DETAILED ACTION
In application filed on 12/15/2023, Claims 1-13 and 15-22 are pending. The claim set submitted on 07/13/2026 is considered because this is the most recent claim set with some preliminary amendments. Claims 1-11, 16-19 and 21-22 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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/15/2025 and 06/30/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 07/13/2026 is acknowledged. Claims 12-13 and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/13/2026.
Group I, Claims 1-11, 16-19 and 21-22 are considered on the merits below.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-3 and 5-6 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites the limitation "the sum". There is insufficient antecedent basis for this limitation in the claim.
For the purpose of expedited examination, Examiner interprets "the sum" as "a sum".
Applicant should provide clarification.
Claim 3 recites the limitation "the negative" and “the solution”. There is insufficient antecedent basis for this limitation in the claim.
For the purpose of expedited examination, Examiner interprets "the negative" and “the solution” as "a negative" and “a solution”
Applicant should provide clarification.
Claim 5 recites the limitation "the main compound”. There is insufficient antecedent basis for this limitation in the claim.
For the purpose of expedited examination, Examiner interprets "the main compound” as "a main compound”.
Applicant should provide clarification.
Claim 6 recites the limitation "the production process”. There is insufficient antecedent basis for this limitation in the claim.
For the purpose of expedited examination, Examiner interprets "the production process” as "a production process”.
Applicant should provide clarification.
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 1-11, 16-19 and 21-22 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 1-11, 16-19 and 21-22) (Step 1: YES).
Analysis:
Claim 1: Ineligible.
Step 1:
The claim recites a series of steps or acts, including “method of determining an analyte in a sample by mass spectrometry (MS)”. 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 “(b) determining MS signals of ions generated from said analyte (analyte signal) and from said at least two isotopologues (isotopologue signals) (mental step); (c) providing a calibration based on the analyte signal and the isotopologue signals determined in step (b) (math step); and(d) determining said analyte based on the calibration provided in step (c)(mental step)”.
Therefore, the claim is directed towards an abstract idea, and more specifically to the abstract idea group of a mental processes since claim 1 relates to using a mental/math processes to “(b) determining MS signals of ions generated from said analyte (analyte signal) and from said at least two isotopologues (isotopologue signals) (mental step); (c) providing a calibration based on the analyte signal and the isotopologue signals determined in step (b) (math step); and(d) determining said analyte based on the calibration provided in step (c)(mental step)” (Step 2A, Prong 1: Patent Ineligible).
Step 2A, Prong 2:
This judicial exception is not integrated into a practical application.
Once the determination and providing are done, No further action takes place.
Also the steps of “(a) admixing a pre-determined amount of internal calibrator to said sample, wherein said internal calibrator comprises at least two non-identical isotopologues of the analyte at predetermined amounts” are recited at a high level of generality that it amounts to mere data gathering (insignificant extra-solution activity). See MPEP 2106.05(g).
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 steps of “(b) determining MS signals of ions generated from said analyte (analyte signal) and from said at least two isotopologues (isotopologue signals) (mental step); (c) providing a calibration based on the analyte signal and the isotopologue signals determined in step (b) (math step); and (d) determining said analyte based on the calibration provided in step (c)(mental step)” appears to be well-understood, routine, and conventional (WURC) in the field of clinical diagnostics, as evidenced by Cournoyer et al. (US20220308066A1).
(Step 2B: NO).
Therefore, Claim 1 is ineligible.
Moreover, Claims 2-11, 16-19 and 21-22 are rejected by virtue of their dependency on Claim 1.
Also, each of the dependent claims 2-11, 16-19 and 21-22 do not solve the issues of claim 1.
Claims 2-4: Ineligible.
Step 2A, Prong One and Prong Two: Claims 2-4 further presents an abstract ideas “step (c) comprises providing a calibration based on ratios of (i) the sum of the isotopologue signal and the analyte signal for each of said at least two isotopologues (ii) and the amounts for each of said at least two isotopologues; a regression equation is fitted into said ratios, and wherein the amount of the analyte is determined as the negative value of the solution of the regression equation for the value of the MS signal of ions being zero; and said regression equation is a linear regression equation”.
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claims 2-4 are ineligible.
Claims 5-11, 16-19 and 21-22: Ineligible.
Step 2A, Prong One and Prong Two: Claims 5-11, 16-19 and 21-22 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 5-11, 16-19 and 21-22 are ineligible.
Claim Rejections - 35 USC § 102
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 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)(2) 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, 6-11 and 16-19 are rejected under 35 U.S.C. 102 (a) (2) as being anticipated by Cournoyer et al. (US20220308066A1).
Regarding Claim 1, Cournoyer teaches a method of determining an analyte (See Para 0025… , the molecule that is being tested for is a peptide or a hormone. In some embodiments, the molecule is testosterone) in a sample by mass spectrometry (MS) (See Para 0002…methods, composition, kits, and apparatuses for mass spectrometric analysis of a sample utilizing external calibration for quantifying a target analyte in a separate sample run), the method (See Para 0002…methods, composition, kits, and apparatuses for mass spectrometric analysis of a sample utilizing external calibration for quantifying a target analyte in a separate sample run) comprising
(a) admixing a pre-determined amount of internal calibrator (See Abstract… a known quantity of a plurality of calibrants) to said sample (See abstract…calibration mixtures are provided containing a known quantity of a plurality of calibrants for a target analyte of interest), wherein said internal calibrator (See Abstract… a known quantity of a plurality of calibrants) comprises at least two non-identical isotopologues (See Para 0008… one or more stable isotopic analogs) of the analyte at predetermined amounts (See Para 0008…calibration mixtures are provided containing a known quantity of a plurality of calibrants selected from the group comprising a standard of a target analyte and one or more stable isotopic analogs of the target analyte);
(b) determining MS signals of ions (See Para 0071… Exemplary techniques result in the generation of a mass spectrometer signal corresponding to the quantity of parent ions (e.g., via MS), product ions, (e.g., via MS/MS), or…) generated from said analyte (See Para 0025… , the molecule that is being tested for is a peptide or a hormone. In some embodiments, the molecule is testosterone.) (analyte signal) (See Para 0008… each of the calibrants in the calibration mixture distinguishable by mass spectrometry such that a complete calibration curve can be generated from a single external calibration run; See Para 0009… obtaining a mass spectrometer signal for a calibration mixture,) and from said at least two isotopologues (isotopologue signals) (See Para 0008…one or more stable isotopic analogs);
(c) providing a calibration based on the analyte signal and the isotopologue signals determined in step (b) (See Para 0009… The method further includes generating a single calibration curve for the calibration mixture based on said characteristic responses of said plurality of calibrants.); and
(d) determining said analyte (See Para 0025… , the molecule that is being tested for is a peptide or a hormone. In some embodiments, the molecule is testosterone.) based on the calibration provided in step (c) (See Para 0009… In some embodiments, the method also includes obtaining a mass spectrometer signal from each of the series of samples, identifying from the mass spectrometer signal for each sample a characteristic response indicative of the concentration of the target analyte in each sample, and comparing the characteristic response of the target analyte in each sample to the single calibration curve to quantify the target analyte in each sample).
Regarding Claim 2, Cournoyer teaches wherein step (c) comprises providing a calibration based on ratios of (i) the sum of the isotopologue signal and the analyte signal for each of said at least two isotopologues (See Para 0098… ratio of analyte peak area/IS peak area ) (ii) and the amounts for each of said at least two isotopologues (See Para 0098… the ratio of calibrator concentration/IS concentration; See Para 0014… Isotopic analogs in accordance with the present teachings can also be used as internal standards in the sample and/or inter-sample controls such as quality controls.).
Regarding Claim 7, Cournoyer teaches wherein said isotopologues (See Para 0008… one or more stable isotopic analogs) are comprised in a single isotopically labelled preparation (See Para 0068…Further, for stable isotopic calibrants, synthesis can provide appropriate isotopic labels in the appropriate parts of the molecules) of the analyte (See Para 0025… , the molecule that is being tested for is a peptide or a hormone. In some embodiments, the molecule is testosterone.).
Regarding Claim 8, Cournoyer teaches wherein the ions (See Para 0071… Exemplary techniques result in the generation of a mass spectrometer signal corresponding to the quantity of parent ions (e.g., via MS), product ions, (e.g., via MS/MS), or…) determined for the isotopologues (See Para 0008… one or more stable isotopic analogs) are structurally identical (See Para 0057… different isotopes of the same chemical element generally have essentially the same chemical characteristics and therefore behave essentially identically in chemical and/or biological systems.).
Regarding Claim 9, Cournoyer teaches wherein said sample (See Abstract…sample) is a sample of a subject (See Para 0085… quantify serum thyroglobulin, which is typically monitored in thyroid cancer patients).
Regarding Claim 10, Cournoyer teaches wherein said analyte (See Para 0025… the molecule that is being tested for is a peptide or a hormone. In some embodiments, the molecule is testosterone) is a low-molecular weight compound (See Para 0025… the molecule that is being tested for is a peptide or a hormone. In some embodiments, the molecule is testosterone, thereby teaching “low-molecular weight compound”).
Regarding Claim 11, Cournoyer teaches wherein said analyte (See Para 0025… the molecule that is being tested for is a peptide or a hormone. In some embodiments, the molecule is testosterone) is Testosterone (See Para 0025… the molecule that is being tested for is a peptide or a hormone. In some embodiments, the molecule is testosterone) and wherein said internal calibrator is 2,3,4-13C3-Testosterone (See Para 0050…analytical target (e.g. 2,3,4-13C3-testosterone).
Regarding Claim 16, Cournoyer teaches wherein the ions (See Para 0084…As shown in FIG. 6, various precursor and product ions could be detected by the mass analyzer, with the m/z ratio of the ionized/derivatized testosterone analogs selected in Q1 as follows: 13C3-testosterone associated ion (m/z=406.3), D3-testoserone associated ion (m/z=406.3), standard testosterone associated ion (m/z=403.3), determined for the analyte (See Para 0025… the molecule is testosterone) are structurally identical (See Para 0084… 13C3-testosterone associated ion (m/z=406.3) and , D3-testoserone associated ion (m/z=406.3) are structurally identical).
Regarding Claim 17, Cournoyer teaches wherein said sample (See Abstract…sample) is a medical or diagnostic sample (See Para 0111… his methodology is particularly useful for cases where authentic matrix is hardly available, such as biomarker measurement and quantitative proteomics, where the low throughput and long turnaround time are the main issues preventing the use of LC-MS/MS technique, such as the clinical diagnosis in clinical diagnostic laboratories, and where calibration curve preparation is cumbersome, such as the fresh frozen and FFPE tissue analysis; See Para 0120… There are numerous potential applications of MIRM-ISCC-LC-MS/MS methodology such as use in quantitative analysis of small molecules, peptides, proteins, biomarkers, quantitative proteomics, clinical diagnostic laboratories and other areas., thereby teaching “medical or diagnostic sample”).
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Regarding Claim 18, Cournoyer teaches wherein said sample (See Abstract…sample) is a sample of a bodily fluid or of a tissue sample (See Para 0111… his methodology is particularly useful for cases where authentic matrix is hardly available, such as biomarker measurement and quantitative proteomics, where the low throughput and long turnaround time are the main issues preventing the use of LC-MS/MS technique, such as the clinical diagnosis in clinical diagnostic laboratories, and where calibration curve preparation is cumbersome, such as the fresh frozen and FFPE tissue analysis).
Regarding Claim 19, Cournoyer teaches wherein said analyte (See Para 0025… the molecule that is being tested for is a peptide or a hormone. In some embodiments, the molecule is testosterone) is a low-molecular weight compound having a molecular mass of at most 2.5 kDa (Under BRI, the molecular weight (molar mass) of testosterone is 288.43 g/mol (288.43 Da), which is not up to 2.5 kDa ).
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 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Cournoyer et al. (US20220308066A1) as applied to claim 1 above, and further in view of Nelson et al. (US20010019829A1).
Regarding Claim 3, Cournoyer teaches wherein a regression equation (See Para 0073… Suitable regression algorithms… The function can be, but is not necessarily, linear over the entire analytical range) is fitted into said ratios (See Para 0098… All calibration curves were plots of the ratio of analyte peak area/IS peak area versus the ratio of calibrator concentration/IS concentration and the linear regression was weighted 1/x.).
Cournoyer further teaches that in step 405, an external calibration curve may then be generated based on the characteristic responses of each calibrant, for example, by plotting the intensity of the mass spectrometer signal at a particular m/z against and the known concentration of the corresponding calibrants in the calibration mixture. Calibration curves may be obtained by applying a suitable regression algorithm (e.g., a Gauss least-square fitting method) to the data, for example (See Para 0073).
However, Cournoyer does not explicitly teach “and wherein the amount of the analyte is determined as the negative value of the solution of the regression equation for the value of the MS signal of ions being zero”.
In the analogous art of rapid mass spectrometric immunoassay methods for detecting and/or quantifying antibody and antigen analytes utilizing affinity capture to isolate the analytes and internal reference species (for quantification) followed by mass spectrometric analysis of the isolated analyte/internal reference species, Nelson teaches “and wherein the amount of the analyte is determined as the negative value of the solution of the regression equation for the value of the MS signal of ions being zero”. (See Para 0110…The analyte/IRS signal ratios in the addition-present mass spectra are then used to determine the analyte concentration in the addition-absent sample…This mathematical relationship may be expressed in a variety of ways, including but not limited to a line, a mathematical function, a graph, or computerized data. The standard addition mathematical relationship is then extrapolated to the intercept point for zero mass spectrometric response. The intercept point's value for standard addition concentration will be in negative units. The absolute value of this value inferentially represents the concentration of the analyte in the specimen).
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 Cournoyer to include “wherein the amount of the analyte is determined as the negative value of the solution of the regression equation for the value of the MS signal of ions being zero”, as taught Nelson for the benefit of determining the analyte concentration in the addition-absent sample (Nelson, Para 0110), allowing for the provision of a mass spectrometric immunoassay which is capable of qualitatively and quantitatively determining the presence of single or multiple antigen or antibody species in a specimen. It is toward the fulfillment of that need that the present invention is directed (Nelson, Para 0110).
Regarding Claim 4, the method of claim 3 is obvious over Cournoyer in view of Nelson.
Cournoyer teaches wherein said regression equation (See Para 0073… Suitable regression algorithms… The function can be, but is not necessarily, linear over the entire analytical range; See Para 0098…MultiQuant were then converted to measured testosterone concentrations using the linear regression equations) is a linear regression equation (See Para 0098…MultiQuant were then converted to measured testosterone concentrations using the linear regression equations).
Claims 5-6 and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Cournoyer et al. (US20220308066A1) as applied to claim 1 above.
Regarding Claim 5, Cournoyer teaches wherein said internal calibrator (See Abstract… a known quantity of a plurality of calibrants) comprises a first isotopologue of the analyte as the main compound (See Para 0060… the concentration of the heaviest isotopic analog of the target analyte) and at least a second isotopologue (See Para 0060… concentration of the other of said isotopic analogs in the calibration mixture) at a relative fraction (See Para 0060…the concentration of the heaviest isotopic analog of the target analyte in the calibration mixture is less than the concentration of the other of said isotopic analogs in the calibration mixture. Additionally or alternatively, in some embodiments the concentration of the lightest isotopic analog of the target analyte in the calibration mixture is greater than the concentration of the other of said isotopic analogs in the calibration mixture).
Cournoyer does not explicitly teach that “a relative fraction of at most 20%”.
However, MPEP § 2144.05, Part II, Subpart B holds that a particular parameter that is recognized as a result effective variable (“a variable that achieves a recognized result”) would be one, but not the only motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. In the use of In quantitative mass spectrometry (LC-MS/MS), the selection of optimal experimental conditions including the use of using two internal standards (IS1 and IS2) and adjusting their ratio is a specialized technique primarily used for dual-isotope dilution, matrix effect correction, retention time window mapping, or absolute quantification using an IS-calibration curve. Thus, “the relative fraction of at most 20%” is a result effective variable.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to design a mass spectrometry method to include “ wherein said internal calibrator comprises a first isotopologue of the analyte as the main compound and at least a second isotopologue at a relative fraction of at most 20%”, for the benefit of quantifying a target analyte in a series of samples by mass spectrometry is provided that comprises obtaining a mass spectrometer signal for a calibration mixture, wherein the calibration mixture comprises a plurality of calibrants selected from the group comprising a standard of the target analyte, a first isotopic analog of the target analyte, and a second isotopic analog of the target analyte, wherein said plurality of calibrants are distinguishable by mass spectrometry from one another and have different, known concentrations from one another in said calibration mixture (Cournoyer, Para 0010), allowing for the provision for conventional external calibration techniques can increase productivity, reduce cost per sample, and render the subsequent analysis of a small batch of samples efficient (Cournoyer, Para 0006).
Regarding Claim 6, the method of claim 3 is obvious over Cournoyer.
Cournoyer teaches wherein the relative fraction (See Para 0060…the concentration of the heaviest isotopic analog of the target analyte in the calibration mixture is less than the concentration of the other of said isotopic analogs in the calibration mixture. Additionally or alternatively, in some embodiments the concentration of the lightest isotopic analog of the target analyte in the calibration mixture is greater than the concentration of the other of said isotopic analogs in the calibration mixture) of the second isotopologue (See Para 0060… concentration of the other of said isotopic analogs in the calibration mixture) is a consequence of relative isotope distribution in the production process (See Para 0057…isotopes relate to nuclides with the same number of protons but differing numbers of neutrons (i.e., they have the same atomic number and are therefore the same chemical element). Typically, different isotopes of the same chemical element generally have essentially the same chemical characteristics and therefore behave essentially identically in chemical and/or biological systems…, thereby teaching “consequence of relative isotope distribution in the production process”) of the internal calibrator (See Abstract… a known quantity of a plurality of calibrants).
Regarding Claim 21, the method of claim 5 is obvious over Cournoyer.
Cournoyer teaches wherein said internal calibrator (See Abstract… a known quantity of a plurality of calibrants) comprises a first isotopologue of the analyte as the main compound (See Para 0060… the concentration of the heaviest isotopic analog of the target analyte) and at least a second isotopologue (See Para 0060… concentration of the other of said isotopic analogs in the calibration mixture) at a relative fraction (See Para 0060…the concentration of the heaviest isotopic analog of the target analyte in the calibration mixture is less than the concentration of the other of said isotopic analogs in the calibration mixture. Additionally or alternatively, in some embodiments the concentration of the lightest isotopic analog of the target analyte in the calibration mixture is greater than the concentration of the other of said isotopic analogs in the calibration mixture) of the first isotopologue (See Para 0060… the concentration of the heaviest isotopic analog of the target analyte).
Cournoyer does not explicitly teach that “a relative fraction of at most 10%”.
However, MPEP § 2144.05, Part II, Subpart B holds that a particular parameter that is recognized as a result effective variable (“a variable that achieves a recognized result”) would be one, but not the only motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. In the use of In quantitative mass spectrometry (LC-MS/MS), the selection of optimal experimental conditions including the use of using two internal standards (IS1 and IS2) and adjusting their ratio is a specialized technique primarily used for dual-isotope dilution, matrix effect correction, retention time window mapping, or absolute quantification using an IS-calibration curve. Thus, “the relative fraction of at most 10%” is a result effective variable.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to design a mass spectrometry method to include “ wherein said internal calibrator comprises a first isotopologue of the analyte as the main compound and at least a second isotopologue at a relative fraction of at most 10%”, for the benefit of quantifying a target analyte in a series of samples by mass spectrometry is provided that comprises obtaining a mass spectrometer signal for a calibration mixture, wherein the calibration mixture comprises a plurality of calibrants selected from the group comprising a standard of the target analyte, a first isotopic analog of the target analyte, and a second isotopic analog of the target analyte, wherein said plurality of calibrants are distinguishable by mass spectrometry from one another and have different, known concentrations from one another in said calibration mixture (Cournoyer, Para 0010), allowing for the provision for conventional external calibration techniques can increase productivity, reduce cost per sample, and render the subsequent analysis of a small batch of samples efficient (Cournoyer, Para 0006).
Regarding Claim 22, the method of claim 5 is obvious over Cournoyer.
Cournoyer teaches wherein said internal calibrator (See Abstract… a known quantity of a plurality of calibrants) comprises a first isotopologue of the analyte as the main compound (See Para 0060… the concentration of the heaviest isotopic analog of the target analyte) and at least a second isotopologue (See Para 0060… concentration of the other of said isotopic analogs in the calibration mixture) at a relative fraction (See Para 0060…the concentration of the heaviest isotopic analog of the target analyte in the calibration mixture is less than the concentration of the other of said isotopic analogs in the calibration mixture. Additionally or alternatively, in some embodiments the concentration of the lightest isotopic analog of the target analyte in the calibration mixture is greater than the concentration of the other of said isotopic analogs in the calibration mixture) of the first isotopologue (See Para 0060… the concentration of the heaviest isotopic analog of the target analyte).
Cournoyer does not explicitly teach that “a relative fraction of at most 5%”.
However, MPEP § 2144.05, Part II, Subpart B holds that a particular parameter that is recognized as a result effective variable (“a variable that achieves a recognized result”) would be one, but not the only motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. In the use of In quantitative mass spectrometry (LC-MS/MS), the selection of optimal experimental conditions including the use of using two internal standards (IS1 and IS2) and adjusting their ratio is a specialized technique primarily used for dual-isotope dilution, matrix effect correction, retention time window mapping, or absolute quantification using an IS-calibration curve. Thus, “the relative fraction of at most 5%” is a result effective variable.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to design a mass spectrometry method to include “ wherein said internal calibrator comprises a first isotopologue of the analyte as the main compound and at least a second isotopologue at a relative fraction of at most 5%”, for the benefit of quantifying a target analyte in a series of samples by mass spectrometry is provided that comprises obtaining a mass spectrometer signal for a calibration mixture, wherein the calibration mixture comprises a plurality of calibrants selected from the group comprising a standard of the target analyte, a first isotopic analog of the target analyte, and a second isotopic analog of the target analyte, wherein said plurality of calibrants are distinguishable by mass spectrometry from one another and have different, known concentrations from one another in said calibration mixture (Cournoyer, Para 0010), allowing for the provision for conventional external calibration techniques can increase productivity, reduce cost per sample, and render the subsequent analysis of a small batch of samples efficient (Cournoyer, Para 0006).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OYELEYE ALEXANDER ALABI whose telephone number is (571)272-1678. The examiner can normally be reached on M-F 7:30am-5:30pm.
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/OYELEYE ALEXANDER ALABI/ Examiner, Art Unit 1797
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