, in the presence of other electroactive species in the blood, which generate overlapping electrochemical signals [Abstract]. The thickness of the electrodeposited chitosan-carbon nanotubes film was 60.5 ± 3.0 µm [Page 3, Col. 2, Para. 1] which is a thick film as evidenced by the instant specification which defines a thick film as 3 to 100 μm [Page 4, lines 1-3 of the instant specification].
Given the teachings of Ben-Yoav above regarding that the nature of the working electrodes may be different from one another and such a testing configuration and protocol provides more accurate sensing performance with human serum and a major challenge in the analysis of biological samples is the electrochemical reactivity and non-specific adsorption of molecules which increase the background signal, decrease the signal-to-noise ratio, and deteriorate the sensitivity of the sensor, and that one of the electrodes may be modified or coated with a film, selected from the group consisting of a chitosan-coated electrode [chitosan corresponds to a polysaccharide] [see rejection above, Para. 0100, 0089 and 0075 of Ben-Yoav] and the teachings of Ben-Yoav II regarding including an array of non-selective working electrodes that differ from each other by combining film-coated electrodes, conductive additives-incorporated film coated electrodes, and bare electrodes for analyzing samples containing more than one type of redox molecule [such as biofluids, blood, relevant to monitoring antipsychotics] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information (Para. 0010, 0004, 0006, 0019, Fig. 3 of Ben-Yoav II), it would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify one or more of the working microelectrodes in the array of modified Ben-Yoav to include one or more thick film-coated microelectrodes, polysaccharide-coated microelectrodes with conductive additives incorporated into the coating, as taught by Shukla, since Shukla teaches it would be beneficial for detecting clozapine oxidation current, in the presence of other electroactive species in the blood, which generate overlapping electrochemical signals [Abstract of Shukla]. Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A].
optionally with conductive additive incorporated into the coating (As outlined in the rejection above, Modified Ben-Yoav yields one or more thick film-coated microelectrodes, polysaccharide-coated microelectrodes with conductive additives incorporated into the coating [see rejection above; Abstract and Page 3, Col. 2, Para. 1 of Shukla);
wherein the electrochemical microsensor further comprises a counter electrode (Ben-Yoav teaches the electrochemical lab-on-a-chip device 1110 [corresponding to an electrochemical microsensor] comprises counter electrodes 1111 a 1, 1111 b 1, 1111 c 1, 1211 a 1, 1211 b 1, 1211 c 1, 1311 a 1, 1311 b 1, 1311 c 1 [see e.g., Fig. 3A-C and Paras. 0075-0089]) and optionally one or more reference microelectrode(s) (This limitation is optional and therefore, does not necessarily limit the claim to the method steps. Thus, Modified Ben-Yoav meets all the required limitations of this claim);
applying varied voltage, fixed voltage, current or impedance across the working microelectrodes (Ben-Yoav teaches the method is performed by potential sweep methods such as cyclic voltammetry and the method includes applying a positive potential with cyclic voltammetry which inherently applies a varied voltage by scanning the voltage as seen in Fig. 4B on the x-axis [Para. 0045, 0053, 0098, Fig. 4B] and Modified Ben-Yoav teaches the working electrodes are working microelectrodes [see rejection above]);
measuring the current flowing or the impedance between Ben-Yoav teaches the method is performed by measuring the electrochemical current, which is achieved by potential sweep methods such as cyclic voltammetry. Alternatively, electrochemical impedance may be employed [Para. 0053]. Cyclic voltammetry inherently measures the current flowing between the working electrode and a counter electrode and obtains a raw data set/cyclic voltammogram of electrochemical signals, such as in Fig. 4B showing current vs potential [see e.g., Fig. 3 and 4B, Para. 0053, 0069]);
Ben-Yoav does not explicitly disclose measuring the current flowing or the impedance between each of the working electrodes and a counter electrode to obtain a raw data set consisting of plurality of electrochemical signals
Ben-Yoav II discloses an electrochemical sensor comprising a counter electrode and an array of multiple working electrodes, preferably made as gold for use as a bare electrode and as the base electrode of the film-coated electrodes (Abstract, Para. 0024, Fig. 3). Ben-Yoav II teaches a method of electrochemical detection of one or more analytes in a liquid sample, wherein the liquid sample is a biofluid (blood) and the analyte is an organic redox compound, the method comprising the steps of bringing a liquid sample into contact with the electrochemical sensor; applying variable voltage, fixed voltage, current or impedance across the working electrodes; measuring the current flowing or the impedance between each of the working electrodes and a counter electrode, or the potential between each of the working electrodes and a reference electrode, to obtain a raw data set consisting of plurality of electrochemical signals; preprocessing the raw data electrochemical signals; and applying chemometric method(s) to the preprocessed data, to quantitively characterize the analyte of interest, and this configuration would be beneficial for analyzing samples containing more than one type of redox molecule [such as biofluids, blood “serum”] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information [Paras. 0010, 0004, 0006, 0012-0019, Fig. 3 and claims 19-27].
It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Ben-Yoav, which includes measuring the current flowing or the impedance between the working electrode and a counter electrode to obtain a raw data set consisting of electrochemical signals, to provide measuring the current flowing or the impedance between each of the working electrodes and a counter electrode to obtain a raw data set consisting of plurality of electrochemical signals, as taught by Ben-Yoav II, since Ben-Yoav II teaches this suitable alternative method for electrochemical analysis of biofluids (blood) and it would be beneficial for analyzing samples containing more than one type of redox molecule [such as biofluids, blood “serum”] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information [Paras. 0010, 0004, 0006, 0012-0019, Fig. 3 and claims 19-27 of Ben-Yoav II]. Furthermore, the use of a known technique (i.e., measuring the current flowing or the impedance between each of the working electrodes and a counter electrode to obtain a raw data set consisting of plurality of electrochemical signals, taught by Ben-Yoav II) to improve similar methods in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143 [I][C]).
optionally preprocessing the raw data electrochemical signals (This limitation is optional and therefore, does not necessarily limit the claim to the method steps. Thus, Modified Ben-Yoav meets all the required limitations of this claim); and
Modified Ben-Yoav is silent to applying chemometric method(s) to the preprocessed or raw data, to quantify clozapine in the sample.
However, Ben-Yoav teaches the analyte in the sample is clozapine (Para. 0102, 0006-0011).
Ben-Yoav II teaches a method of electrochemical detection of one or more analytes in a liquid sample, wherein the liquid sample is a biofluid (blood) and the analyte is an organic redox compound, the method comprising the steps of bringing a liquid sample into contact with the electrochemical sensor; applying variable voltage, fixed voltage, current or impedance across the working electrodes; measuring the current flowing or the impedance between each of the working electrodes and a counter electrode, or the potential between each of the working electrodes and a reference electrode, to obtain a raw data set consisting of plurality of electrochemical signals; preprocessing the raw data electrochemical signals; and applying chemometric method(s) to the preprocessed data, to quantitively characterize the analyte of interest, where the concentration of the analyte is quantified, wherein the one or more chemometric method (s) is selected from partial least square regression or a trained artificial neural network model (ANN) and this configuration would be beneficial for analyzing samples containing more than one type of redox molecule [such as biofluids, blood “serum”] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information [Paras. 0010, 0004, 0006, 0012-0019, 0053, 0056-0058, Fig. 3 and claims 19-27].
It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Ben-Yoav, wherein the analyte in the sample is clozapine, to provide preprocessing the raw data electrochemical signals and applying chemometric method(s) to the preprocessed data, to quantitively characterize the analyte of interest, where the concentration of the analyte is quantified, wherein the one or more chemometric method (s) is selected from partial least square regression or a trained artificial neural network model (ANN), as taught by Ben-Yoav II, since Ben-Yoav II teaches this suitable alternative method for electrochemical analysis of biofluids (blood) and it would be beneficial for analyzing samples containing more than one type of redox molecule [such as biofluids, blood “serum”] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information [Paras. 0010, 0004, 0006, 0012-0019, 0053, 0056-0058, Fig. 3 and claims 19-27 of Ben-Yoav II]. Furthermore, the use of a known technique (i.e., preprocessing the raw data electrochemical signals and applying chemometric method(s) to the preprocessed or raw data, to quantify an analyte in the sample, wherein one or more chemometric method (s) is selected from partial least square regression or a trained artificial neural network model (ANN), taught by Ben-Yoav II) to improve similar methods in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143 [I][C]).
Thus, Modified Ben-Yoav as outlined above yields applying chemometric method(s) to the preprocessed or raw data, to quantify clozapine in the sample, which is the analyte of interest (see rejection above).
Regarding claim 3, the method according to claim 1, wherein the electrochemical microsensor according is in the form of lab-on-a-chip (Ben-Yoav teaches the electrochemical lab-on-a-chip device/microsensor is in the form of a lab-on-a-chip device [see e.g., Para. 0021-0023, 0076 and Fig. 3A-C]).
Regarding claim 4, the method according to claim 3, wherein the chip comprises a base substrate and has a recessed region on its surface, defined by a wall made of electrically insulating polymer which is elevated in respect of said recessed region, such that the recessed region can serve as a receptable for a liquid sample (Ben-Yoav teaches the electrochemical lab-on-a-chip device comprises a silicon wafer “base substrate” insulated by PECVD silicon oxide and has a recessed region or chamber 1116, 1216, 1316 on its surface, defined by a wall of electrically insulating polymer, as microfabrication technology and photolithography process resulted in insulating micrometer-thickness chambers defining a circular chamber/recess, the wall is elevated in respect of the recessed region or chamber 1116, 1216, 1316 as seen in Fig 3A and C, such that the recessed region or chamber 1116, 1216, 1316 serves as a receptable for the liquid sample/blood as the introduced whole blood sample flows through a microchannel into the recess or chamber 1116, 1216, 1316 [Para. 0052, 0077-0085, Fig. 3A-C]), with discrete microstructures placed inside said recessed region, wherein a microstructure consists of a microelectrode deposited atop of an adhesion layer attached to the base substrate (Ben-Yoav teaches 3-electrode set “discrete structures” 1111 a, 1111 b, 1111 c, 1211 a, 1211 b, 1211 c, 1311 a, 1311 b, and 1311 c placed inside the recess or chamber 1116, 1216, 1316, wherein the discrete structure consists of a working electrode 1111 a 2, 1111 b 2, 1111 c 2 and 1211 a 2, 1211 b 2, 1211 c 2 and 1311 a 2, 1311 b 2, 1311 c 2 deposited atop of a chrome layer “adhesion layer” attached to the silicon wafer “base substrate” [Para. 0052, 0077-0085, Fig. 3A-C] and Modified Ben-Yoav teaches the working electrodes are working microelectrodes, thus yielding discrete microstructures consisting of a microelectrode [see rejection of claim 1 above]), wherein each microstructure is encircled by a wall made of electrically insulating polymer, thereby defining a plurality of microchambers, the interior of which is occupied by the microstructures (Ben-Yoav teaches 3-electrode set “discrete structures” 1111 a, 1111 b, 1111 c, 1211 a, 1211 b, 1211 c, 1311 a, 1311 b, and 1311 c is encircled by a wall of electrically insulating polymer as microfabrication technology and photolithography process resulted in insulating micrometer-thickness chambers, thereby defining a plurality of microchambers [micrometer-thickness chambers] 1116, 1216, 1316, the interior of which is occupied by the 3-electrode set “discrete structures” 1111 a, 1111 b, 1111 c, 1211 a, 1211 b, 1211 c, 1311 a, 1311 b, and 1311 c [Para. 0052, 0077-0085, Fig. 3A-C] and Modified Ben-Yoav teaches the working electrodes are working microelectrodes, thus yielding discrete microstructures as the discrete structures contain a microelectrode and therefore are discrete microstructures [see rejection of claim 1 above]).
Regarding claim 5, the method according to claim 4, wherein the counter electrode is located inside the recessed region (Ben-Yoav teaches the counter electrode 1111 a 1, 1111 b 1, 1111 c 1, 1211 a 1, 1211 b 1, 1211 c 1, 1311 a 1, 1311 b 1, 1311 c 1 is located inside the recessed region or chamber 1116, 1216, 1316 [Para. 0052, 0077-0085, Fig. 3A-C]).
Regarding claim 6, the method according to claim 5, wherein the recessed region has a circular shape (Ben-Yoav teaches the recessed region or chamber 1116, 1216, 1316 has a circular shape as microfabrication technology and photolithography process resulted in insulating micrometer-thickness chambers defining a circular chamber/recess [Para. 0052, 0077-0085, Fig. 3A-C]), with the counter electrode being positioned concentrically in the recessed region and the microstructures placed along the perimeter of the recessed region (Ben-Yoav teaches the counter electrode 1111 a 1, 1111 b 1, 1111 c 1, 1211 a 1, 1211 b 1, 1211 c 1, 1311 a 1, 1311 b 1, 1311 c 1 are concentrically arranged around the working electrode tip as seen in Fig. 3A-B and are in the recessed region or chamber 1116, 1216, 1316, [see e.g., Fig. 3 and Para. 0073, 0077-0085] therefore, the counter electrode is positioned concentrically in the recessed region, where the counter electrode is concentric with the working electrode tip in the recessed region. Ben-Yoav further teaches 3-electrode set “discrete structures” 1111 a, 1111 b, 1111 c, 1211 a, 1211 b, 1211 c, 1311 a, 1311 b, and 1311 c are placed along the perimeter/arranged directly along or next to an edge of the recessed region or chamber 1116, 1216, 1316 as seen in Fig. 3A-3B [Para. 0052, 0077-0085, Fig. 3A-C] and Modified Ben-Yoav teaches the working electrodes are working microelectrodes, thus yielding discrete microstructures as the discrete structures contain a microelectrode and therefore are discrete microstructures [see rejection of claim 1 above])
Regarding claim 7, the method according to claim 1, comprising applying variable voltage and measuring current as the electrochemical signal (Ben-Yoav teaches the method is performed by potential sweep methods such as cyclic voltammetry and the method includes applying a positive potential with cyclic voltammetry which inherently applies a varied voltage by scanning the voltage as seen in the cyclic voltammogram of Fig. 4B on the x-axis and measuring the current which is on the y-axis and corresponds to the electrochemical signal [Para. 0045, 0053, 0098, Fig. 4B]. Ben-Yoav discloses the method is performed by measuring the electrochemical current as the electrochemical signal, which is achieved by potential sweep methods such as cyclic voltammetry [Para. 0053]).
Regarding claim 8, the method according to claim 7, Modified Ben-Yoav is silent to wherein the raw data is reduced in dimensions and normalized, the reduction being achieved using extracted electrochemical features recorded by voltammetry.
However, Ben-Yoav teaches the method is performed by potential sweep methods such as cyclic voltammetry, obtaining cyclic voltammograms such as in Fig. 4B [Para. 0045, 0053, 0098, Fig. 4B], which corresponds to electrochemical features recorded by voltammetry.
Ben-Yoav II teaches a method of electrochemical detection of one or more analytes in a liquid sample, wherein the liquid sample is a biofluid (blood) and the analyte is an organic redox compound, the method comprising the steps of bringing a liquid sample into contact with the electrochemical sensor; applying variable voltage, fixed voltage, current or impedance across the working electrodes; measuring the current flowing or the impedance between each of the working electrodes and a counter electrode, or the potential between each of the working electrodes and a reference electrode, to obtain a raw data set consisting of plurality of electrochemical signals; preprocessing the raw data electrochemical signals; and applying chemometric method(s) to the preprocessed data, to quantitively characterize the analyte of interest, where the concentration of the analyte is quantified, wherein the one or more chemometric method (s) is selected from partial least square regression or a trained artificial neural network model (ANN). Ben-Yoav II further discloses the method includes wherein the raw data is reduced in dimensions and normalized, the reduction being achieved using extracted electrochemical features recorded by voltammetry and this configuration would be beneficial for analyzing samples containing more than one type of redox molecule [such as biofluids, blood “serum”] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information [Paras. 0010, 0004, 0006, 0012-0019, 0053, 0056-0058, Fig. 3 and claims 19-27].
It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Ben-Yoav, which includes electrochemical features recorded by voltammetry, to provide wherein the raw data is reduced in dimensions and normalized, the reduction being achieved using extracted electrochemical features recorded by voltammetry, as taught by Ben-Yoav II, since Ben-Yoav II teaches this suitable alternative method for electrochemical analysis of biofluids (blood) and it would be beneficial for analyzing samples containing more than one type of redox molecule [such as biofluids, blood “serum”] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information [Paras. 0010, 0004, 0006, 0012-0019, 0053, 0056-0058, Fig. 3 and claims 19-27 of Ben-Yoav II]. Furthermore, the use of a known technique (i.e., wherein the raw data is reduced in dimensions and normalized, the reduction being achieved using extracted electrochemical features recorded by voltammetry, taught by Ben-Yoav II) to improve similar methods in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143 [I][C]).
Regarding claim 9, the method according to claim 1, comprising applying one or more chemometric method(s) selected from partial least square regression or a trained artificial neural network model (ANN) (As outlined in the rejection of claim 1 above, Modified Ben-Yoav yields applying one or more chemometric method (s) selected from partial least square regression or a trained artificial neural network model (ANN) [see rejection of claim 1 above and 0053, 0056-0058, and claims 19-27 of Ben-Yoav II]).
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ben-Yoav in view of Shukla and Ben-Yoav II as applied to claim 1 above, and further in view of Shukla et al. (A platinum black-modified microelectrode for in situ olanzapine detection in microliter volumes of undiluted serum, 6 January 2020, Journal of Neural Transmission, 127:291–299), hereby referred to as Shukla II, Yin et al. (High-quality molybdenum disulfide nanosheets with 3D structure for electrochemical sensing, 2016, Applied Surface Science, 385, Pages 63-71), and Subramanian et al. (Electrochemically Exfoliated Porous WS2 Nanosheets: A Potential Electrochemical Sensing Platform for Chlorpromazine Detection, 2019, Journal of the Electrochemical Society, Vol. 166, B749-B755).
Regarding claim 2, a method according to claim 2 (As outlined in the 112b rejection above, claim 2 is interpreted to depend on claim 1), wherein the array of working microelectrodes comprises: one or more bare microelectrodes (As outlined in the rejection of claim 1 above, Ben-Yoav teaches at least one electrode set including a working electrode that presents a bare, unmodified surface [Para. 0006, 0011, 0047, 0049, claim 1 of Ben-Yoav] and Modified Ben-Yoav teaches the working electrodes are working microelectrodes [see rejection of claim 1 above];
one or more polysaccharide-coated microelectrodes with conductive additives incorporated into the coating (Modified Ben-Yoav as outlined in the rejection of claim 1 yields one or more polysaccharide-coated microelectrodes with conductive additives incorporated into the coating [see rejection of claim 1 above, see e.g., Abstract; Page 2, Col. 2, last paragraph; Page 11, Col. 2, last paragraph and Fig. 7 of Shukla]);
one or more reduced graphene oxide-coated microelectrodes (Modified Ben-Yoav as outlined in the rejection of claim 1 yields one or more reduced graphene oxide-coated microelectrode [see rejection of claim 1 above, see e.g., Para. 0042 of Ben-Yoav II and Abstract of Shukla]);
one or more polysaccharide-coated microelectrodes (Modified Ben-Yoav as outlined in the rejection of claim 1 yields one or more polysaccharide-coated microelectrodes with conductive additives incorporated into the coating [see rejection of claim 1 above, see e.g., Abstract; Page 2, Col. 2, last paragraph; Page 11, Col. 2, last paragraph and Fig. 7 of Shukla] and thus teaches one or more polysaccharide-coated microelectrodes);
Modified Ben-Yoav is silent to one or more platinum black-coated microelectrodes;
However, Ben-Yoav teaches one of the electrodes may be modified or coated with a film, selected from the group consisting of a chitosan-coated electrode [chitosan corresponds to a polysaccharide] [Para. 0068, 0065, 0089 of Ben-Yoav]. Ben-Yoav discloses the nature of the working electrodes 1111 a 2, 1111 b 2, 1111 c 2 and 1211 a 2, 1211 b 2, 1211 c 2 and 1311 a 2, 1311 b 2, 1311 c 2 may be different from one another and such a testing configuration and protocol provides more accurate sensing performance when fouling of the electrochemical system occurs with human serum as the testing medium [Para. 0089]. Ben-Yoav teaches the electrochemical lab-on-a-chip device 1110 also includes multiple channels to enable concurrent measurements of multiple parameters where the additional channels may also be used to detect the presence of other types of analytes and biomarkers such as drugs, metabolites, vitamins, etc. [Para. 0075 and Fig. 3A-C]. Ben-Yoav further teaches a major challenge in the analysis of biological samples is the electrochemical reactivity and non-specific adsorption of molecules which cause fouling of the electrode. These molecules increase the background signal, decrease the signal-to-noise ratio, and deteriorate the sensitivity of the sensor [Para. 0100].
Shukla II teaches an array of at least 11 gold microelectrodes with two platinum black-coated microelectrodes that improves the overall selectivity and sensitivity of the sensor, the miniaturized electrochemical sensor beneficial for the monitoring and analysis of antipsychotic drugs used in the treatment of schizophrenia and for in-situ detection performed in microliter volumes of undiluted serum (see Fig. 3F and Abstract of Shukla II). Shukla II further teaches that interfering species affect the detection of an analyte of interest in biological samples such as in undiluted serum and that challenges with microscale analytical device include reduced sensitivity and specificity when dealing with biological fluids (serum) due to the presence of other electro-active species in the solution and limit the ability to detect low levels of drugs in biological fluids (Fig. 1 and Page 292, Col. 1, Para. 1 until next column).
Modified Ben-Yoav and Shukla II are considered analogous art to the claimed invention because they are in the same field of electrochemical sensors for analysis of analytes found in the blood/serum of patients [Abstract of Ben-Yoav; Abstract of Shukla II]. Given the teachings of Ben-Yoav above regarding that the nature of the working electrodes may be different from one another and such a testing configuration and protocol provides more accurate sensing performance with human serum and a major challenge in the analysis of biological samples is the electrochemical reactivity and non-specific adsorption of molecules which increase the background signal, decrease the signal-to-noise ratio, and deteriorate the sensitivity of the sensor [see rejection of claim 1 above, Para. 0100, 0089 and 0075 of Ben-Yoav] and the teachings of Ben-Yoav II regarding including an array of non-selective working electrodes that differ from each other by combining film-coated electrodes, conductive additives-incorporated film coated electrodes, and bare electrodes for analyzing samples containing more than one type of redox molecule [such as biofluids, blood, relevant to monitoring antipsychotics] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information (Para. 0010, 0004, 0006, 0019, Fig. 3 of Ben-Yoav II), it would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify one or more of the working microelectrodes in the array of modified Ben-Yoav to include a platinum black coating on the one or more of the working microelectrode, as taught by Shukla II, since Shukla II teaches it would be beneficial for improving the overall selectivity and sensitivity of the sensor and for the monitoring and analysis of antipsychotic drugs used in the treatment of schizophrenia and for in-situ detection performed in microliter volumes of undiluted serum (see Fig. 3F and Abstract of Shukla II). Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A].
Modified Ben-Yoav is silent to one or more MoS2-coated microelectrodes; and
However, Ben-Yoav teaches one of the electrodes may be modified or coated with a film, selected from the group consisting of a chitosan-coated electrode [chitosan corresponds to a polysaccharide] [Para. 0068, 0065, 0089 of Ben-Yoav]. Ben-Yoav discloses the nature of the working electrodes 1111 a 2, 1111 b 2, 1111 c 2 and 1211 a 2, 1211 b 2, 1211 c 2 and 1311 a 2, 1311 b 2, 1311 c 2 may be different from one another and such a testing configuration and protocol provides more accurate sensing performance when fouling of the electrochemical system occurs with human serum as the testing medium [Para. 0089]. Ben-Yoav teaches the electrochemical lab-on-a-chip device 1110 also includes multiple channels to enable concurrent measurements of multiple parameters where the additional channels may also be used to detect the presence of other types of analytes and biomarkers such as drugs, metabolites, vitamins, etc. [Para. 0075 and Fig. 3A-C]. Ben-Yoav further teaches a major challenge in the analysis of biological samples is the electrochemical reactivity and non-specific adsorption of molecules which cause fouling of the electrode. These molecules increase the background signal, decrease the signal-to-noise ratio, and deteriorate the sensitivity of the sensor [Para. 0100].
Yin teaches an electrochemical sensor with pure MoS2 nanosheets-modified electrode for detection of analytes found in blood serum that are relevant to schizophrenia monitoring and has benefit for disease diagnosis [Abstract, Page 63, Cols. 1-2]. Yin further teaches MoS2-based materials have shown the superior biosensing performance for the detection of glucose, nucleic acids, and biomolecules [Page 64, Col. 1, Para. 1]. Yin reports a MoS2-coated electrode, that is a few-layered nanosheets thick that is uniformly dropped onto the surface of the electrode and dried, and thus the layered MOS2 structure coated on the electrode surface is a MOS2 film [Page 65, Col. 1, Para. 3; Page 66, Col. 2, Para. 2; Scheme 1; Page 67, Col. 1, Para. 1]. Yin teaches the MOS2-coated electrode is beneficial for excellent electrocatalytic performance of biomolecule/analyte detection [for analytes found in blood serum, relevant to schizophrenia monitoring] in a wide concentration range with high sensitivity, selectivity, stability and good reproducibility [Conclusion; Abstract, Page 63, Cols. 1-2; Page 64, Col. 2, Para. 1]
Modified Ben-Yoav and Yin are considered analogous art to the claimed invention because they are in the same field of electrochemical sensors for analysis of analytes found in the blood/serum of patients [Abstract of Ben-Yoav; Abstract, Page 63, Cols. 1-2 of Yin]. Given the teachings of Ben-Yoav above regarding that the nature of the working electrodes may be different from one another and such a testing configuration and protocol provides more accurate sensing performance with human serum and a major challenge in the analysis of biological samples is the electrochemical reactivity and non-specific adsorption of molecules which increase the background signal, decrease the signal-to-noise ratio, and deteriorate the sensitivity of the sensor [see rejection of claim 1 above, Para. 0100, 0089 and 0075 of Ben-Yoav] and the teachings of Ben-Yoav II regarding including an array of non-selective working electrodes that differ from each other by combining film-coated electrodes, conductive additives-incorporated film coated electrodes, and bare electrodes for analyzing samples containing more than one type of redox molecule [such as biofluids, blood, relevant to monitoring antipsychotics] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information (Para. 0010, 0004, 0006, 0019, Fig. 3 of Ben-Yoav II), it would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify one or more of the working microelectrodes in the array of modified Ben-Yoav to include a MoS2 coating on the one or more of the working microelectrode, as taught by Yin, since Yin teaches it would be beneficial for excellent electrocatalytic performance of biomolecule/analyte detection [for analytes found in blood serum, relevant to schizophrenia monitoring] in a wide concentration range with high sensitivity, selectivity, stability and good reproducibility [Conclusion; Abstract, Page 63, Cols. 1-2; Page 64, Col. 2, Para. 1 of Yin]. Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A].
Modified Ben-Yoav is silent to one or more WS2-coated microelectrodes.
However, Ben-Yoav teaches one of the electrodes may be modified or coated with a film, selected from the group consisting of a chitosan-coated electrode [chitosan corresponds to a polysaccharide] [Para. 0068, 0065, 0089 of Ben-Yoav]. Ben-Yoav discloses the nature of the working electrodes 1111 a 2, 1111 b 2, 1111 c 2 and 1211 a 2, 1211 b 2, 1211 c 2 and 1311 a 2, 1311 b 2, 1311 c 2 may be different from one another and such a testing configuration and protocol provides more accurate sensing performance when fouling of the electrochemical system occurs with human serum as the testing medium [Para. 0089]. Ben-Yoav teaches the electrochemical lab-on-a-chip device 1110 also includes multiple channels to enable concurrent measurements of multiple parameters where the additional channels may also be used to detect the presence of other types of analytes and biomarkers such as drugs, metabolites, vitamins, etc. [Para. 0075 and Fig. 3A-C]. Ben-Yoav further teaches a major challenge in the analysis of biological samples is the electrochemical reactivity and non-specific adsorption of molecules which cause fouling of the electrode. These molecules increase the background signal, decrease the signal-to-noise ratio, and deteriorate the sensitivity of the sensor [Para. 0100].
Subramanian teaches an electrochemical sensing platform comprising a WS2-coated electrode that is used to test antipsychotic drugs in human biofluid samples [Abstract and Figure 1]. Subramanian further teaches the WS2-coated electrode is beneficial because it has excellent electrocatalytic activity and a low detection limit and the WS2 coating is a WS2 film by drop casting onto the electrode [Abstract and Page B570, Col. 1, Para. 1].
Modified Ben-Yoav and Subramanian are considered analogous art to the claimed invention because they are in the same field of electrochemical sensors for analysis of biofluids [Abstract of Ben-Yoav and Abstract of Subramanian]. Given the teachings of Ben-Yoav above regarding that the nature of the working electrodes may be different from one another and such a testing configuration and protocol provides more accurate sensing performance with human serum and a major challenge in the analysis of biological samples is the electrochemical reactivity and non-specific adsorption of molecules which increase the background signal, decrease the signal-to-noise ratio, and deteriorate the sensitivity of the sensor [see rejection of claim 1 above, Para. 0100, 0089 and 0075 of Ben-Yoav] and the teachings of Ben-Yoav II regarding including an array of non-selective working electrodes that differ from each other by combining film-coated electrodes, conductive additives-incorporated film coated electrodes, and bare electrodes for analyzing samples containing more than one type of redox molecule [such as biofluids, blood, relevant to monitoring antipsychotics] in order to differentiate between interfering redox active molecules generating overlapping electrochemical signals as samples containing more than one type of redox molecule (such as in biofluids) have several redox molecules in the sample generating overlapping electrochemical signals that contribute to the background signal, decreasing the quality of the transduced redox information (Para. 0010, 0004, 0006, 0019, Fig. 3 of Ben-Yoav II), it would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify one or more of the working microelectrodes in the array of modified Ben-Yoav to include a WS2 coating on the one or more of the working microelectrodes, as taught by Subramanian, since Subramanian teaches it would be beneficial because it has excellent electrocatalytic activity and a low detection limit that is useful to test antipsychotic drugs in human biofluid samples [Abstract of Subramanian and Fig. 1]. Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A].
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Kim et al. (Programmable “Semismart” Sensor: Relevance to Monitoring Antipsychotics, 2015, Advanced Functional Materials, 25, Pages 2156-2165) teaches a CNT-chitosan coated gold electrode for analyzing clozapine (Abstract and Fig. 1). Kang et al. (Reliable clinical serum analysis with reusable electrochemical sensor: Toward point-of-care measurement of the antipsychotic medication clozapine, 2017, Biosensors and Bioelectronics, 95, Pages 55-59) teaches an electrochemical sensing with chitosan coated gold electrode for rapidly measuring serum levels of clozapine [Abstract and Fig. 2A]. Kelly et al. (Blood Draw Barriers for Treatment with Clozapine and Development of a Point-of-Care Monitoring Device, 2018, Clinical Schizophrenia & Related Psychoses, Pages 23-30) discloses a point-of-care monitoring device to detect clozapine, the fabricated arrayed electrochemical lab-on-a-chip includes an array of working microelectrodes which was used for clozapine detection by cyclic voltammetry [Abstract, Fig. 1; Page 26, Col. 2, last paragraph].
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/S.Y.O./Examiner, Art Unit 1794
/JAMES LIN/Supervisory Patent Examiner, Art Unit 1794
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