DETAILED ACTION
In application filed on 02/23/2022, Claims 1-13 and 15-21 are pending. The claim set submitted on 07/23/2025 are considered in the current office 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/05/2026 has been entered.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-13 and 15-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims have been analyzed for eligibility in accordance with their broadest reasonable interpretation. All claims are directed to statutory categories, i.e., a method (Claims 1-13 and 15-21) (Step 1: YES).
Analysis:
Claim 1: Ineligible.
Step 1:
The claim recites a series of steps or acts, including “determining a first change in the electrochemical current signal flowing through the electrochemical cell by comparing the first electrochemical current signal and the second electrochemical current signal”; “determining a second change in the electrochemical current signal flowing through the electrochemical cell by comparing the third electrochemical current signal and the fourth electrochemical current signal; and determining a ratio of the first change in the electrochemical current signal and the second change in the electrochemical current signal to determine a relative quantity of the target compound in the first and second samples”.
Thus, the claim is directed to a method, which is one of the statutory categories of invention (Step 1: YES).
Step 2A Prong 1:
Claim 1 recites “determining a first change in the electrochemical current signal flowing through the electrochemical cell by comparing the first electrochemical current signal and the second electrochemical current signal;
determining a second change in the electrochemical current signal flowing through the electrochemical cell by comparing the third electrochemical current signal and the fourth electrochemical current signal; and
determining a ratio of the first change in the electrochemical current signal and the second change in the electrochemical current signal to determine a relative quantity of the target compound in the first and second samples” (math step).
Therefore, the claim is directed towards an abstract idea, and more specifically to the abstract idea group of a math or mental process since claim 1 relates to using a math process to “determine a first change in the electrochemical current signal flowing through the electrochemical cell by comparing the first electrochemical current signal and the second electrochemical current signal”;
“determine a second change in the electrochemical current signal flowing through the electrochemical cell by comparing the third electrochemical current signal and the fourth electrochemical current signal; and
determine a ratio of the first change in the electrochemical current signal and the second change in the electrochemical current signal to determine a relative quantity of the target compound in the first and second samples” (math step). (Step 2A, Prong 1: YES).
Step 2A, Prong 2:
This judicial exception is not integrated into a practical application.
Once the quantifying and determination is done, No further action takes place, much less a particular practical application. (Step 2A, Prong 2: NO).
Step 2B:
Furthermore, the courts have found that limitations adding insignificant extrasolution activity to the judicial exception, such as mere data gathering in conjunction with a law of nature or abstract idea, are limitations found not to be enough to qualify as ‘significantly more’ when recited in a claim with a judicial exception (see the 2014 Interim Guidance on Patent Subject Matter Eligibility of the Federal Register dated December 16, 2014; and MPEP 2106.05(I)(A)). Note that mere data gathering is not significantly more than the abstract idea. See MPEP 2106.05(g).
Here, there are no additional elements which are significantly more than the abstract idea. The applying, passing and measuring steps appear to be mere data gathering. Please note that mere data gathering is not significantly more than the abstract idea. See MPEP 2106.05(g).
In addition, the steps of applying, passing and measuring; and the electrochemical cell (which could be a detector) appears to be well-understood, routine, and conventional (WURC) in the field of laboratory/chemical diagnostics., as evidenced by any of Xu et al. ("A new quantification method using electrochemical mass spectrometry." Journal of The American Society for Mass Spectrometry 30.4 (2019): 685-693.), Suri et al. (US20170219521A1) and Chen et al. (WO2018081228A1), (See (Step 2B: NO).
Therefore, Claim 1 is ineligible.
Moreover, Claims 2-13 and 15-21 are rejected by virtue of their dependency on Claim 1.
Claim 2-3 and 5-20: Ineligible.
Step 2A, Prong One and Prong Two: Claims 2-3 and 5-20 further define the data gathering steps which appear to be generic and WURC.
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claims 2-3 and 5-20 are ineligible.
Claim 4: Ineligible.
Step 2A, Prong One: Claim 4 further recites “determining a third change in the electrochemical current signal flowing through the electrochemical cell by comparing the fifth electrochemical current signal and the sixth electrochemical current signal; and determining a ratio of (i) the first change in the electrochemical current signal and the third change in the electrochemical current signal, and/or (ii) the second change in the electrochemical current signal and the third change in the electrochemical current signal.(math step). Specifically, math equation as noted in MPEP 2106.04(a)(2)(B)
Step 2A, Prong Two:
Once the steps of determination is done, No further action takes place, much less a particular practical application. (Step 2A, Prong Two: NO).
Step 2B: The claims do not recite any elements which are significantly more.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 4-12, 15 and 19-21 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 4-12, 15 and 19-21 which recites the limitation “target compound” does not further limit the recitation of Claim 1 which recites “a target compound” and “wherein the target compound has a molecular weight in a range of from 5 kDa to 1 MDa”.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Moreover, Claims 5-16 and 21 are rejection by virtue of dependency on Claims 4-5, 11 and 15.
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.
Claims 1-2, 4-10 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over by Xu et al. ("A new quantification method using electrochemical mass spectrometry." Journal of The American Society for Mass Spectrometry 30.4 (2019): 685-693) in view of Suri et al. (US20170219521A1).
Regarding Claim 1, Xu teaches a method for determining relative quantity (See Page 689…peptide quantification where Glutathione (GSH) was chosen as the test example, thereby teaching “relative quantity”) of a target compound (referred to as Glutathione (GSH) [Page 689]) in a plurality of samples (See Fig. S3 for the 1st, 2nd and 3rd injections of samples of GSH samples (triplicate measurements)), the method comprising:
applying a first potential (‘+ 1.3 V’) to an electrochemical cell (‘electrochemical cell’; See Page 687, LC/EC with Online MS Analysis…EC for GSH analysis). Further See Page 689…+ 1.3 V was applied to the cell for GSH oxidized into glutathione disulfide;
measuring a first electrochemical current signal (See Fig. S3…See the GSH oxidation current peak at zero…Electric current response due to e) the blank sample) flowing through the electrochemical cell (‘electrochemical cell’; See Page 687, LC/EC with Online MS Analysis…EC for GSH analysis) when applying the first potential (See Page 689…the applied potential of… + 1.3 V,) in the absence of the target compound (See Fig. S3e…blank, thereby teaching “absence of the target compound”; See Page 689…Figure S3e shows the background current diagram for blank solvent sample as a contrast);
passing a first sample (See Page 689; Fig. S3f…injection of GSH sample; See Fig. S3, ref. f, for 1st injection of GSH) containing the target compound (referred to as Glutathione (GSH) [Page 689]) through the electrochemical cell (‘electrochemical cell’; See Page 687, LC/EC with Online MS Analysis…EC for GSH analysis);
measuring a second electrochemical current signal (See Fig. S3f…See the GSH oxidation current peak at about 2.5 µA…Electric current response due to f) the oxidation of GSH sample flowing through the electrochemical cell (‘electrochemical cell’; See Page 687, LC/EC with Online MS Analysis…EC for GSH analysis) when applying the first potential (See Page 689…the applied potential of… + 1.3 V) in the presence of the target compound (See Fig. S3f…GSH , 1st injection, thereby teaching “presence of the target compound”; See Page 689…Figure S3f shows the GSH oxidation current peak was detected. Further See Page 689…+ 1.3 V was applied to the cell for GSH oxidized into glutathione disulfide;
determining a first change in the electrochemical current signal (See Page 689… the GSH oxidation current peak was detected, as shown in Figure S3f, S3 g and S3 h (Figure S3e shows the background current diagram for blank solvent sample as a contrast, thereby teaching “determining a first change in the electrochemical current signal”) flowing through the electrochemical cell (‘electrochemical cell’; See Page 687, LC/EC with Online MS Analysis…EC for GSH analysis) by comparing (“Figure S3e shows the background current diagram for blank solvent sample as a contrast, thereby teaching “comparing”) the first electrochemical current signal (See Fig. S3…See the GSH oxidation current peak at zero…Electric current response due to e) the blank sample) and the second electrochemical current signal (See Fig. S3f…See the GSH oxidation current peak at about 2.5 µA…Electric current response due to f);
applying a second potential (‘-0.35 V’; See Fig. S3 for 2nd injection of GSH) to an electrochemical cell (‘electrochemical cell’; See Page 687, LC/EC with Online MS Analysis…EC for GSH analysis). Further See Page 689…+ 1.3 V was applied to the cell for GSH oxidized into glutathione disulfide.
While Xu does not explicitly teach that the target compound has a molecular weight in a range of from 5 kDa to 1 MDa
Xu does disclose that in our study, the utilization of thiol oxidation for quantifying peptide GSH indicates that our method could find valuable applications in quantitation of large molecules such as proteins (it is known that proteins have a molecular weight in the range of 5kDa to 1 MDa). Such an investigation is underway (Page 692, See Conclusions). Further Xu discloses that in particular, the success for GSH quantification suggests the possibility of using our approach for proteins carrying thiols or disulfide bonds. For example, a cysteine-containing protein could be digested enzymatically into peptides carrying thiol groups, which can be analyzed using our method. Such an investigation is underway and will be reported on due course (See Page 690-691).
It would have been obvious to one with ordinary skill in the art before the effective filing date to substitute GSH of Xu with protein of Xu because this is a substitution of equivalent elements yielding predictable results. Please See MPEP 2143 (KSR Rationale B). Xu teaches that the success for GSH (peptide) quantification suggests the possibility of using our approach for proteins (Xu, Page 690)
As a result, Examiner submits that Xu teaches that the target compound has a molecular weight in a range of from 5 kDa to 1 MDa (See Page 690-692 for proteins, which could have molecular weights in a range of from 5 kDa to 1 MDa) which functions for the benefit of providing valuable applications in quantitation of large molecules such as proteins (See conclusions) allowing for utilizing MS in combination with electrochemistry (EC) with the goal of achieving accurate chemical quantification of analytes in mixtures without using any standards or isotope-labeled compounds (Xu, Introduction).
Further, Xu does not teach explicitly teach:
measuring a third electrochemical current flowing through the electrochemical cell when applying the second potential in the absence of the target compound;
passing a second sample containing the target compound through the electrochemical cell, wherein the second sample has a different concentration of the target compound than the first sample;
measuring a fourth electrochemical current signal flowing through the electrochemical cell when applying the second potential in the presence of the target compound;
determining a second change in the electrochemical current signal flowing through the electrochemical cell by comparing the third electrochemical current signal and the fourth electrochemical current signal; and
determining a ratio of the first change in the electrochemical current signal and the second change in the electrochemical current signal to determine a relative quantity of the target compound in the first and second samples.
In the analogous art of electrochemical sensors, Suri teaches:
measuring a third electrochemical current (Annotated See Fig. 5 for current of about -2.75 µA) flowing through the electrochemical cell (referred to as electrochemical sensor [Para 0023]) when applying the second potential (referred to as -0.35 volts [Para 0023]) in the absence of the target compound (See Fig. 5…0 mg/dL glucose);
passing a second sample containing the target compound (referred to as 50mg/dL glucose [Fig. 5]) through the electrochemical cell (referred to as electrochemical sensor [Para 0023]), wherein the second sample (referred to as 50mg/dL [Fig. 5]) has a different concentration (See Annotated Fig. 5 for the difference) of the target compound than the first sample (See Fig. 5…0 mg/dL glucose, thereby teaching the first sample);
measuring a fourth electrochemical current signal (See Annotated Fig. 5…-2.55 µA) flowing through the electrochemical cell (referred to as electrochemical sensor [Para 0023] when applying the second potential (referred to as -0.35 volts [Para 0023]) in the presence of the target compound (referred to as 50mg/dL [Fig. 5]);
determining a second change in the electrochemical current signal (See Annotated Fig. 5 for the difference between -2.55 µA and -2.75 µA; The exemplary teachings of Suri discloses the second change as 0.2 µA) flowing through the electrochemical cell (referred to as electrochemical sensor [Para 0023] by comparing (See Annotated Fig. 5 for the comparison) the third electrochemical current signal (Annotated See Fig. 5 for current of about -2.75 µA) and the fourth electrochemical current signal (See Annotated Fig. 5…-2.55 µA);and
determining a ratio (The exemplary teachings of Suri in Fig. 8 discloses the ratio as 0.75/1)) of the first change (See Fig. 8; I/Io of 0 mg/dL is 1) in the electrochemical current signal and the second change in the electrochemical current signal (See Fig. 8; I/Io of 50 mg/dL is about 0.75) to determine a relative quantity of the target compound (See Para 0120…The measured current is compared with a reference signature, for example, a calibration plot, or a calibration equation to determine the concentration of the target analyte in the sample ) in the first (See Fig. 5…0 mg/dL glucose, thereby teaching the first sample) and second samples (referred to as 50mg/dL [Fig. 5]).
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Annotated Fig. 5, Suri
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xu to incorporate “
measuring a third electrochemical current flowing through the electrochemical cell when applying the second potential in the absence of the target compound; passing a second sample containing the target compound through the electrochemical cell, wherein the second sample has a different concentration of the target compound than the first sample; measuring a fourth electrochemical current signal flowing through the electrochemical cell when applying the second potential in the presence of the target compound; determining a second change in the electrochemical current signal flowing through the electrochemical cell by comparing the third electrochemical current signal and the fourth electrochemical current signal; and determining a ratio of the first change in the electrochemical current signal and the second change in the electrochemical current signal to determine a relative quantity of the target compound in the first and second samples” as taught by Suri for the benefit of using a calibration plot or a calibration equation to determine the concentration of the target analyte in the sample (Suri, Para 0120), allowing for the development of new electrochemical sensors and biosensing molecules for in vitro and in vivo measurement that can provide a higher signal to noise ratio, longer life, and do not consume the target analyte (Suri, Para 0006).
Regarding Claim 2, the method of claim 1 is obvious over Xu in view of Suri.
Xu further teaches that the potential (See Page 689…+ 1.3 V was applied to the cell for GSH oxidized into glutathione disulfide; See Fig. S3… the applied potential of (a) +1.3 V) comprises oxidative potential, reductive potential or a combination thereof (See Para 0686…positive potential (ranging from + 1.2 to + 1.3 V) was applied to the WE electrode for oxidation of the LC-separated target compounds, thereby teaching “oxidative potential”).
Regarding Claim 4, the method of claim 1 is obvious over Xu in view of Suri.
Xu further applying a third potential (‘-0.35 V’; See Fig. S3 for 3rd injection of GSH) to an electrochemical cell (‘electrochemical cell’; See Page 687, LC/EC with Online MS Analysis…EC for GSH analysis). Further See Page 689…+ 1.3 V was applied to the cell for GSH oxidized into glutathione disulfide.
Xu does not teach:
measuring a fifth electrochemical current signal flowing through the electrochemical cell when applying the third potential in the absence of the target compound;
passing a third sample containing the target compound through the electrochemical cell, wherein the third sample has a different concentration of the target compound than the first sample and/or the second sample;
measuring a sixth electrochemical current signal flowing through the electrochemical cell when applying the third potential in the presence of the target compound;
determining a third change in the electrochemical current signal flowing through the electrochemical cell by comparing the fifth electrochemical current signal and the sixth electrochemical current signal; and
determining a ratio of (i) the first change in the electrochemical current signal and the third change in the electrochemical current signal, and/or (ii) the second change in the electrochemical current signal and the third change in the electrochemical current signal.
In the analogous art of electrochemical sensors, Suri teaches:
measuring a fifth electrochemical current signal (Annotated See Fig. 5 for current of about -2.75 µA) flowing through the electrochemical cell (referred to as electrochemical sensor [Para 0023]) when applying the third potential (referred to as -0.3 volts [Para 0023; 0044]) in the absence of the target compound (See Fig. 3…0 mg/dL glucose);
passing a third sample containing the target compound (referred to as 100mg/dL glucose [Fig. 5]) through the electrochemical cell (referred to as electrochemical sensor [Para 0023]), wherein the third sample (referred to as 100mg/dL glucose [Fig. 5]) has a different concentration (Annotated Fig. 5 for the difference in concentration) of the target compound than the first sample and/or the second sample (See Fig. 5…50 mg/dL and/or 0 mg/dL glucose, thereby teaching the first sample and/or third sample);
measuring a sixth electrochemical current signal (Annotated See Fig. 5 for current of about -2.40 µA) flowing through the electrochemical cell (referred to as electrochemical sensor [Para 0023]) when applying the third potential (referred to as -0.3 volts [Para 0023; 0044]) in the presence of the target compound (See Fig. 3; Fig. 5…100 mg/dL glucose);
determining a third change in the electrochemical current signal (See Annotated Fig. 5 for the difference between -2.40 µA and -2.75 µA; The exemplary teachings of Suri discloses the second change as 0.35 µA) flowing through the electrochemical cell by comparing (See Annotated Fig. 5 for the comparison) the fifth electrochemical current signal (Annotated See Fig. 5 for current of about -2.75 µA) and the sixth electrochemical current signal (Annotated See Fig. 5 for current of about -2.40 µA); and
determining a ratio (The exemplary teachings of Suri in Fig. 8 discloses the ratio as 1.5/1)) of the first change (See Fig. 8; I/Io of 0 mg/dL is 1) in the electrochemical current signal and the third change in the electrochemical current signal (See Fig. 8; I/Io of 100 mg/dL is about 1.5).
Examiner submits that the limitation “and/or (ii) the second change in the electrochemical current signal and the third change in the electrochemical current signal” is viewed as optional in light of the recited “and/or” and therefore not required by the claim.)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xu to incorporate “measuring a fifth electrochemical current signal flowing through the electrochemical cell when applying the third potential in the absence of the target compound; passing a third sample containing the target compound through the electrochemical cell, wherein the third sample has a different concentration of the target compound than the first sample and/or the second sample; measuring a sixth electrochemical current signal flowing through the electrochemical cell when applying the third potential in the presence of the target compound; determining a third change in the electrochemical current signal flowing through the electrochemical cell by comparing the fifth electrochemical current signal and the sixth electrochemical current signal; and determining a ratio of (i) the first change in the electrochemical current signal and the third change in the electrochemical current signal, and/or (ii) the second change in the electrochemical current signal and the third change in the electrochemical current signal” as taught by Suri for the benefit of using a calibration plot or a calibration equation to determine the concentration of the target analyte in the sample (Suri, Para 0120), allowing for the development of new electrochemical sensors and biosensing molecules for in vitro and in vivo measurement that can provide a higher signal to noise ratio, longer life, and do not consume the target analyte (Suri, Para 0006).
Regarding Claim 5, the method of claim 1 is obvious over Xu in view of Suri.
Xu further teaches identifying the target compound (‘GSH’) (See Page 687… LC/EC with Online MS Analysis of GSH; See Page 689…before electrolysis (Figure S3c, Supporting Information), the protonated GSH was detected at m/z 308; See Introduction…Mass spectrometry (MS) has become a widely used technique for characterization and identification of both small and large molecule; Further See Xu…a target compound… is first introduced to an electrochemical cell for electrochemical redox conversion (oxidation or reduction) followed by MS detection (‘identified’)).
Regarding Claim 6, the method of claim 5 is obvious over Xu in view of Suri.
Xu further teaches that the target compound (GSH) is identified based upon molecular weight (See Page 687… LC/EC with Online MS Analysis of GSH; See Page 689…before electrolysis (Figure S3c, Supporting Information), the protonated GSH was detected at m/z 308; and structural information (See Fig. S3a and S3b, for Figure S3a and S3b show the EIC (m/z 308, the protonated GSH) of 200 μM GSH with an injection volume of 6 μL (injected amount: 1200 pmol)).
Regarding Claim 7, the method of claim 5 is obvious over Xu in view of Suri.
Xu further teaches that the target compound (‘GSH’) is identified by a method (See Page 687… LC/EC with Online MS Analysis of GSH) comprising one or more of mass spectrometry, UV-VIS spectroscopy, and fluorescence spectroscopy (See Page 687… LC/EC with Online MS Analysis of GSH); See Introduction…MS is mass spectrometry).
Regarding Claim 8, the method of claim 5 is obvious over Xu in view of Suri.
Xu further teaches that the target compound (‘GSH’) is identified by mass spectrometry (See Page 687… LC/EC with Online MS Analysis of GSH; See Introduction…MS is mass spectrometry).
Regarding Claim 9, the method of claim 8 is obvious over Xu in view of Suri.
Xu further teaches that the mass spectrometry (See Page 687…LC/EC with Online MS Analysis… GSH was analyzed using online LC/EC/DESI-MS apparatus) comprises ionizing the target compound (See Page 689, protonated GSH; See Page 689…GSH is detected as an ion).
Regarding Claim 10, the method of claim 9 is obvious over Xu in view of Suri.
Xu further teaches that ionizing the target compound (See Page 689, protonated GSH; See Page 689…GSH is detected as an ion, thereby teaching “ionizing the target compound’) comprises electrospray ionization, laser ionization, plasma ionization, high energy particle ionization or combinations thereof (See Page 686, Apparatus… For nano-ESI-MS analysis…the sample can be ionized…; Also see…analysis using nano-electrospray ionization mass spectrometry (nano-ESI-MS, Scheme 2a)).
Regarding Claim 21, the method of claim 4 is obvious over Xu in view of Suri.
The combination of Xu and Suri does not teach “determining a relative quantity of the target compound in the third sample relative to the first and/or second sample”.
In the analogous art of electrochemical sensors, Suri teaches:
“determining a relative quantity of the target compound (See Para 0120…The measured current is compared with a reference signature, for example, a calibration plot, or a calibration equation to determine the concentration of the target analyte in the sample) in the third sample (referred to as 100mg/dL glucose [Fig. 5]) relative to the first and/or second sample (See Fig. 5…50 mg/dL and/or 0 mg/dL glucose, thereby teaching the first sample and/or third sample)”.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xu to incorporate “determining a relative quantity of the target compound in the third sample relative to the first and/or second sample” as taught by Suri for the benefit of using a calibration plot or a calibration equation to determine the concentration of the target analyte in the sample (Suri, Para 0120), allowing for the development of new electrochemical sensors and biosensing molecules for in vitro and in vivo measurement that can provide a higher signal to noise ratio, longer life, and do not consume the target analyte (Suri, Para 0006).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. ("A new quantification method using electrochemical mass spectrometry." Journal of The American Society for Mass Spectrometry 30.4 (2019): 685-693) in view of Suri et al. (US20170219521A1) as applied to claim 1 above, and further in view of Coope et al. (US20140202859A1).
Regarding Claim 3, the method of claim 1 is obvious over Xu in view of Suri.
Xu further teaches the potential (See Page 689… the applied potential of 0 V and + 1.3 V, respectively for GSH).
The combination of Xu and Jaffrey does not teach that the potential comprises direct current potential and a pulsed mode potential.
In the analogous art of apparatus and methods for size selecting nucleic acid molecules having wide range of applications including the production of DNA libraries for sequencing technologies, Coope teaches that the potential (referred to as potential difference [Para 0047]) comprises direct current potential (referred to as a DC electrical potential [Para 0047]) and a pulsed mode potential (referred to as a pulsed DC electrical potential [Para 0047]). Also, Coope teaches that the channel current is also individually controllable via pulse width modulation of the DC voltage so that if adjacent samples are running at different speeds, the extractions times can be altered so that no two samples need to be extracted at the same moment (Para 0010).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xu and Suri to utilize the potential comprising direct current potential and a pulsed mode potential, as taught Coope for the benefit of using pulse width modulation of the DC voltage to control the channel current individually so as to control the speed of samples from the loading well along the channel toward an extraction well (Coope, Para 0010, 0047), allowing for the generation of r timed nucleic acid extractions are generated provide size selected nucleic acid molecules of required size ranges, for a wide range of applications including the production of DNA libraries for sequencing technologies (Coope Abstract).
Claims 11-13 is rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. ("A new quantification method using electrochemical mass spectrometry." Journal of The American Society for Mass Spectrometry 30.4 (2019): 685-693) in view of Suri et al. (US20170219521A1) as applied to claim 1 above, an further in view of Tipple et al. ("Methods for the determination of plasma or tissue glutathione levels." Developmental Toxicology: Methods and Protocols. Totowa, NJ: Humana Press, 2012. 315-324.).
Regarding Claim 11, the method of claim 1 is obvious over Xu in view of Suri.
Xu further teaches separating (See Page 687…use of LC/UPLC for separation of GSH using 80%A isocratic elution program for 10 min was used for GSH) the target compound (See Page 687…elution of GSH) from a GSH solution (See Page 687…) in the first sample and/or the second sample (See Page 689; Fig. S3f…injection of GSH sample; See Fig. S3, ref. f, for 1st injection of GSH; The claimed “and/or” second sample is viewed as optional).
The combination of Xu and Suri does not teach “separating a target compound from a mixture”.
In the analogous art of the methods for the determination of plasma or tissue glutathione, Tipple teaches “separating a target compound” (See Page 5; Section 3.2…GSH and GSSG measurement by HPLC; See Page 6…plasma samples having GSH and GSSG; See Page 7, for the HPLC gradient condition for separation).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xu and Suri to incorporate “separating a target compound from a mixture”, as taught by Tipple for the benefit of measuring the GSH and GSSG levels in biosamples such as plasma, cells and tissues via HPLC (Tipple, Section 3.2; Pages 5-6), allowing for the provision of an analysis method that is particularly useful for situations in which sample amounts are limited (Tipple, Abstract).
Regarding Claim 12, the method of claim 11 is obvious over Xu in view of Suri and in view of Tipple.
Xu further teaches separating (See Page 687…use of LC/UPLC for separation of GSH using 80%A isocratic elution program for 10 min was used for GSH) the target compound (See Page 687…elution of GSH) comprises using one or more or a chromatography device and an electrophoresis device (See Page 686, Apparatus…Waters ultra-performance liquid chromatography (UPLC)).
Regarding Claim 13, the method of claim 12 is obvious over Xu in view of Suri and in view of Tipple.
Xu further teaches that the chromatography device comprises Ultra- Performance Liquid Chromatography (UPLC), High-Performance Liquid Chromatography (HPLC) or Nanoscale liquid chromatography (nanoLC) (See Page 686, Apparatus…Waters ultra-performance liquid chromatography (UPLC)).
Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. ("A new quantification method using electrochemical mass spectrometry." Journal of The American Society for Mass Spectrometry 30.4 (2019): 685-693) in view of Suri et al. (US20170219521A1) as applied to claim 1 above, and further in view of McCord et al. ("Identifying per-and polyfluorinated chemical species with a combined targeted and non-targeted-screening high-resolution mass spectrometry workflow." Journal of visualized experiments: JoVE 146 (2019): 10-3791.).
Regarding Claim 15, the method of claim 1 is obvious over Xu in view of Suri (See Claim 1 rejection).
The combination of Xu and Suri does not teach that the target compound comprises peptides, proteins, nucleic acids, lipids, carbohydrates, drugs, drug metabolites, synthetic polymers, organic pollutants or combinations thereof.
In the analogous art of a liquid chromatography-tandem mass spectrometry determination method of perfluoroalkyl alcohol in textiles, McCord teaches that the target compound (referred to as Polyfluoro and perfluoroalkyl compounds (PFASs) [Introduction]) comprises peptides, proteins, nucleic acids, lipids, carbohydrates, drugs, drug metabolites, synthetic polymers, organic pollutants or combinations thereof. (See Abstract.. perfluoroalkyl compounds thereby teach organic pollutants) (See Introduction… The class of per- and polyfluoroalkyl substances (PFASs) are persistent organic pollutants with significant public health concern).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xu and Suri to have the target compound comprising peptides, proteins, nucleic acids, lipids, carbohydrates, drugs, drug metabolites, synthetic polymers, organic pollutants or combinations thereof, as taught by McCord for the benefit of providing targeted LC-MS/MS analysis of fluorochemical species in water where analytical standards are available and detailing the seamless integration of a non-targeted, high-resolution mass spectrometry-based approach for data analysis that enables the detection of unknown or unexpected compounds in the same samples (McCord, Introduction , Page 1), allowing for aligning targeted LC-MS/MS PFAS quantitation with the need to identify and semi-quantitatively monitor emerging compounds of interest (McCord, Introduction , Page 2).
Regarding Claim 16, the method of claim 15 is obvious over Xu in view of Suri in further view of McCord.
The combination of Xu and Suri does not teach that the organic pollutant comprises per- and polyfluoroalkyl substances (PFAS).
In the analogous art of a liquid chromatography-tandem mass spectrometry determination method of perfluoroalkyl alcohol in textiles, McCord teaches that the organic pollutant (See Introduction… The class of per- and polyfluoroalkyl substances (PFASs) are persistent organic pollutants with significant public health concern) comprises per- and polyfluoroalkyl substances (PFAS) (referred to as Polyfluoro and perfluoroalkyl compounds (PFASs) [Introduction]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xu and Suri to incorporate the organic pollutant comprising per- and polyfluoroalkyl substances (PFAS), as taught by McCord for the benefit of monitoring the class of per- and polyfluoroalkyl substances (PFASs) with targeted LC-MS/MS as there are persistent organic pollutants with significant public health concern, (McCord, Introduction , Page 1), allowing for aligning targeted LC-MS/MS PFAS quantitation with the need to identify and semi-quantitatively monitor emerging compounds of interest (McCord, Introduction , Page 2).
Claims 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. ("A new quantification method using electrochemical mass spectrometry." Journal of The American Society for Mass Spectrometry 30.4 (2019): 685-693) in view of Suri et al. (US20170219521A1) as applied to claim 1 above, and further in view of Chen et al. (WO2018081228A1).
Regarding Claim 17, the method of claim 1 is obvious over Xu in view of Suri (See Claim 1 rejection).
Xu further teaches wherein the electrochemical cell (referred to as an electrochemical thin-layer flow cell [Page 686, Apparatus]) comprises an inlet (See Annotated Scheme 2…inlet), an outlet (See Annotated Scheme 2…outlet), an electrode (See Apparatus Page 686… working electrode (WE)); a current signal (‘electrochemical current’) (See Page 691…The electric current response due to the uric acid oxidation is shown in Figure 3d–f, in which a sharp peak at 2 min was observed).
The combination of Xu and Suri does not teach a potentiostat, the potentiostat is configured to measure the electrochemical current signal flowing through the electrochemical cell.
In the analogous art of methods and devices for chemical quantification using mass spectrometry (MS) combined with electrochemistry (EC), Chen teaches a potentiostat (See Page 6…potentiostat), the potentiostat (See Page 6…potentiostat) is configured to measure the electrochemical current signal(‘oxidation/reduction current responses’) (See Page 6…During the application of the oxidation/reduction potential, the oxidation/reduction current responses are monitored and recorded by the potentiostat 22 or another sensor) flowing through the electrochemical cell (See Page 6…When the LC eluent flows through the electrochemical cell 14, an oxidation/reduction potential is applied by a potentiostat).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the electrochemical cell of Xu and Suri to have a potentiostat, the potentiostat is configured to measure the electrochemical current signal flowing through the electrochemical cell, as taught by Chen for the benefit of using the potentiostat to apply an oxidation/reduction potential to the LC eluent flowing through the electrochemical cell and also monitoring the oxidation/reduction current responses (Chen, Page 6) allowing for the provision of a quantification method does not involve the use of standard compounds and is applicable for analysis of target compounds in a complex mixture, especially where the chemical standard is not commercially available or is difficult to synthesize (e.g., drug metabolites or proteins) (Chen, Para 0004).
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Annotated Scheme 2, Xu
Regarding Claim 18, the method of claim 17 is obvious over Xu in view of Suri in further view of Chen (See Claim 17 rejection).
Xu teaches that the electrode (See Apparatus Page 686… working electrode (WE)) comprises a porous electrode, a flat electrode, or a modified electrode (See Apparatus, Page 686…a Magic Diamond (boron doped diamond) disc electrode (i.d., 8 mm) as the working electrode (WE), thereby teaching a “flat electrode”).
In addition, Examiner submits that the claimed “flat electrode” is not specifically defined in the specification and will therefore be given the broadest reasonable interpretation in light of the specification. Any electrode that has a flat form/shape such as a disc shape will be considered a “flat electrode”. As such, a disc electrode would satisfy a “flat electrode”.
Regarding Claim 19, the method of claim 17 is obvious over Xu in view of Suri in further view of Chen (See Claim 17 rejection).
Xu teaches a mass spectrometer (See Annotated Scheme 2) is operatively connected to the outlet (See Annotated Scheme 2) for detecting the target compound (referred to as Glutathione (GSH) [Page 689]).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. ("A new quantification method using electrochemical mass spectrometry." Journal of The American Society for Mass Spectrometry 30.4 (2019): 685-693) in view of Suri et al. (US20170219521A1) further in view of Chen et al. (WO2018081228A1) as applied to claim 17 above, and further in view of Tipple et al. ("Methods for the determination of plasma or tissue glutathione levels." Developmental Toxicology: Methods and Protocols. Totowa, NJ: Humana Press, 2012. 315-324.).
Regarding Claim 20, the method of claim 17 is obvious over Xu in view of Suri in further view of Chen (See Claim 17 rejection).
Xu teaches a liquid chromatography or an electrophoresis device (See Page 686, Apparatus…a C18 column for LC separation) is operatively connected to the inlet (See Annotated Scheme 2) for separating (See Page 687…use of LC/UPLC for separation of GSH using 80%A isocratic elution program for 10 min was used for GSH) the target compound (See Page 687…elution of GSH) from a GSH solution (See Page 687…) in the first sample and/or the second sample (See Page 689; Fig. S3f…injection of GSH sample; See Fig. S3, ref. f, for 1st injection of GSH; The claimed “and/or” second sample is viewed as optional).
The combination of Xu, Suri and Chen does not teach “separating a target compound from a mixture”.
In the analogous art of the methods for the determination of plasma or tissue glutathione, Tipple teaches “separating a target compound” (See Page 5; Section 3.2…GSH and GSSG measurement by HPLC; See Page 6…plasma samples having GSH and GSSG; See Page 7, for the HPLC gradient condition for separation).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xu, Suri and Chen to incorporate “separating a target compound from a mixture”, as taught by Tipple for the benefit of measuring the GSH and GSSG levels in biosamples such as plasma, cells and tissues via HPLC (Tipple, Section 3.2; Pages 5-6), allowing for the provision of an analysis method that is particularly useful for situations in which sample amounts are limited (Tipple, Abstract).
Response to Arguments
Applicant's arguments filed on 01/05/2026, with respect to the 35 U.S.C. §101 rejections on Claims 1-20 (Claims 1-13 and 15-21) have been fully considered but they are not persuasive.
Specifically, regarding Step 2A-Prong I, "quantifying a first change in an electrochemical current signal flowing through the electrochemical cell", "quantifying a second change in the electrochemical current signal flowing through the electrochemical cell" and "determining a ratio of the first change in the electrochemical current signal and the second change in the electrochemical current signal to determine a relative quantity of the target compound in the first and second samples" are "math steps" and thus directed to an abstract idea.
However, quantifying a change in the electrochemical current signal is not a mental step or a math step. Instead, it requires measuring a change in the electrochemical current signal, i.e. measuring the electrochemical current signal in the absence and presence of the target compound. As described in paragraph [00031] and FIG. 2 of the present patent application, the electrochemical current signal can be measured by a potentiostat operatively connected to the electrodes. As described in paragraphs [00033]-[00034] of the present patent application, when a sample analyte passes through the electrochemical cell, the target compound is subjected to electrochemical oxidation or reduction, thus causing the rise of a current signal. A change in the current signal is determined when the target compound undergoes an electrochemical reaction. In other words, quantifying a change in the electrochemical current signal flowing through the electrochemical cell requires particular measurements with specific equipment, and thus is more than a simple math step.
Claim 1 has been amended to clarify the steps of the method by explicitly reciting: (1) measuring a first electrochemical current signal flowing through the electrochemical cell when applying the first potential in the absence of the target compound; (2) measuring a second electrochemical current signal flowing through the electrochemical cell when applying the first potential in the presence of the target compound; (3) determining a first change in the electrochemical current signal flowing through the electrochemical cell by comparing the first electrochemical current signal and the second electrochemical current signal; (4) measuring a third electrochemical current flowing through the electrochemical cell when applying the second potential in the absence of the target compound; (5) measuring a fourth electrochemical current signal flowing through the electrochemical cell when applying the second potential in the presence of the target compound; and (6) determining a second change in the electrochemical current signal flowing through the electrochemical cell by comparing the third electrochemical current signal and the fourth electrochemical current signal.
According to MPEP 216.04(a), there are 3 categories of abstract ideas: 1) mathematical concepts; (2) certain methods of organizing human activity and (3) mental processes. As the claimed measuring steps described above are not mathematical concepts, methods of organizing human activity, or mental steps, Applicant submits that these steps are not directed to abstract ideas.
Applicant’s arguments with respect to independent claim 1 has been considered and Examiner respectfully disagrees. In response to applicant's argument, Examiner submits that this is not persuasive as “determining a first change in the electrochemical current signal flowing through the electrochemical cell by comparing the first electrochemical current signal and the second electrochemical current signal”; “determining a second change in the electrochemical current signal flowing through the electrochemical cell by comparing the third electrochemical current signal and the fourth electrochemical current signal; and determining a ratio of the first change in the electrochemical current signal and the second change in the electrochemical current signal to determine a relative quantity of the target compound in the first and second samples.” is certainly an abstract idea as it is a math process, as disclosed in the Claim 1 rejection. Specifically, math equation as noted in MPEP 2106.04(a)(2)(B)
Further Examiner submits that the steps of “determining…” appears to be mental/mathematical evaluations, and therefore an abstract idea.
Lastly, in light of Applicant’s specification [Para 00036], a ratio of the change in current or Q is calculated to determine relative quantities of the target compound in different samples, which is mathematical step, further confirming the abstract nature of the step.
Specifically, regarding Step 2A-Prong 2, Applicant notes that even if the Examiner determines that the claim includes a judicial exception, the "mere recitation of a judicial exception does not mean that the claim is 'directed to' that judicial exception under Step 2A Prong Two. Instead, under Prong Two, a claim that recites a judicial exception is not directed to that judicial exception, if the claim as a whole integrates the recited judicial exception into a practical application of that exception. Prong Two thus distinguishes claims that are "directed to" the recited judicial exception from claims that are not "directed to" the recited judicial exception." (MPEP 2106.04 (II)(A)(2))…
Thus, as none of the cited references, alone or in combination, provide for the electrochemical measurement of a relative quantity of the claimed target compound in a plurality of samples having different concentrations of the target compound, Applicant respectfully submits the claims 1-13 and 15-20 are not obvious over the cited references. Accordingly, Applicant respectfully requests that the rejections be reconsidered and withdrawn.
Applicant’s arguments with respect to independent claim 1 has been considered and Examiner respectfully disagrees. In response to applicant's argument, Examiner submits that this is not persuasive and that the steps of applying, passing and measuring” steps, from the background section of the claim, appear well-understood, routine, and conventional (WURC) in the field of laboratory diagnostics, as evidenced by any of Xu et al. ("A new quantification method using electrochemical mass spectrometry." Journal of The American Society for Mass Spectrometry 30.4 (2019): 685-693.), Suri et al. (US20170219521A1) and Chen et al. (WO2018081228A1).
Applicant’s arguments, see Page 10, filed 01/05/2026, with respect to the rejection(s) of claim(s) 1-2, 4-10 and 14 under 35 U.S.C. §103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Xu et al. ("A new quantification method using electrochemical mass spectrometry." Journal of The American Society for Mass Spectrometry 30.4 (2019): 685-693) in view of Suri et al. (US20170219521A1).
Applicant submits that none of the cited references is directed to the electrochemical measurement of a relative quantity of a target compound in a plurality of samples. In particular, as described in paragraph [0006] of the present patent application, both Xu and Chen relate to the absolute quantification of analytes. Notably, Xu takes triplicate measurements of the same sample to confirm that the measurements were consistent and to calculate an average value (see Xu at p. 688, second paragraph under the heading "LC/EC with Offline MS Analysis"; see also Figs. 1 b-1d, 2f-2h, 3d-3f). Xu then integrates the measured current areas and calculates a absolute total quantity of analyte that is oxidized or reduced using the formula n = Q/zF where Q is the integrated current over time, z is the number of electrons transferred per molecule for the redox reaction, and F is the Faraday constant (see Xu at p. 686, first paragraph)…Thus, as none of the cited references, alone or in combination, provide for the electrochemical measurement of a relative quantity of the claimed target compound in a plurality of samples having different concentrations of the target compound, Applicant respectfully submits the claims 1-13 and 15-20 are not obvious over the cited references. Accordingly, Applicant respectfully requests that the rejections be reconsidered and withdrawn.
Applicant’s arguments with respect to amended claim 1 has been considered and Examiner respectfully disagrees.
Examiner submits that the limitations of amended Claim 1 is taught as disclosed in the rejection of Claim 1 (Supra) by Xu et al. (Xu, Chang, et al. "A new quantification method using electrochemical mass spectrometry." Journal of The American Society for Mass Spectrometry 30.4 (2019): 685-693), in further view of Suri et al. (US20170219521A1).
Applicant’s arguments, see Page 12, filed 01/05/2026, with respect to the rejection(s) of claim(s) 1-2, 4-15 and 17-20 on the ground of nonstatutory double patenting have been fully considered and are persuasive; claim(s) 3 on the ground of nonstatutory double patenting have been fully considered and are persuasive; and claim(s) 16 on the ground of nonstatutory double patenting have been fully considered and are persuasive. Therefore, the rejection has been withdrawn.
Applicant respectfully traverses these bases for rejection. The cited claims of U.S. Patent No. 11,360,058 are directed to a method for determining an absolute total amount of a target compound in a sample. U.S. Patent No. 11,360,058 claims has similar disclosure to Chen described above, and indeed both U.S. Patent No. 11,360,058 and Chen claim priority to the same provisional application.
As set above, Xu relates to the absolute quantification of analytes, and none of Jaffrey, Coope or McCord is directed to the relative quantification of an analyze in a plurality of samples. Moreover, the claims of U.S. Patent No. 11,360,058 (like Xu described above) do not teach or suggest measuring concentrations of a target compound having a molecular weight in a range of from 5 kDa to 1 MDa. Thus, for the reasons described above, Applicant submits that claims 1-13 and 15-20 are not obvious over the claims of U.S. Patent No. 11,360,058 in view of the cited references.
Examiner submits that the that claims 1-13 and 15-20 are not obvious over the claims of U.S. Patent No. 11,360,058 in view of the cited references.
Conclusion
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/OYELEYE ALEXANDER ALABI/Examiner, Art Unit 1797