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 .
Response to Arguments
Applicant’s arguments, see pages 6 and 7, filed 6/17/2026, with respect to the amendments to claims 6 and 15 have been fully considered and are persuasive. The §112 rejections of claims 6 and 15 have been withdrawn.
Applicant's arguments, see pages 7-9, filed 6/17/2026, with respect to the §102 and §103 rejections of claims 1-6, 11, and 13-22 have been fully considered but they are not persuasive.
Regarding Applicant’s argument (on page 8) that searching for a specified MZ value (in Liebler) is different from finding an MZ value based on a recurrence of the MZ value across runs; Applicant provides no evidence or elaboration as to how these concepts differ. In Liebler, searching for a specified MZ value is the same as finding an MZ value, because the searching of Liebler finds the MZ value that is being searched for (“the spectra are searched for ions having this specified m/z value… The product ion match of these spectra is then scored as the % TIC value I1” [0059] – where TIC refers to “total ion current” [0055]). Searching for the MZ value in Liebler is performed based on a recurrence of the MZ value across runs (“Each set of multiple scans is then averaged and all further operations are performed on the averaged scans. In this case, averaging means that an average value is calculated for the signal intensity at each product ion mass per unit charge (hereinafter referred to as m/z) value for the set of scans to be averaged” [0053]). Liebler discusses that “Although sets of three MS-MS scans are commonly acquired, any number of scans may be acquired in a set” [0053].
Regarding Applicant’s argument (on page 8) that paragraph [0074] of Liebler describes scoring characteristics and does not disclose the claimed feature of identifying recurrent MZ values as corresponding to a background ion; the characteristics of Liebler that are scored are the MZ values: “The product ion spectral characteristic is specified as a m/z value” [0059]. Scoring these characteristics/MZ values identifies recurrent MZ values because Liebler identifies abundance of a specific MZ value (“searching is performed within a window centered at the specified m/z value±b m/z and a most abundant ion ii in the window is selected” [0059] – abundance refers to the total number of ions having the specified MZ value, and therefore the recurrence of ions having the specified MZ value). Paragraph [0074] identifies that “spectral characteristics that are either weak or irregular indicators in spectra or that are common in background spectra are good candidates for secondary classification” [0074]. It is understood from the description of paragraphs [0074] and [0059] that the spectral characteristics are a measurement of the abundance/recurrence of ions of a particular MZ value, based on an identification of these recurrent MZ values (by identifying that the spectral characteristics/MZ values are either weak or irregular), these specific MZ values associated with the identified spectral characteristics are scored as “secondary spectral characteristics” [0074], which are identified as “background spectra” [0074].
Importantly, the claim does not specify any action beyond the mere identification of a recurrent MZ value as corresponding to a background ion. Paragraph [0074] makes such a correspondence identification that secondarily classified (secondary spectral characteristics) are background spectra (for background ions), where the analyzed spectral characteristics are an abundance/recurrence of a particular MZ value (as discussed with respect to paragraph [0059]).
Applicant does not provide additional/specific arguments with respect to claims 2-6, 11, and 13-22 and no additional response is necessary.
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 patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 2, 3, 4, 5, 6, 11, 13, 14, 16, 17, 18, 19, 20, 21, and 22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liebler et al. U.S. PGPUB No. 2002/0023078.
Regarding claim 1, Liebler discloses a method for performing mass spectrometry (MS) (“Mass spectrometry (MS) instruments generate and analyze ions from chemical substances” [0006]), the method comprising: receiving MS data corresponding to a plurality of MS runs (“a series of MS-MS scans producing mass spectral data as raw data 1” [0053]), wherein MS data corresponding to an MS run of the plurality of MS runs comprises detected intensities for a plurality of mass over charge ratios (MZ values) during the MS run (“In the exemplary mass spectrum, the x-axis indicates mass-to-charge ratio (m/z) of the ion signals detected and the y-axis indicates the relative abundance of particular ions detected by the mass spectrometer” [0045]); finding a recurrent MZ value of the plurality of MZ values (“To match spectra to the specified product ion characteristic, the spectra are searched for ions having this specified m/z value” [0059]), wherein: a detected intensity for the recurrent MZ value appears as a recurrent peak in MS data corresponding to a subset of the plurality of MS runs (“searching is performed within a window centered at the specified m/z value ±b m/z and a most abundant ion ii in the window is selected” [0059]); and the subset of the plurality of MS runs includes at least two MS runs of the plurality of MS runs (“The scores are reported for all sets of averaged MS-MS scans receiving nonzero scores. In addition to the score, the scan number, retention time, the precursor m/z, and the ions detected in the MS-MS spectrum that matched the hypothetical series are reported” [0075]); and identifying the recurrent MZ value as corresponding to a background ion (“spectral characteristics that are either weak or irregular indicators in spectra or that are common in background spectra are good candidates for secondary classification. Scores for secondary characteristics are adjusted to insure that the final scores are most heavily influenced by primary characteristics” [0074]).
Regarding claim 2, Liebler discloses that the subset of the plurality of MS runs includes a majority of the plurality of MS runs (“searching is performed within a window centered at the specified m/z value ±b m/z and a most abundant ion ii in the window is selected” [0059]).
Regarding claim 3, Liebler discloses that the recurrent MZ value is a member of a subset of MZ values for which corresponding intensities exceed a threshold intensity (“If, however, the score exceeds the predetermined threshold, then a match is made and the result is displayed in step 716 in easily comprehensible tabular or graphical form as shown in FIG. 7B” [0097]).
Regarding claim 4, Liebler discloses that finding the recurrent MZ value includes performing at least one of a clustering analysis, an unsupervised multivariate analysis, a supervised multivariate analysis, a pattern recognition analysis (“Identification of peptide sequences from MS-MS spectra may be done by direct interpretation (de novo sequence analysis)” [0008]), or a most likely intensity analysis.
Regarding claim 5, Liebler discloses that finding the recurrent MZ value includes finding MZ values for which corresponding intensities in the subset of the plurality of MS runs are comparable (“searching is performed within a window centered at the specified m/z value ±b m/z and a most abundant ion ii in the window is selected” [0059]).
Regarding claim 6, Liebler discloses that finding the recurrent MZ value includes: for a pair of MS runs of the plurality of MS runs, dividing the detected intensities to generate an intensity ratio dataset; generating a frequency dataset corresponding to frequencies of values in the intensity ratio dataset; and finding the recurrent MZ value as an MZ values for which corresponding frequency ratio is in a neighborhood of 1 (“The precursor charge is then estimated by calculating the ratio of the summed ion current for ions with m/z greater than the precursor to the total ion current for the remaining ions in step 238. Spectra with a ratio greater than 0.1 are defined as arising from doubly charged precursors. Spectra with a ratio less than or equal to 0.1 are defined as arising from singly charged precursors, and all ions with m/z greater than the precursor are subtracted from the spectra” [0057]).
Regarding claim 11, Liebler discloses identifying a background ion (“spectral characteristics that are either weak or irregular indicators in spectra or that are common in background spectra are good candidates for secondary classification. Scores for secondary characteristics are adjusted to insure that the final scores are most heavily influenced by primary characteristics” [0074]) and therefore necessarily discloses that the background ion includes either one of a sample dependent background ion and a sample independent background ion.
Regarding claim 13, Liebler discloses subtracting the background ion from the MS data to derive sample data (“Spectra with a ratio less than or equal to 0.1 are defined as arising from singly charged precursors, and all ions with m/z greater than the precursor are subtracted from the spectra” [0057]).
Regarding claim 14, Liebler discloses that the plurality of MS runs utilize liquid chromatography for sample introduction (“liquid chromatography coupled to tandem MS (LC-MS-MS)” [0007] – “sets of MS-MS scans were recorded for this chemical species eluting in the LC-MS-MS analysis between 38.36 and 40.94 minutes” [0116]).
Regarding claim 16, Liebler discloses that the plurality of MS runs utilize time of flight mass spectrometry (“A widely used MS analysis is liquid chromatography coupled to tandem MS (LC-MS-MS) with triple quadrupole, quadrupole-ion trap, quadrupole-time of flight or tandem time of flight MS instruments” [0007]).
Regarding claim 17, Liebler discloses that the plurality of MS runs include full scan MS (“MS instruments can generate full-scan mass spectra, which represent all ions generated from chemical substances entering the MS instrument at any particular point in time” [0006]).
Regarding claim 18, Liebler discloses identifying a section of the MS data as background data; and determining a scaling factor corresponding to the background data (“spectral characteristics that are either weak or irregular indicators in spectra or that are common in background spectra are good candidates for secondary classification. Scores for secondary characteristics are adjusted to insure that the final scores are most heavily influenced by primary characteristics” [0074]).
Regarding claim 19, Liebler discloses utilizing the scaling factor (“spectral characteristics that are either weak or irregular indicators in spectra or that are common in background spectra are good candidates for secondary classification. Scores for secondary characteristics are adjusted to insure that the final scores are most heavily influenced by primary characteristics” [0074]) for subtracting the background ion from the MS data to derive sample data (“The precursor charge is then estimated by calculating the ratio of the summed ion current for ions with m/z greater than the precursor to the total ion current for the remaining ions in step 238. Spectra with a ratio greater than 0.1 are defined as arising from doubly charged precursors. Spectra with a ratio less than or equal to 0.1 are defined as arising from singly charged precursors, and all ions with m/z greater than the precursor are subtracted from the spectra” [0057]).
Regarding claim 20, Liebler discloses including the sample data in a spectra reference library (“a local database or the instrument computer 10 may be used to store the mass spectral data rather than the server 24” [0052]).
Regarding claim 21, Liebler discloses subtracting the background ion from subsequent MS runs (“The precursor charge is then estimated by calculating the ratio of the summed ion current for ions with m/z greater than the precursor to the total ion current for the remaining ions in step 238. Spectra with a ratio greater than 0.1 are defined as arising from doubly charged precursors. Spectra with a ratio less than or equal to 0.1 are defined as arising from singly charged precursors, and all ions with m/z greater than the precursor are subtracted from the spectra” [0057]) on the fly (“the mass spectral mining is performed in real time so that the control settings of the mass spectrometer can be adjusted to improve the generated spectra” [0095]).
Regarding claim 22, Liebler discloses a system for analyzing ions, the system comprising: a mass spectrometer (“Mass spectrometry (MS) instruments generate and analyze ions from chemical substances” [0006]) for receiving ions generated by an ion source (“generate and analyze ions from chemical substances” [0006]); an analyzer module operatively coupled to the mass spectrometer, the analyzer module comprising: a processor (“The mechanisms and processes set forth in the present description may be implemented using a conventional general purpose microprocessor programmed according to the teachings in the present specification, as will be appreciated to those skilled in a relevant art(s)” [0121]), and a memory (“The present invention thus also includes a computer-based product which may be hosted on a storage medium and include instructions which can be used to program a computer to perform a process in accordance with the present invention. This storage medium can include but is not limited to any type of disk including floppy disk, optical disk, CD-ROMs, magneto-optical disk, ROMs, RAMs, EPROMS, EEPROMS, flash memory, magnetic or optical cards, or any type of media suitable for storing electronic instructions” [0122]) including program code configured to, when executed, cause the processor to: receive MS data corresponding to a plurality of MS runs (“a series of MS-MS scans producing mass spectral data as raw data 1” [0053]), wherein MS data corresponding to an MS run of the plurality of MS runs comprises detected intensities for a plurality of mass over charge ratios (MZ values) during the MS run (“In the exemplary mass spectrum, the x-axis indicates mass-to-charge ratio (m/z) of the ion signals detected and the y-axis indicates the relative abundance of particular ions detected by the mass spectrometer” [0045]); find a recurrent MZ value of the plurality of MZ values (“To match spectra to the specified product ion characteristic, the spectra are searched for ions having this specified m/z value” [0059]), wherein: a detected intensity for the recurrent MZ value appears as a recurrent peak in MS data corresponding to a subset of the plurality of MS runs (“searching is performed within a window centered at the specified m/z value ±b m/z and a most abundant ion ii in the window is selected” [0059]); and the subset of the plurality of MS runs includes at least two MS runs of the plurality of MS runs (“The scores are reported for all sets of averaged MS-MS scans receiving nonzero scores. In addition to the score, the scan number, retention time, the precursor m/z, and the ions detected in the MS-MS spectrum that matched the hypothetical series are reported” [0075]); and identify the recurrent MZ value as corresponding to a background ion (“spectral characteristics that are either weak or irregular indicators in spectra or that are common in background spectra are good candidates for secondary classification. Scores for secondary characteristics are adjusted to insure that the final scores are most heavily influenced by primary characteristics” [0074]).
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.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liebler et al. U.S. PGPUB No. 2002/0023078 in view of Everson et al. U.S. PGPUB No. 2021/0318274.
Regarding claim 15, Liebler discloses the claimed invention except that while Liebler discloses the use of a mass spectrometer (“Mass spectrometry (MS) instruments generate and analyze ions from chemical substances” [0006]), there is no explicit disclosure that the plurality of MS runs utilize Echo MS for sample introduction.
Everson discloses “The MS or MS/MS may also involve acoustic ejection mass spectrometry (AEMS), for example, combining open port interface (OPI) with acoustic droplet ejection (ADE) to allow sample analysis directly from plate without LC. One example of ADE is AB Sciex Echo MS” [0300].
It would have been obvious to one possessing ordinary skill in the art before the effective filing date of the claimed invention to have modified Liebler with the Echo ionization of Everson in order to utilize a commercially available ion source for generating the ions for analysis in Liebler.
Allowable Subject Matter
Claims 7, 8, and 9 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Regarding claim 7; Liebler et al. U.S. PGPUB No. 2002/0023078 discloses a method for performing mass spectrometry (MS) (“Mass spectrometry (MS) instruments generate and analyze ions from chemical substances” [0006]), the method comprising: receiving MS data corresponding to a plurality of MS runs (“a series of MS-MS scans producing mass spectral data as raw data 1” [0053]), wherein MS data corresponding to an MS run of the plurality of MS runs comprises detected intensities for a plurality of mass over charge ratios (MZ values) during the MS run (“In the exemplary mass spectrum, the x-axis indicates mass-to-charge ratio (m/z) of the ion signals detected and the y-axis indicates the relative abundance of particular ions detected by the mass spectrometer” [0045]); finding a recurrent MZ value of the plurality of MZ values (“To match spectra to the specified product ion characteristic, the spectra are searched for ions having this specified m/z value” [0059]), wherein: a detected intensity for the recurrent MZ value appears as a recurrent peak in MS data corresponding to a subset of the plurality of MS runs (“searching is performed within a window centered at the specified m/z value ±b m/z and a most abundant ion ii in the window is selected” [0059]); and the subset of the plurality of MS runs includes at least two MS runs of the plurality of MS runs (“The scores are reported for all sets of averaged MS-MS scans receiving nonzero scores. In addition to the score, the scan number, retention time, the precursor m/z, and the ions detected in the MS-MS spectrum that matched the hypothetical series are reported” [0075]); and identifying the recurrent MZ value as corresponding to a background ion (“spectral characteristics that are either weak or irregular indicators in spectra or that are common in background spectra are good candidates for secondary classification. Scores for secondary characteristics are adjusted to insure that the final scores are most heavily influenced by primary characteristics” [0074]). Liebler discloses the claimed invention except that there is no explicit disclosure that finding the recurrent MZ value comprises: performing a most likely ratio (MLR) analysis of the frequency dataset; and extracting from the MLR analysis at least one MLR feature.
While most likely ratio (MLR) analysis is generally known, as in paragraph [0039] of McEachern et al. U.S. PGPUB No. 2017/0023627, the prior art does not perform a most likely ratio (MLR) analysis of the frequency dataset corresponding to frequencies of values in an intensity ratio dataset that is generated by dividing detected intensities for a pair of mass spectrometry runs of a plurality of mass spectrometry runs.
The prior art fails to teach or reasonably suggest, in combination with the other claim limitations, a method for performing mass spectrometry (MS), the method comprising: receiving MS data corresponding to a plurality of MS runs, wherein MS data corresponding to an MS run of the plurality of MS runs comprises detected intensities for a plurality of mass over charge ratios (MZ values) during the MS run; dividing, for a pair of MS runs of the plurality of MS runs, the detected intensities to generate an intensity ratio dataset; and performing a most likely ratio (MLR) analysis of the frequency dataset.
Regarding claims 8 and 9; these claims would be allowable at least for their dependence upon claim 7.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JASON L MCCORMACK whose telephone number is (571)270-1489. The examiner can normally be reached M-Th 7:00AM-5:00PM EST.
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/JASON L MCCORMACK/Examiner, Art Unit 2881
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