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 .
Status of the Claims
The Amendment filed April 2, 2026 has been entered. Claims 1, 3, and 6-7 have been amended; claims 19-20 are new; claims 10-18 have been withdrawn; and claims 2, 4-5, and 8-9 have been cancelled. Claims 1, 3, 6-7, and 19-20 are currently examined herein.
Status of the Rejection
Applicant’s amendments to the specification partially overcomes the specification objection previously set forth in the Non-Final Office Action mailed October 2, 2025, and new grounds of specification objection are necessitated by the amendment as outlined below.
Applicant’s amendments to claims overcome the claim objections and the 112(b) rejections in the previous office action.
New grounds of claim objection are necessitated by the amendment as outlined below.
All 35 U.S.C. § 102 and 103 rejections from the previous office action are withdrawn in view of the Applicant’s amendment.
New grounds of rejection under 35 U.S.C. § 103 are necessitated by the amendments as outlined below.
Specification
35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, requires the specification to be written in “full, clear, concise, and exact terms.” The specification is replete with terms which are not clear, concise and exact. The specification should be revised carefully in order to comply with 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112. Examples of some unclear, inexact or verbose terms used in the specification are: The amended Table 1 corrected the molecular weight of Fe(CN)63-- to 211.95. However, [para. 0084] in PG-pub of the instant specification still describes: “For example, the difference between the molecular weights of the anions is not less than 100 g/mol. Specifically, the mixture of analytes comprises … a trivalent anion with a molecular weight above 300 g/mol”, which is not consistent with the amended Table 1 since based on the amended Table 1 the difference between the molecular weights of the anions is 211.95-176.1=35.85 g/mol (instead of not less than 100 g/mol), and a trivalent anion with a molecular weight is 211.95 instead of above 300 g/mol. Thus, there is inconsistence in the amended specification.
Claim Objection
Claim 1 is objected to because of the following informalities:
Claim 1: please amend “the film” to – the films--.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 1, 3, 6-7 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Ben-Yoav et al. (WO2018225058A1), and further in view of Shukla et al. (The effect of loading carbon nanotubes onto chitosan films on electrochemical dopamine sensing in the presence of biological interference, Talanta, 2018, 181, 57-64) and 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, Advanced healthcare materials, 2019, 8, 1900462; hereinafter Shukla_I). Nakatsuka et al. (Differentiating siblings: the case of dopamine and norepinephrine, ACS Chemical Neuroscience, 2017, 8, 218-220) is used as an evidence for claim 1.
Regarding claim 1, Ben-Yoav teaches an electrochemical method of determining the presence and optionally the concentration of at least two analytes in a test sample which contains a mixture of analytes (a method of electrochemical detection of one or more analytes in a liquid sample [claim 19]; the analyte of interest is dopamine and/or norepinephrine and the interferant is uric acid [claim 22]; a preferred embodiment of the invention is directed to the analysis of biofluid sample for determining the presence and concentration of neurotransmitters [dopamine and/or norepinephrine] [the first paragraph on page 6]), wherein the analytes differ from one another in electrical charge and/or size (dopamine [DA] and norepinephrine [NE] differ from one another in electrical charge and/or size since their molar weights are different and there is an additional hydroxyl group [OH] on the ethylamine side chain of NE compared to DA, as evidenced by Fig.1 in Nakatsuka), comprising the steps of:
applying variable voltage, fixed voltage, current or impedance across an array of working electrodes (applying variable voltage, fixed voltage, current or impedance across the working electrodes of an electrochemical sensor as defined in any one of claims 1 to 11 [claim 19]) consisting of electrodes coated with films of varying thickness and optionally a bare electrode (An electrochemical sensor comprising a counter electrode, optionally a reference electrode, and an array of multiple working electrodes, wherein at least one of the working electrodes is a film-coated electrode, and wherein the film- forming material has repeat unit that comprises six-membered non-aromatic ring [claim 1]; wherein the array of working electrodes comprises: a first subarray consisting of one or more bare electrode; a second subarray consisting of one or more film-coated electrodes [claim 2]; two distinct film-coated electrodes may differ from one another in the film material and/or film thickness [the 2nd paragraph on page 7]), when the array of working electrodes is in contact with the test sample (bringing a liquid sample into contact with an electrochemical sensor as defined in any one of claims 1 to 11 [claim 19]);
measuring a current flowing, an impedance between each of the film-coated working electrodes and a counter electrode, or a potential between each of the film-coated working electrodes and a reference electrode, to obtain a raw data set consisting of a plurality of electrochemical signals (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 [claim 19]);
preprocessing the raw data set to obtain processed data (preprocessing the raw data set [claim 19]); and
applying chemometric method(s) to the processed data, to qualitatively or quantitively characterize the at least two analytes of interest (applying chemometric method (s) to the preprocessed data, to qualitatively or quantitively characterize the analyte of interest [claim 19]; wherein the analyte of interest is dopamine and/or norepinephrine and the interferant is uric acid [claim 22]);
wherein the working electrodes are coated with films which contain covalently-bonded ionizable chemical groups, such that the films assume an electrical charge in the test sample (wherein the six-membered, non-aromatic ring bears amine group, carboxylic acid group, hydroxyl group or sulfonic acid group covalently bonded to a carbon atom of said ring [claim 4]; the film-forming material is chitosan [claim 6], which is an amino-substituted polysaccharide [the third paragraph on page 8], thus chitosan has amine group, which is further evidenced by Shukla: “the positively charged amine groups of the chitosan film may interact with a negatively charged molecule” [the first paragraph in Col. 1 on page 58 in Shukla]),
wherein the films contain protonatable chemical groups (wherein the six-membered, non-aromatic ring bears amine group, carboxylic acid group, hydroxyl group or sulfonic acid group covalently bonded to a carbon atom of said ring [claim 4]; the film-forming material is chitosan [claim 6], which is an amino-substituted polysaccharide [the third paragraph on page 8],the film-forming material is chitosan [claim 6], which is an amino-substituted polysaccharide [the third paragraph on page 8]. The amine group, carboxylic acid group, hydroxyl group or sulfonic acid group is a protonatable chemical group),
wherein conductive additives are not included in the films (wherein the array of working electrodes comprises at least one of: subarray consisting of one or more film-coated electrodes; subarray consisting of one or more conductive additive- incorporated film-coated electrodes [claim 1]; thus, Ben-Yoav teaches conductive additives are not included in the films in the subarray consisting of one or more film-coated electrodes).
Ben-Yoav is silent to: wherein at least one of the analytes possesses an electrical charge that is opposite to the charge assumed by the films; and wherein the mixture of analytes comprises: at least one anion, or a compound dissociating in solution to liberate an anion; and at least one neutral molecule.
Shukla teaches an electrochemical method of determining dopamine in the presence of biological interference (uric acid) by using a working electrode coated with chitosan-carbon nanotubes (abstract and Fig.1). Shukla further teaches the positively charged amine groups of the chitosan film may interact with a negatively charged molecule, this affecting the diffusion coefficient of this molecule and increasing its generated electrochemical current, according to Randles-Sevcik relationship (the first paragraph in Col. 1 on page 58). Other properties of the chitosan-CNT film, such as its thickness, can also influence the electrochemical signal. To improve the resolution of the studied film properties, an array of micro-electrodes, with better control of the process dynamics, can be used (the 2nd paragraph in Conclusions on page 62).
Ben-Yoav and Shukla are considered analogous art to the claimed invention because they are in the same field of electrochemical method of sensing neurotransmitter dopamine in the presence of UA by using electrochemical sensor comprising working electrode coated with chitosan film. Since the positively charged amine groups of the chitosan film may interact with a negatively charged molecule, affect the diffusion coefficient of this molecule and increase its generated electrochemical current (as taught by Shukla), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the electrical charges of the films in Ben-Yoav to provide at least one of the analytes possesses an electrical charge that is opposite to the electrical charge assumed by the films, since the interaction between the oppositely charged analyte and film would
affect the diffusion coefficient of the analyte and increase its generated electrochemical current (the first paragraph in Col. 1 on page 58 in Shukla).
Modified Ben-Yoav is silent to: wherein the mixture of analytes comprises: at least one anion, or a compound dissociating in solution to liberate an anion; and at least one neutral molecule.
Shukla_I teaches a chitosan-carbon nanotube-modified microelectrode (see Fig.1) for the detection of clozapine in the presence of interfering species (a mixture of clozapine, uric acid, ascorbic acid, L-homocysteine and dopamine [Table 2]). CLZ standard solution were prepared by diluting the CLZ stocks solution with a PBS solution of pH 7.4 or with an undiluted serum or whole blood. UA, L-HCy, AA, and DA were prepared in PBS solution according to their bioavailability in human blood for the interference study. A redox couple ferrocyanide/ferricyanide testing solution consisted of Fe(CN)6]4- and Fe(CN)6]3- were dissolved in the PBS solution [the 1st paragraph in Col. 2 on page 11].
Shukla teaches an electrochemical method of determining dopamine in the presence of biological interference (uric acid) by using a working electrode coated with chitosan-carbon nanotubes (abstract and Fig.1). Shukla further teaches a PBS
Solution (pH 7.4) containing ferricyanide and ferrocyanide was used as a supporting electrolyte for the electrochemical measurements (section 2.1).
Ben-Yoav, Shukla and Shukla_I are considered analogous art to the claimed invention because they are in the same field of electrochemical method of sensing target analyte in the presence of interfering species by using a similar electrochemical sensor comprising working electrode coated with chitosan film. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the mixture of analytes in Ben-Yoav with a mixture of analytes comprising clozapine, uric acid, ascorbic acid, L-homocysteine and dopamine in a PBS solution of pH 7.4 containing redox couple of ferricyanide and ferrocyanide, as taught by combined Shukla_I and Shukla, since it would provide a method for rapid and minimally invasive clozapine detection at the point-of -care (abstract in Shukla_I).
The substituted mixture of analytes comprises at least one anion (AscH- of the ascorbic acid and anions of Fe(CN)6]3-/ Fe(CN)6]4- of the redox couple; note that anions of the redox couple in the mixture of analytes are considered part of the overall mixture of analytes); and at least one neutral molecule (L-homocysteine). The disclosed L-homocysteine is the same as the neutral molecule of L-homocysteine in this instant application, as evidenced by Table 1 of the instant specification. Thus, the disclosed L-homocysteine is deemed as the neutral molecule. Accordingly, products of identical chemical composition cannot have mutually exclusive properties, and thus, the claimed property (i.e. L-homocysteine being neutral molecule), is necessarily present in the prior art material. The courts have held that “[p]roducts of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01 (II).
Regarding claim 3, modified Ben-Yoav teaches the method according to claim 1, and Ben-Yoav further teaches the electrochemical sensor comprises an array consisting of a total of n working electrodes (3<n≤50, preferably 3<n≤30, e.g., 3<n≤10) subdivided to include k bare electrodes (l≤k≤n/2, for example, l≤k≤n/3), and m film-coated working electrodes (l≤m≤n-k, preferably at least two film- coated electrodes) (the 3rd paragraph on page 7). The array of multiple working electrodes comprises a set of film-coated working electrodes which differ from one another in one or more of the following features: film material, film thickness, film density and loading level of conductivity additives that are incorporated into the film (the 2nd paragraph on page 11). Thus, Ben-Yoav teaches wherein the array includes a set of film-coated one or more working electrodes coated with different film thickness.
Ben-Yoav is silent to wherein the array of working electrodes includes: one or more working electrodes coated with 15 to 35 nm thick films; one or more working electrodes coated with 35 to 50 nm thick films; one or more working electrodes coated with 50 to 65 nm thick films; one or more working electrodes coated with 65 to 80 nm thick films; and one or more working electrodes coated with 80 to 100 nm thick films.
Shukla teaches an electrochemical method of determining dopamine in the presence of biological interference (uric acid) by using a working electrode coated with chitosan-carbon nanotubes (abstract and Fig.1). Shukla further teaches other properties of the chitosan-CNT film, such as its thickness, can also influence the electrochemical signal. To improve the resolution of the studied film properties, an array of micro-electrodes, with better control of the process dynamics, can be used (the 2nd paragraph in Conclusions on page 62).
Since Shukla teaches the film thickness influences the electrochemical signal and suggests the use of an array of micro-electrodes to improve the resolution of the studied film properties, and Ben-Yoav teaches wherein the array includes a set of film-coated one or more working electrodes coated with different film thickness, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the array of working electrodes in Ben-Yoav to include one or more working electrodes coated with a film thickness of range A; one or more working electrodes coated with a film thickness of range B; one or more working electrodes coated with a film thickness of range C; one or more working electrodes coated with a film thickness of range D; and one or more working electrodes coated with a film thickness of range E, since it would allow to improve the resolution of the film thickness on the electrochemical signal (the 2nd paragraph in Conclusions on page 62 in Shukla).
As the electrochemical signal is a variable that can be modified, among others, by adjusting the film thickness, the precise film thickness ranges A-E for the respective one or more working electrodes would have been considered a result effective variable by one having ordinary skill in the art before the effective filing date of the invention. As such, without showing unexpected results, the claimed thickness ranges A-E cannot be considered critical. Accordingly, one of ordinary skill in the art before the effective filing date of the invention would have optimized, by routine experimentation, the film thickness ranges A-E in Ben-Yoav to obtain the desired film thickness for each of the one or more working electrodes in order to improve the resolution of the film thickness on the electrochemical signal, as taught by Shukla. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The discovery of an optimum value of a known result effective variable, without producing any new or unexpected results, is within the ambit of a person of ordinary skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980) (see MPEP § 2144.05, II.).
Regarding claim 6, modified Ben-Yoav teaches the method according to claim 1, wherein the mixture of analytes comprises two or more anions (AscH- of the ascorbic acid and anions of Fe(CN)6]3-/ Fe(CN)6]4- of the redox couple, as outlined in the rejection of claim 1 above), wherein the anions differ in ionic charge and/or molecular weight (AscH- of the ascorbic acid and Fe(CN)6]3- differ in ionic charge and molecular weight).
Regarding claim 7, modified Ben-Yoav teaches the method according to claim 6, wherein the anions in the mixture of analytes differ in ionic charge and molecular weight (AscH- of the ascorbic acid and Fe(CN)6]3- differ in ionic charge and molecular weight).
Regarding claim 19, modified Ben-Yoav teaches the method according to claim 3, wherein the mixture of analytes comprises two or more anions (AscH- of the ascorbic acid and anions of Fe(CN)6]3-/ Fe(CN)6]4- of the redox couple, as outlined in the rejection of claim 1 above), wherein the anions differ in ionic charge and/or molecular weight (AscH- of the ascorbic acid and Fe(CN)6]3- differ in ionic charge and molecular weight).
Regarding claim 20, modified Ben-Yoav teaches the method according to claim 19, wherein the anions in the mixture of analytes differ in ionic charge and molecular weight (AscH- of the ascorbic acid and Fe(CN)6]3- differ in ionic charge and molecular weight).
Response to Arguments
Applicant's arguments, see Remarks Pgs. 10-19, filed 4/2/2026, with respect to the 35 U.S.C. § 102(a)(1) and 35 U.S.C. § 103 rejections have been fully considered, and all 102 and 103 rejections from the previous office action are withdrawn.
Applicant’s Argument #1:
Regarding claim 1, Applicant argues at pages 10-11 that claim 1 has been amended to render the rejection moot by incorporating the subject matter of claims 2, 4, and 5. As claims 2 and 5 were not rejected as being anticipated by Ben-Yoav, claim 1 as amended, is not anticipated by Ben-Yoav for at least the same reasons.
Examiner’s Response #1:
Applicant’s arguments have been fully considered, but are moot in view of the new grounds of rejection for claim 1 above.
Applicant’s Argument #2:
Regarding claim 3, applicant argues at pages 11-14 that a skilled artisan would not have been motivated to modify the electrode array of Ben-Yoav by switching to electrodes coated with varying thin films (i.e., one or more working electrodes
coated with 15 to 35 nm thick films; one or more working electrodes coated with 35 to 50 nm thick films; one or more working electrodes coated with 50 to 65 nm thick films; one or more working electrodes coated with 65 to 80 nm thick films; and one or more working electrodes coated with 80 to 100 nm thick films), with a reasonable expectation to resolve a mixture of analytes of a type that was not tested experimentally in Ben-Yoav. Further, a skilled artisan could not have expected that upon variation of film thickness within a very narrow thickness range from 15 to 100 nm. Moreover, the specification of the subject application demonstrates that the claimed method would have been unexpected over the closest prior art, Ben-Yoav.
Examiner’s Response #2:
Applicant’s arguments have been fully considered, but are not persuasive. Firstly, Ben-Yoav does teach varying thickness, as outlined in the rejection of claim 1 above. Secondly, as outlined in the rejection of claim 3 above, since the film thickness is a result effective variable, one of ordinary skill in the art would optimize the thicknesses of films. Thirdly, applicant has not established criticality of the claimed film thicknesses. To establish unexpected results over a claimed thickness range, applicant should compare a sufficient number of tests both inside and outside the claimed thickness range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).
Applicant’s Argument #3:
Regarding claims 5-9, applicant argues at pages 14-18 that the prior art does not teach the amended feature of “wherein conductive additives are not included in the film” recited in the amended claim 1.
Examiner’s Response #3:
Applicant’s arguments have been fully considered but are moot in view of the new grounds of rejection for the amended claim 1 above. Note that Ben-Yoav teaches wherein the array of working electrodes comprises a subarray consisting of one or more bare electrode; and at least one of: subarray consisting of one or more film-coated electrodes; subarray consisting of one or more conductive additive- incorporated film-coated electrodes. Thus, Ben-Yoav teaches the array of working electrodes comprising a subarray consisting of one or more bare electrode and subarray consisting of one or more film-coated electrode. The subarray consisting of one or more film-coated electrode does not include conductive additives in the films.
Applicant’s Argument #4:
Regarding claim 7, applicant argues at pages 18-19 that there was no suggestion to determine the concentrations of Fe(CN)63-.
Examiner’s Response #4:
Applicant’s arguments have been fully considered but are not persuasive since claim 6 recites wherein the mixture of analytes comprises two or more anions, and the mixture of analytes comprises clozapine, uric acid, ascorbic acid, L-homocysteine and dopamine in a PBS solution of pH 7.4 containing redox couple of ferricyanide and ferrocyanide, as outlined in the rejection of claim 1 above. Thus, anions of the redox couple in the mixture of analytes are considered part of the overall mixture of analytes. Furthermore, claim 1 recites determining the presence and optionally the concentration of at least two analytes in a test sample which contains a mixture of analytes. Thus, it does not require all analytes in the mixture of analytes to be measured. The claimed limitation does not recite the at least two analytes comprising two or more anions.
Examiner suggests applicant to further amend claim 1 by reciting wherein the at least two analytes comprise a trivalent anion. Alternatively, Amend claim 1 by reciting wherein the at least two analytes comprising two or more anions differ in ionic charge and molecular weight.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHIZHI QIAN whose telephone number is (571)272-3487. The examiner can normally be reached Monday-Thursday 8:00 am-5:00 pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Luan V Van can be reached on 571-272-8521. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SHIZHI QIAN/Examiner, Art Unit 1795
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