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 .
Drawings
The drawings (Figs. 2A, 2B, and 5) are objected to because the information in the tables of Figs. 2A-2B and the graph of Fig. 5 appear blurry and are not clearly legible. Clear and legible drawings are required to ensure proper understand and examination of the claimed invention. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
In addition to Replacement Sheets containing the corrected drawing figure(s), applicant is required to submit a marked-up copy of each Replacement Sheet including annotations indicating the changes made to the previous version. The marked-up copy must be clearly labeled as “Annotated Sheets” and must be presented in the amendment or remarks section that explains the change(s) to the drawings. See 37 CFR 1.121(d)(1). Failure to timely submit the proposed drawing and marked-up copy will result in the abandonment of the application.
Claim Objections
Claim 1 is objected to because of the following informalities:
Regarding claim 1, l. 9 recites “each sample for analysis“. Applicant may amend the claim to read “each of the plurality of samples for analysis“. 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 1-4 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (Step 2A/1)(i.e., a law of nature, a natural phenomenon, or an abstract idea) without practical application (Step 2A/2) or significantly more (Step 2B) (See MPEP 2106). Although the instant claims encompass a process (Step 1), they are directed to the following judicial exceptions (Step 2, Prong 1):
Regarding claim 1, The determination step, selection step, and data creation steps recite mental processes and mathematical concepts. Specifically, the determination step recites analyzing mass spectrum data to identify metabolite types and determine numbers of metabolites and signal intensities. The selection step recites comparing the determined numbers and signal intensities and selecting a sample for analysis. The data creation step recites integrating isotope distribution data obtained from the selected sample. These limitations constitute observation, evaluation, judgment, comparison, and selection of information, which can be performed in the human mind or with pen and paper. The claim is therefore, directed to a judicial exception.
Step 2A/2: These judicial exceptions are not integrated into a practical application.
The preparation step solely prepares samples having different metabolite concentrations, and the analysis step only performs conventional mass spectrometry on the samples. These steps are simply data gathering limitations (pre-solution activity, see MPEP 2106.05 (g)) only for the purpose of executing the abstract idea of the determination, selection, and data creation steps. The claims fail to provide a specific improvement to a computer, technology, or a technical field resulting in a practical application of the judicial exception. Once the isotope distribution data has been created, there is no further action. The results of the abstract ideas are not used in practical application, for example, treating a patient with a specific drug when metabolite levels are above a threshold (See MPEP 2106.04(d)(2)). Accordingly, these additional elements do not integrate the abstract idea into a practical application because it does not impose any meaningful limits on practicing the abstract ideas. The claims are directed to an abstract idea with no practical application.
Step 2B: The claims do not include additional elements that are sufficient to amount to
significantly more than the judicial exception.
Preparing samples with different analyte concentrations, analyzing them using instrumentation, and creating distribution data is well-understood, routine and conventional in the art. For example, a reference Lo et al. (“A roadmap to defining the clinical reportable ranges of chemistry analytes: Increasing automation efficiency and decreasing manual dilutions”) prepares samples at multiple dilution levels and reports each analyte concentration at a particular dilution based on instrumentation output (See Tables 1-2). Accordingly, the sample preparation and instrumental analysis steps do not amount to significantly more than the judicial exception, and the rejection of claim 1 under 35 U.S.C. 101 is maintained. Claims 2-4 are rejected upon dependency of all the limitations of claim 1.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, and 4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Evers et. al (“Simultaneous Quantification of the Concentration and Carbon Isotopologue Distribution of Polar Metabolites in a Single Analysis by Gas Chromatography and Mass Spectrometry” and Supporting Information; 06-01-2021).
Regarding claim 1, A method for creating isotope distribution data (quantify the absolute concentrations and 13C-isotope distributions of CAC intermediates and amino acids in cell samples; p. 8254, col. 2, Conclusion, ll. 1-4), comprising:
a preparation step of preparing a plurality of samples for analysis having different concentrations of metabolites as samples containing metabolites of cells cultured in a medium containing a substrate labeled with a stable isotope (“human A375 cells, cultured for 8 h on [U-13C]glucose, were pooled and a serial dilution, ranging from 0.03 up to 1.50 mg protein, prepared for GC/MS analysis,” wherein glucose is a substrate labeled with the stable isotope 13C; p. 8251, col. 1, ll. 9-12; Fig. 1);
an analysis step of performing mass spectrometry under the same analysis condition for each of the plurality of samples for analysis (Evers teaches preparing a serial dilution and analyzing them by GC/MS to determine the working range for accurate isotopologue quantification. Because Evers compares the responses across the dilution series as a function of sample amount, a person of ordinary skill in the art would understand that the samples are analyzed using the same GC/MS method while varying the sample concentration; p. 8251, col. 1-2; See Figs. 2, S2,S3);
a determination step of, for each of the plurality of samples for analysis, analyzing mass spectrum data obtained by the mass spectrometry to identify a type of the metabolite contained in each sample for analysis (Using sample dilutions between 0.03 up to 1.50 mg protein, the working range for an accurate isotopologue quantification of the metabolites of interest was determined; See p. 8251, col. 1; Figs. 2, S3 and S4 show the identification of metabolites (CIT, Lac, Pyr, and amino acids) across the dilution series); and
determining a number of metabolites included in a metabolite group made of unlabeled metabolites that are metabolites of the same type and in which the stable isotope is not incorporated and/or isotopic isomers that are metabolites in which one or a plurality of the stable isotopes are incorporated, and signal intensities of mass peaks corresponding to metabolites included in the metabolite group (Figs. 2, S3 and S4 determine isotopologue responses (M0, M1, M2, etc.) of metabolites (CIT, Lac, Pyr, and amino acids) across the dilution series as well as the fractional contribution for each. The fractional contributions are calculated from the measured isotopologue peak signals and therefore require determination of the corresponding mass peak intensities);
a selection step of selecting a sample for analysis for obtaining an isotope distribution of each metabolite by comparing the number of metabolites included in the metabolite group corresponding to all types of metabolites and the signal intensities of mass peaks of metabolites included in the metabolite group among the plurality of samples for analysis, both the number and the signal intensities having been determined in the determination step (Evers determines the sample dilution amounts at which isotopologue fractional contributions remain constant, thereby establishing an acceptable range for reliable isotopologue quantification (e.g., >0.06 mg for Lac and Pyr, >0.13mg for Val, etc.; p. 8251, cols. 1-2; Figs. 2, S2,S3). Evers further determines that different metabolites require different minimum sample amounts and concludes: “to include all metabolites of interest for isotopologue quantification, a minimum of 0.50 mg protein is advised”; p. 8251, col. 2, para. 2, ll. 5-7); and
a data creation step of integrating data on an isotope distribution of the metabolite obtained by analyzing mass spectrum data of a sample for analysis selected for each metabolite to create isotope distribution data of all types of metabolites determined in the determination step (Fig. 5(c and d) present the fractional 13C-MID (Mass Isotopologue Distribution) for multiple metabolites, including CAC intermediates and amino acids. Evers states that the disclosed simultaneous quantification method operates on cell samples starting at 1.00 mg protein sample, and Fig. 5(c and d) presents the results of that same simultaneous quantification method. Therefore, a person of ordinary skill in the art would have understood the Fig. 5 MID data to be generated from a 1.00 mg protein sample which is a minimum of 0.50 mg protein as advised).
Regarding claim 2, The method for creating isotope distribution data according to claim 1, wherein the selection step is a step of selecting a sample for analysis in which signal intensities of mass peaks corresponding to all metabolites included in a certain metabolite group are within a predetermined range and that has a largest number of metabolites included in the metabolite group as a sample for analysis for obtaining an isotope distribution of the metabolites of the metabolite group (Evers teaches a predetermined range by determining the sample dilution amounts over which isotopologue responses remain constant, thereby identifying a reliable response range for the corresponding mass peaks (See p. 8251, cols. 1-2). Evers further teaches selecting a sample having the largest number of metabolites by stating: “to include all metabolites of interest for isotopologue quantification, a minimum of 0.50 mg protein is advised,” thereby selecting the condition that accommodates the greatest number of metabolite groups (See p. 8251, col. 2, para. 2, ll. 5-7)).
Regarding claim 4, The method for creating isotope distribution data according to claim 1, wherein the selection step is a step of determining spectrum data selected for each metabolite group such that a number of metabolite groups from which a common sample for analysis is to be selected is maximized (to include all metabolites of interest for isotopologue quantification, a minimum of 0.50 mg protein is advised; Evers, p. 8251, col. 2, ll. 5-7).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable Evers et. al (“Simultaneous Quantification of the Concentration and Carbon Isotopologue Distribution of Polar Metabolites in a Single Analysis by Gas Chromatography and Mass Spectrometry” and Supporting Information; 06-01-2021; 06-01-2021).
Regarding claim 3, The method for creating isotope distribution data according to claim 2.
Evers fails to teach the selection step is a step of further comparing a maximum mass peak, which is a mass peak having a highest signal intensity among the mass peaks corresponding to all metabolites included in the metabolite group, among the plurality of samples for analysis, and selecting a sample for analysis having a highest signal intensity of the maximum mass peak as a sample for analysis for obtaining an isotope distribution of the metabolites of the metabolite group.
However, Evers does teach that conventional IDMS quantifies absolute metabolite concentration using the highest intensity isotopologues (m0-mi), while alternatively teaching that metabolite concentration can be determined using the full isotopologue spectrum and an unlabeled internal standard (See p. 8249, ll. 7-13). Thus, Evers recognizes that isotopologue peaks having the highest signal intensities are conventionally used for metabolite quantification. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the isotopologue peak with the highest intensity for the full isotopologue spectrum and selected this peak out of all of the dilution samples for each metabolite because Evers teaches both as known techniques for determining absolute metabolite concentration, and this includes substitution of one known element for another to obtain predictable results (See MPEP 2143(I)(B)).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Lo et al., 2015 (instant PTO-892) teaches analyzing a sample at multiple dilution levels and reporting each analyte concentration at a particular dilution.
No claims are allowed.
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/V.S./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758
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