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 .
Preliminary Amendment
The preliminary amendments of claims, filed 03/13/2024, has been fully considered.
Status of Claims
Claim 1-6 are pending and under examination.
Information Disclosure Statement
The information disclosure statement (IDS) document(s) submitted on 01/22/2024 and 10/10/2025 are compliant with the provisions of 37 CFR 1.97. Accordingly, the IDS document(s) has/have been fully considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 lines 3-4 recite “a portion of liquid … in the first step”. However, the first step recites “the sample”. The claims would be clearer if applicant were to recite “a portion of the sample … in the first step. Further, line 5 recites “the sample subjected to reduction treatment” and line 7 refers to “both samples”. The examiner suggest applicant amend line 5 to recite “the portion of the sample subjected to reduction treatment” and line 7 to recite “the sample and the portion of the sample subjected to reduction treatment”.
Appropriate correction is required.
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 1-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1: Claim 1 is directed toward a method.
Step 2A, Prong One: Identify the law of nature/natural phenomenon/abstract ideas.
Claims 1, 13, and 15 recite the abstract ideas, “comparing results of analysis of both samples”, “determining components of signals disappeared by the reduction treatment as candidates for the active sulfur in the sample”, “confirming that the signals are derived from the alkylating agent”, and “performing structural analysis of the components”.
These abstract ideas are mental processes that could be performed by a human person by pen and paper or by a black box computer. See MPEP 2106.04(a)(2)(III).
Step 2A, Prong Two: Has the abstract idea been integrated into a particular practical application?
No. These judicial exceptions are not integrated into a practical application because upon analysis on the components, nothing further is performed with the analysis.
Claim 1 recites the additional elements: (a) “labeling active sulfur in the sample with an alkylating agent”, (b) “adding a reducing agent to a portion of liquid extracted in the first step to decompose active sulfur”, (c) “applying the sample subjected to reduction treatment and the sample not subjected to reduction treatment after the labeling to an analyzer”, and (d) “extraction and purification of the components of the signals from the sample”.
However, the these additional elements do not impose any meaningful limits on practicing the abstract ideas because:
Steps (a) “labeling active sulfur in the sample with an alkylating agent”, (b) “adding a reducing agent to a portion of liquid extracted in the first step to decompose active sulfur”, (c) “applying the sample subjected to reduction treatment and the sample not subjected to reduction treatment after the labeling to an analyzer”, and (d) “extraction and purification of the components of the signals from the sample” are interpreted as generally linking the abstract idea to the field of endeavor, and also as extra-solution activity incidental to the primary process as mere data gathering which is not considered significantly more than the abstract idea. See MPEP § 2106.05(g), Insignificant Extra-Solution Activity, and MPEP § 2106.05(h), Field of Use and Technological Environment).
Step 2B: Does the claim recite any elements which are significantly more than the abstract idea?
Claim 1 recites the additional elements (a) “labeling active sulfur in the sample with an alkylating agent”, (b) “adding a reducing agent to a portion of liquid extracted in the first step to decompose active sulfur”, (c) “applying the sample subjected to reduction treatment and the sample not subjected to reduction treatment after the labeling to an analyzer”, and (d) “extraction and purification of the components of the signals from the sample”.
These additional elements do not amount to significantly more as they are well-understood, routine, and conventional (WURC) in the art as evidenced by Hamid et al. (Polysulfide stabilization by tyrosine and hydroxyphenyl-containing derivatives that is important for a reactive sulfur metabolomics analysis, February 2019, Redox Biology, Vol. 21, pp. 1-7; hereinafter “Hamid”) in view of Akaike et al. (Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell?, February 2019, British Journal of Pharmacology, 176(4), pp. 646-670; hereinafter “Akaike”). Hamid and Akaike teach (a) “labeling active sulfur in the sample with an alkylating agent”, (Hamid; fig. 2, p. 3, Section 2.5), (b) “adding a reducing agent to a portion of liquid extracted in the first step to decompose active sulfur”, (Hamid; fig. 1A, p. 2, col. 1 last paragraph), (c) “applying the sample subjected to reduction treatment and the sample not subjected to reduction treatment after the labeling to an analyzer” (Hamid; fig. 2, p. 3, Section 2.5 and pp. 3-4, Section 3), and (d) “extraction and purification of the components of the signals from the sample” (Hamid; p. 3, Section 2.5 and Akaike; fig. 9, pp. 650, 661, 664-665).
Claim 2 further limits the alkylating agent. However, these elements are interpreted as generally linking the abstract idea to the field of endeavor which does not amount to significantly more. Further, these additional elements are WURC as evidenced by Hamid (Hamid; fig. 2, p. 3, Section 2.5).
Claims 3 further limits the analyzer to HPLC-MS/MS. However, these elements are interpreted as generally linking the abstract idea to the field of endeavor which does not amount to significantly more. Further, these additional elements are WURC as evidenced by Hamid (Hamid; fig. 2, p. 3, Section 2.5 and pp. 3-4, Section 3).
Claim 4 further limits the extraction and purification as being performed using an ODS solid phase extraction pretreatment column. However, these elements are interpreted as generally linking the abstract idea to the field of endeavor which does not amount to significantly more. Further, these additional elements are WURC as evidenced by Hamid (Hamid; fig. 2, p. 3, Section 2.5 and pp. 3-4, Section 3).
Claim 5 further limits the extraction and purification as being performed using an ODS solid phase extraction pretreatment column. However, these elements are interpreted as generally linking the abstract idea to the field of endeavor which does not amount to significantly more. Further, these additional elements are WURC as evidenced by Hamid (Hamid; fig. 2, p. 3, Section 2.5 and pp. 3-4, Section 3).
Claim 6 further limits the structural analysis as being performed using a high-resolution mass spectrometer and a nuclear magnetic resonator (NMR). However, these elements are interpreted as generally linking the abstract idea to the field of endeavor which does not amount to significantly more. Further, these additional elements are WURC as evidenced by Hamid and Akaike (Hamid; p. 3, Section 2.5 and Akaike; fig. 9, pp. 650, 661, 664-665).
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Hamid et al. (Polysulfide stabilization by tyrosine and hydroxyphenyl-containing derivatives that is important for a reactive sulfur metabolomics analysis, February 2019, Redox Biology, Vol. 21, pp. 1-7 – hereinafter “Hamid”) in view of Akaike et al. (Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell?, February 2019, British Journal of Pharmacology, 176(4), pp. 646-670 – hereinafter “Akaike”).
Regarding claim 1, Hamid disclose a method for identifying active sulfur in a sample (Hamid disclose reactive sulfur metabolomics analysis by using RSS metabolic profiling; abstract), comprising:
(a) a first step of labeling active sulfur in the sample with an alkylating agent (Hamid disclose adding isotope-labeled MBB, HPE-IAM, NEM, alkylating reagents, or Tyrosine, to 10 µM and 1 µM of GS-SS-SG sample; fig. 2, p. 3, Section 2.5 “Analysis of decomposition products of GS-SS-SG”);
(b) a second step of adding a reducing agent to a portion of liquid extracted in the first step to decompose active sulfur (Hamid disclose the decomposition reaction of GS-SS-SG in fig. 1A without the alkylating agent; fig. 1A, p. 2, col. 1 last paragraph);
(c) a third step of applying the sample subjected to reduction treatment and the sample not subjected to reduction treatment after the labeling to an analyzer, comparing results of analysis of both samples, and determining components of signals disappeared by the reduction treatment as candidates for the active sulfur in the sample (Hamid disclose comparing the decomposition reaction of GS-SS-SG in fig. 1A with each alkylating reagent adduct using LC-ESI-MS/MS; fig. 2, p. 3, Section 2.5 “Analysis of decomposition products of GS-SS-SG” and pp. 3-4, Section 3 “Results”. Specifically, the presence evaluation of GS-SS-SG stability in the presence of dimedone which promotes alkaline hydrolysis of GS-SS-SG by pushing the reaction equilibrium forward enhancing the degradation of GS-SS-SG);
(d) a fourth step of confirmation that the signals are derived from the alkylating agent (Hamid disclose comparing the decomposition reaction of GS-SS-SG in fig. 1A with each alkylating reagent adduct using LC-ESI-MS/MS; fig. 2, p. 3, Section 2.5 “Analysis of decomposition products of GS-SS-SG” and pp. 3-4, Section 3 “Results”. The measure of decomposition of GS-SS-SG over time is a confirmation that the signals are derived from the alkylating agent as compared to the control and other alkylating agent(s)); and
(e) a fifth step of, after the confirmation, extraction and purification of the components of the signals from the sample (Hamid disclose H2S (Bis-S-adduct), hydrogen disulfide (Bis-SS-adduct), thiosulfate (HS2O3-adduct), GSH (GS-adduct), GSH persulfide (GSS-adduct), GSH trisulfide (GSSS-adduct), oxidized GSH (GSSG), and GS-S-SG were detected by using MRM; p. 3, Section 2.5 “Analysis of decomposition products of GS-SS-SG”).
Hamid does not teach (e) the fifth step comprise performing structural analysis of the components.
However, Akaike teach the analogous art of a method for identifying active sulfur in a sample (Akaike; figs. 1 & 9, pp. 648-650, “Methods”), comprising performing structural analysis of the components (Akaike; fig. 9, pp. 650, 661, 664-665, “Equilibrium analyses and competitive trapping of GSH polysulfur species”, “Inorganic polysulfide speciation in non-aqueous systems”, “Speciation of cysteine polysulfide species”, and “Speciation of polysulfide species in organic media”).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the method for identifying active sulfur species in a sample of Hamid to further comprise a fifth step of performing structural analysis of the components after the confirmation, extraction and purification of the components of the signals from the sample, as taught by Akaike, because Akaike teach the structural analysis of the components is a reliable detection method for providing mechanistic insights into redox biology (Akaike; p. 646, “Background and purpose”). One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since Hamid and Akaike both teach measuring reactive sulfur species after their reactions with alkylating agents.
Regarding claim 2, modified Hamid teach the method for identifying active sulfur according to claim 1 above, wherein the alkylating agent is TME-IAM or a similar structure thereto (Hamid teach HPE-IAM alkylating reagents, or Tyrosine; fig. 2, p. 3, Section 2.5 “Analysis of decomposition products of GS-SS-SG”).
Regarding claim 3, modified Hamid teach the method for identifying active sulfur according to claim 1 above, wherein the analyzer is a liquid chromatography-tandem mass spectrometer (HPLC-MS/MS) (Hamid disclose comparing the decomposition reaction of GS-SS-SG in fig. 1A with each alkylating reagent adduct using LC-ESI-MS/MS by the LCMS-8050 Nexera UHPLC system with a YMC-Triart C18 column; fig. 2, p. 3, Section 2.5 “Analysis of decomposition products of GS-SS-SG” and pp. 3-4, Section 3 “Results”).
Regarding claim 4, modified Hamid teach the method for identifying active sulfur according to claim 1 above, wherein, in the fifth step, the extraction and purification is performed by using an ODS solid phase extraction pretreatment column (Hamid disclose comparing the decomposition reaction of GS-SS-SG in fig. 1A with each alkylating reagent adduct using LC-ESI-MS/MS by the LCMS-8050 Nexera UHPLC system with a YMC-Triart C18 column; fig. 2, p. 3, Section 2.5 “Analysis of decomposition products of GS-SS-SG” and pp. 3-4, Section 3 “Results”).
Regarding claim 5, modified Hamid teach the method for identifying active sulfur according to claim 1 above, wherein a purified liquid obtained by the extraction and purification is fractionated by a preparative HPLC and applied to the analyzer (Hamid disclose comparing the decomposition reaction of GS-SS-SG in fig. 1A with each alkylating reagent adduct using LC-ESI-MS/MS by the LCMS-8050 Nexera UHPLC system with a YMC-Triart C18 column; fig. 2, p. 3, Section 2.5 “Analysis of decomposition products of GS-SS-SG” and pp. 3-4, Section 3 “Results”).
Regarding claim 6, modified Hamid teach the method for identifying active sulfur according to claim 1, wherein the structural analysis of the components is performed by using a high-resolution mass spectrometer and a nuclear magnetic resonator (NMR) (Hamid disclose The modification of the method for identifying active sulfur species in a sample of Hamid to further comprise a fifth step of performing structural analysis of the components after the confirmation, extraction and purification of the components of the signals from the sample, as taught by Akaike, has previously been discussed in claim 1 above. Akaike teach using high-resolution mass spectrometer and a nuclear magnetic resonator (NMR); figs. 1 & 9, pp. 648, 650, 661, 664-665, “Speciation of inorganic polysulfides”, “Equilibrium analyses and competitive trapping of GSH polysulfur species”, “Inorganic polysulfide speciation in non-aqueous systems”, “Speciation of cysteine polysulfide species”, and “Speciation of polysulfide species in organic media”).
Other References Cited
The prior art of made of record and not relied upon is considered pertinent to Applicant’s disclosure include:
Akaike et al. (Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics, October 2017, Nature Communication, Article No. 1177, pp.1-15) disclose a reactive sulfur metabolomics analysis using LC-MS combined with trapping or derivatizing RSS.
Doka et al. (A novel persulfide detection method reveals protein persulfide- and polysulfide-reducing functions of thioredoxin and glutathione system, January 2016, Science Advances, Vol. 2, Issue 1, pp. 1-14) disclose a protein persulfide detection protocol in kidney cells and mouse liver.
Ida et al., (Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling, May 2014, PNAS, Vol. 111, No. 21, pp. 7607-7611) disclose a method for quantifying reactive persulfides and polysulfides in tissue.
Citations to art
In the above citations to documents in the art, an effort has been made to specifically cite representative passages, however rejections are in reference to the entirety of each document relied upon. Other passages, not specifically cited, may apply as well.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CURTIS A THOMPSON whose telephone number is (571) 272-0648. The examiner can normally be reached on M-F: 7:00 a.m. - 5:00 p.m..
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/C.A.T./Examiner, Art Unit 1798
/BENJAMIN R WHATLEY/Primary Examiner, Art Unit 1798
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