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 filed on 06/03/2026 have been fully considered but they are not persuasive.
The claim objections regarding claims 9, 10, 12, 16, and 25 of record are withdrawn in light of applicant’s amendments.
The indefiniteness rejections of record are withdrawn in light of applicant’s amendments.
Regarding the 103 rejections to independent claim 1:
Applicant asserts that, Luethy teaches away combining MS1 analyses data because it uses FT data for better precursor mass accuracy and allegedly ignores IT data. This is not persuasive. Luethy does not teach away from using IT MS1 data. Luethy expressly teaches its system performs “a full ion-trap (IT) survey scan ... a full FT survey scan ... and then 4 MS/MS IT scans on the 4 largest peaks from the preceding IT or FT survey scan” and recognizes that “the IT may have better sensitivity and thus may be able to trigger MS/MS events and identify peptides for which no signal was present in the FT.” Thus, Luethy teaches complementary benefits of the two MS1 datasets: FT provides higher mass accuracy, while IT provides higher sensitivity.
Applicant further argues that Norton only merges replicate spectra post-acquisition not concurrent MS1 data from two analyzers. This is not persuasive. Norton is not relied upon to teach the same two-analyser instrument as Luethy. Norton is cited for the data-processing feature of combining peak lists into a merged/composed peak list, and in the modified system, Norton’s peak list merging technique is applied to Luethy’s parallel FT-MS1 and IT-MS1 peak output to produce combined MS1 precursor information.
Finally, applicant argues that Luethy/Norton combination is hindsight. This is not persuasive. Any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instance case, Luethy provides two MS1 datasets used in the same tandem MS acquisition cycle, and Norton teaches that peak information from multiple spectra may be merged into a composited peak list to improve downstream analysis. One of ordinary skilled would have had reason to combine the complementary FT and IT MS1 information so precursor identification/quantification benefits from both the higher mass accuracy of FT and the higher sensitivity of IT.
Regarding the 103 rejections to dependent claim 3 and new dependent claim 26:
Applicant’s arguments with respect to claims 3 and 26 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Claim Objections
Claim 3 is objected to because it contains grammatical errors/typo: “generating a combined list of precursor ions peaks” should be “precursor ion peaks”;
Claim 25 is objected to because it contains grammatical error in “a second mass analyser configured to analyser…” (verb/noun mismatch).
Appropriate correction is required.
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 3 and 26 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.
Claims 3 and 26 each recite “the combined list is filtered…by filtering the second set of precursor ion peaks to remove any precursor ion peaks having a relatively large intensity that are expected to be recorded by the MS1 analysis performed by the first mass analyser.” This limitation fails to define the scope of claimed filtering. First, the claim does not specify how to determine that a large peak detected by the higher-sensitivity second mass analyser would also be detected by the lower-sensitivity first mass analyser. Without such a definition, a peak that appears large in the more-sensitive second analyzer may not necessarily be large enough to be detected by the less-sensitive first analyzer and thus should not be removed. Second, the claim is unclear about the order of filtering large peaks from second set and combining the first and second sets. If the large peaks are filtered before combing, the claim does not explain how the system determines that those peaks are repeated in the first set; if the filtering occurs after comparing and combining the two sets, the step appears to be ordinary repeated peak removal rather than a distinct intensity-based filtering step. Accordingly, the scope of claims 3 and 26 is unclear.
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.
Claims 1-2, 7-9, 19-20, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Luethy et al., Precursor-Ion Mass Re-Estimation Improves Peptide Identification on Hybrid Instruments. Journal of Proteome Research, 7(9), 4031–4039 (2008) [hereinafter Luethy] in view of US 2003/0078739 A1 [hereinafter Norton].
Regarding Claim 1:
Luethy teaches a method of tandem mass spectrometry for analysing precursor ions across a mass to charge (m/z) range of interest (Page 1: method of using LTQ-FT instruments having two mass spectrometer to identify precursor ions) comprising:
analysing some of the precursor ions across the m/z range of interest in the MS1 domain using a first mass analyser of a tandem mass spectrometer (Pages 2, 4: a Fourier transform-ICR (FT) (“first mass analyzer”) performs FT-MS1 scans on precursor ions across a m/z range from 400 to 1800 m/z in the FT-MS1 spectra (“MS1 domain”));
analysing some of the precursor ions across the m/z range of interest in the MS1 domain using a second mass analyser of the tandem mass spectrometer (Pages 2, 4: a fast ion trap (IT) (“first mass analyzer”) IT-MS1 scans on precursor ions across a m/z range from 400 to 1800 m/z in the IT-MS1 spectra (“MS1 domain”));
the first mass analyser operated at a first sensitivity, the second mass analyser operated at a second sensitivity, wherein the second sensitivity is higher than the first sensitivity (Page 9: Luethy notes that IT-triggered MS/MS events lacking a corresponding precursor signal in the FT full-scan, “suggesting … that the sensitivity of the IT was greater than the FT,” and further notes that when considering all IT-triggered MS/MS, a likely precursor could not be found in the FT for nearly 12% of spectra, accordingly higher effective IT sensitivity for triggering low-level precursor events that may be absent or below detection in the FT survey);
wherein the analysis in the MS1 domain performed by the second mass analyser is performed concurrently with the analysis performed in the MS1 domain by the first mass analyser (Pages 2: “The LTQ-FT instrument used in this study have two mass spectrometers that can operate mostly in parallel…a cycle consists of an FT MS scan in parallel with an IT MS scan…”);
[use] data from the MS1 analyses performed by the first and second mass analysers to identify and/or quantify precursor ions ( Pages 4 and 14: performs “a full ion-trap (IT) survey scan ... a full FT survey scan ... and then 4 MS/MS IT scans on the 4 largest peaks from the preceding IT or FT survey scan, ” and “msPrefix intercedes between data collection and computational identification to improve the precision of the precursor mass by inspection of the preceding full-resolution FTMS survey-scan”); and
analysing some of the precursor ions in the MS2 domain using the second mass analyser of the tandem mass spectrometer (Page 2: “Regardless of which spectrum is used to trigger an MS/MS, the isolation and fragmentation is performed in the IT, which isolates ions within a window of the triggering m/z,” i.e., IT-MS performs precursor ion analyses in the MS/MS spectra (“MS2 domain”)).
However, Luethy does not specifically note data from the MS1 analyses performed by the first and second mass analysers are combined.
Norton teaches combining data from the MS1 analyses performed by the first and second mass analysers (para. [0024]: generate a merged peak/composite peak list from peak lists of all of the spectra, i.e., combine the MS spectra produced by the first/second mass analyser).
Luethy teaches a tandem MS workflow using two MS-level datasets whose MS1 peak detection relies on a noise threshold (i.e., peaks are defined as local maxima exceeding a threshold above the noise floor). Norton teaches combining MS peak information from multiple spectra to generate in a merged peak/composite list. Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to applying Norton’s peak-list merging technique to Luethy’s two MS1 peak outputs so that MS1 data from both analyzers/sources is combined (e.g., merged into a composite peak list) for identifying and/or quantifying precursor ions as claimed. A POSITA would be motivated to combine MS1 data from both analyzers because, as Norton explains, conventional threshold-based peak selection would introduce an artificial discontinuity and makes peaks just above vs. just below the threshold appear qualitatively different, potentially dominating downstream analysis, which are problem implicated in Luethy because Luethy likewise defines peaks using a noise-floor threshold. Accordingly, combining MS1 peak lists from different spectra/analyzers mitigates this issue by allowing corresponding peaks to be aligned and consolidated into a merged/composite list, so precursor identification/quantification relies on the combined evidence rather than treating near-threshold signals as “present” in one list and “zero” in the other.
Regarding Claim 2:
Luethy in view of Norton teaches the method according to claim 1. Luethy further teaches wherein the first mass analyser is operated at a first sensitivity and a first mass accuracy and the second mass analyser analyses some of the precursor ions in the MS1 domain at a second sensitivity and a second mass accuracy, wherein the second mass accuracy is lower than the first mass accuracy (Pages 4: as discussed in claim 1, Luethy teaches each first/second mass analyser has a corresponding first/second sensitivity. Luethy further teaches that the “FT-triggered delta-masses were on average significantly smaller than IT-triggered.” Here, “delta-mass” is the mass error (deviation from the expected/assigned m/z), so a smaller delta-mass indicates higher mass accuracy; accordingly, Luethy teaches that the FT analyser provides higher mass accuracy than the ion-trap analyser).
Regarding Claim 7:
Luethy in view of Norton teaches the method according to claim 1. Luethy further teaches the analyses performed in the MS2 domain are based on the precursor ions identified by the MS1 analyses (Pages 2: “a cycle consists of an FT MS scan in parallel with an IT MS scan and several IT, MS/MS scans whose precursor ions are selected in a data-dependent manner… selected from the preceding IT spectrum or from the first quarter of the FT scan”).
Regarding Claim 8:
Luethy in view of Norton teaches the method according to claim 1. Luethy further teaches wherein analysing the precursor ions in the MS2 domain comprises: fragmenting the precursor ions to generate product ions; and analysing the product ions using the second mass analyser (Pages 2-3: “…trigger an MS/MS, the isolation and fragmentation is performed in the IT, which isolates ions within a window of the triggering m/z,” “msPrefix intercedes between data collection and computational identification to improve the precision of the precursor mass by inspection of the preceding full-resolution FTMS survey-scan”).
Regarding Claim 9:
Luethy in view of Norton teaches the method according to claim 1. Luethy further teaches the method comprises performing a plurality of analysis cycles using the tandem mass spectrometer (Page 2: teaches a “cycle” as the basic repeated acquisition unit “under our operation, a cycle consists of…”), wherein each cycle comprises:
performing a single analysis across the m/z range of interest in the MS1 domain using the first mass analyser (Page 2: “a cycle consists of an FT MS scan…”); and
performing a single analysis across the m/z range of interest in the MS1 domain using the second mass analyser (Page 2: “a cycle consists of …an IT MS scan…”); and
performing analyses of some of the precursor ions in the MS2 domain using the second mass analyser (Page 2: “a cycle consists of … several IT MS/MS scans whose precursor ions are selected in a data-dependent manner”),
wherein the analyses performed in the MS1 and MS2 domains by the second mass analyser are performed concurrently with the single analysis in the MS1 domain performed by the first mass analyser (Page 2: “a cycle consists of an FT MS scan in parallel with an IT MS scan and several IT MS/MS scans whose precursor ions are selected in a data-dependent manner”).
Regarding Claim 19:
Luethy in view of Norton teaches the method according to claim 1. Luethy further teaches wherein the precursor ions to be analysed are filtered to remove or reduce the number of singly-charged precursor ions (teaches rejecting singly-charged precursors as “Potential precursor masses of FT triggered MS/MS scans were rejected if the precursor ion was identified as being singly charged”).
Regarding Claim 20:
Luethy in view of Norton teaches the method according to claim 1. Luethy further teaches wherein the precursor ions to be analysed are provided by an ion source which is configured to ionise molecules provided from a chromatographic separation apparatus (Pages 1, 3: “…protein samples are… further separated by liquid chromatography (one or more stages) and analyzed with a [tandem] mass spectrometer…”).
Regarding Claim 23:
Claim 23 includes two causes linked by “and/or”. Examiner interprete “and/or” as “or” and relied on the first clause (“first mass analyser”).
Luethy in view of Norton teaches the method according to claim 1. Luethy further teaches wherein the first mass analyser is a mass analyser selected from the group comprising: an orbital trapping mass analyser, a Fourier-transform ion cyclotron resonance (FTICR) mass analyser, and a Time Of Flight (TOF) mass analyser (page 2: “The LTQ-FT instruments used in this study have two mass spectrometers that can operate mostly in parallel: a slower Fourier transform-ICR (FT) (“first mass analyzer”) , i.e., FTICR); and/or the second mass analyser is a TOF mass analyser.
Regarding Claim 24:
Luethy in view of Norton teaches the method according to claim 1. Luethy further teaches the first mass analyser is operated at a first dynamic range to perform the respective MS1 analysis; and the second mass analyser is operated at a second dynamic range larger than the first dynamic range to perform the respective MS1 analysis, wherein the dynamic range is a ratio of the largest detectable signal to the smallest detectable signal (As discussed for claim 1, Luethy supports that the IT may have greater sensitivity than the FT. Accordingly, the IT MS1 can detect lower-intensity precursor ions that may not be detected in the FT MS1, and thus the IT can be operated to cover a wider effective MS1 intensity span than the FT (i.e., a larger effective dynamic range).
Regarding Claim 25:
Luethy teaches a tandem mass spectrometer for analysing precursor ions across a mass to charge (m/z) range of interest comprising (Page 1: an LTQ-FT instruments having two mass spectrometer to identify precursor ions) comprising:
a first mass analyser configured to analyse precursor ions in the MS1 domain (Pages 2, 4: a Fourier transform-ICR (FT) (“first mass analyzer”) performs FT-MS1 scans on precursor ions in the FT-MS1 spectra (“MS1 domain”));
a second mass analyser configured to analyser precursor ions in the MS1 domain and the MS2 domain (Pages 2, 4: a fast ion trap (IT) (“first mass analyzer”) IT-MS1 scans on precursor ions in the IT-MS1 spectra (“MS1 domain”));
a controller (processing unit of the ITQ-FT instrument) configured to:
cause the first mass analyser to analyse some of the precursor ions across the m/z range of interest in the MS1 domain (Pages 2, 4: a Fourier transform-ICR (FT) (“first mass analyzer”) performs FT-MS1 scans on precursor ions across a m/z range from 400 to 1800 m/z in the FT-MS1 spectra (“MS1 domain”));
cause the second mass analyser to analyse some of the precursor ions across the m/z range of interest in the MS1 domain (Pages 2, 4: a fast ion trap (IT) (“first mass analyzer”) IT-MS1 scans on precursor ions across a m/z range from 400 to 1800 m/z in the IT-MS1 spectra (“MS1 domain”));
the first mass analyser operated at a first sensitivity, the second mass analyser operated at a second sensitivity, wherein the second sensitivity is higher than the first sensitivity (Pages 8-9, teaches “any transit of ions from IT-to-FT may lead the ion trap to be more sensitive than the FT”, and “IT may have better sensitivity” than FT);
wherein the second mass analyser analyses the precursor ions in the MS1 domain concurrently with the first mass analyser analysing the precursor ions in the MS1 domain (Pages 2: “The LTQ-FT instrument used in this study have two mass spectrometers that can operate mostly in parallel…a cycle consists of an FT MS scan in parallel with an IT MS scan…”);
[use] data from the MS1 analyses performed by the first and second mass analysers to identify and/or quantify precursor ions ( Pages 4 and 14: performs “a full ion-trap (IT) survey scan ... a full FT survey scan ... and then 4 MS/MS IT scans on the 4 largest peaks from the preceding IT or FT survey scan, ” and “msPrefix intercedes between data collection and computational identification to improve the precision of the precursor mass by inspection of the preceding full-resolution FTMS survey-scan”); and
cause the second mass analyser to analyse some of the precursor ions in the MS2 domain (Page 2: “Regardless of which spectrum is used to trigger an MS/MS, the isolation and fragmentation is performed in the IT, which isolates ions within a window of the triggering m/z,” i.e., IT-MS performs precursor ion analyses in the MS/MS spectra (“MS2 domain”)).
However, Luethy does not specifically note data from the MS1 analyses performed by the first and second mass analysers are combined.
Norton teaches combining data from the MS1 analyses performed by the first and second mass analysers (para. [0024]: generate a merged peak/composite peak list from peak lists of all of the spectra, e.g., the MS spectra produced by the first/second mass analyser).
Luethy teaches a tandem MS workflow using two MS-level datasets whose MS1 peak detection relies on a noise threshold (i.e., peaks are defined as local maxima exceeding a threshold above the noise floor). Norton teaches combining MS peak information from multiple spectra to generate in a merged peak/composite list. Therefore, it have been obvious for an ordinary skilled person in the art, before the effective time of filing, to applying Norton’s peak-list merging technique to Luethy’s two MS1 peak outputs so that MS1 data from both analyzers/sources is combined (e.g., merged into a composite peak list) for identifying and/or quantifying precursor ions as claimed. A POSITA would be motivated to combine MS1 data from both analyzers because, as Norton explains, conventional threshold-based peak selection would introduce an artificial discontinuity and makes peaks just above vs. just below the threshold appear qualitatively different, potentially dominating downstream analysis, which are problem implicated in Luethy because Luethy likewise defines peaks using a noise-floor threshold. Accordingly, combining MS1 peak lists from different spectra/analyzers mitigates this issue by allowing corresponding peaks to be aligned and consolidated into a merged/composite list, so precursor identification/quantification relies on the combined evidence rather than treating near-threshold signals as “present” in one list and “zero” in the other.
Claims 3-6 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Luethy in view of Norton, further in view of US 20180108521A1 [hereinafter Campbell].
Regarding Claims 3 and 26:
Luethy in view of Norton teaches the method according to claim 1 and the tandem mass spectrometer of claim 25. The combined references further teach:
combining data from the MS1 analyses performed by the first and second mass analysers comprises generating a combined list of precursor ions peaks in the MS1 domain, wherein the combined list of precursor ion peaks comprises a first set of precursor ion peaks identified from the MS1 analysis performed by the first mass analyser and a second set of precursor ion peaks identified from the MS1 analysis performed by the second mass analyser (Norton (para. [0024]) teaches generate a merged peak/composite peak list from peak lists of all of the spectra, e.g., the MS spectra produced by the first/second mass analyser, and thus in the modified system a first set of precursor ions identified from the MS1 analysis and a second set of precursor ions identified from the MS2 analysis are combined as a combined list of precursor ion peaks),
wherein the combined list is filtered to remove precursor ion peaks which are repeated between the first and second sets of precursor ion peaks (Norton-Fig. 3C and para. [0026]: when two peaks from each peak list are sufficiently close in m/z and correspond to the same ion, they are removed and represented by a merged single peak in the merged peak/composite peak list).
However, the combined references do not specially note that filtering the second set of precursor ion peaks to remove any precursor ion peaks having a relatively large intensity that are expected to be recorded by the MS1 analysis performed by the first mass analyser.
Campbell teaches setting upper and low threshold limits for peak intensity and using only peaks whose intensity falls between those limits and peaks above the upper intensity limit are excluded from further MS/MS selection/use (Abstract).
As such, modifying the Luethy-Norton system with Campbell entails applying an upper threshold filtering to the second set of ion peaks and removing peaks above that threshold.
Therefore, it would have been obvious for an ordinary skilled person in art, before the effective time of filing, to modified the Luethy-Norton system with Campbell’s filtering step, to apply an upper intensity limit to detected MS peaks and exclude peaks above that limit before/when forming the combined precursor list for further MS/MS analysis, thereby allowing the second set to supplement the firsts et with useful lower-abundance peaks while avoiding redundant high-intensity peaks.
Regarding Claim 4:
Luethy in view of Norton and Campbell teach the method according to claim 3. Norton further teaches wherein the second set of precursor ion peaks is filtered to remove any low intensity peaks in the mass spectrum which are indistinguishable from noise (para. [0023]: “a noise analysis is performed on the processed data in step 26 to extract peaks from background noise. A conventional noise analysis method computes an average signal intensity and defines a threshold exceeding the average value by a multiple of the standard deviation in intensity. Local maxima above the threshold are identified as candidate peaks”).
Regarding Claim 5:
Luethy in view of Norton and Campbell teach the method according to claim 4. Campbell further teaches the second set of precursor ion peaks is thresholded to remove any precursor ion peaks below a first predetermined intensity level and any precursor ion peaks above a second predetermined intensity level (Abstract: “setting of an upper and lower threshold limit on peak intensity and only triggering an enhanced product ion scan when a detected intensity of a peak in an initial scan falls between the upper and lower threshold limits”).
Regarding Claim 6:
Luethy in view of Norton and Campbell teach the method according to claim 4.
Luethy further teaches calibrate the tandem mass spectrometer (Page 5: calibrating the LTQ-FT data by applying an instrument calibration function to convert detected monoisotopic peaks from the frequency domain back to calibrated m/z values).
Norton further teaches a first precursor ion peak generated by the second mass analyser and a corresponding first precursor ion peak generated by the first mass analyser are used to calibrate, wherein the calibration is used to identify precursor ion peaks which are repeated between the first and second sets of precursor ion peaks (Fig. 3C and para. [0026]: using the (calibrated/aligned) peak information to identify when peaks from two peak sets correspond to the same ion (i.e., are repeats) by determining whether they are sufficiently close in m/z (and retention time, when applicable), and then combining them into a single peak in a merged/composite peak list, thereby eliminating repeated peaks between the contributing sets).
As such, substituting Norton’s repeated-peak removal step for Luethy’s peak-list collapsing step entails performing Luethy’s peak detection and conversion to calibrated m/z values by comparing the first and second precursor peak sets and treat peaks sufficiently close in m/z (and RT) as the same ion, consolidating them into a single merged peak, thereby identifying/removing peaks repeated between the two sets.
Claims 10-18 are rejected under 35 U.S.C. 103 as being unpatentable over Luethy in view of Norton, and further in view of Kang et al., Improved segmented-scan spectral stitching for stable isotope resolved metabolomics (SIRM) by ultra-high-resolution Fourier transform mass spectrometry. Analytica Chimica Acta, 1080, 104–115 (2019) [hereinafter Kang].
Regarding Claim 10:
Luethy in view of Norton teaches the method according to claim 1.
Luethy further teaches performing a plurality of analysis cycles using the tandem mass spectrometer (uses the LTQ-FT instrument in Luethy to perform multiple cycles as discussed in claim 1), wherein each cycle comprises:
performing a single analysis across the m/z range of interest in the MS1 domain using the first mass analyser; and performing analyses of some of the precursor ions in the MS2 domain using the second mass analyser, wherein the analyses performed in the MS1 and MS2 domains by the second mass analyser are performed concurrently with the single analysis in the MS1 domain performed by the first mass analyser (all limitations discussed in claim 1)
However, the combined references do not specifically note that subdividing the m/z range of interest into a plurality of m/z subranges and performing an analysis across each m/z subrange of interest in the MS1 domain using the second mass analyser.
Kang teaches subdividing the m/z range of interest into a plurality of m/z subranges and performing an analysis across each m/z subrange of interest in the MS1 domain using the second mass analyser (Abstract, Fig. 1, and Pages 6 and 17: a linear ion trap (LIT)-based stitching method, where the m/z ranges are divided to multiple segments with different widths and perform MS scans over each segment, for example, fig. 1 shows divide a full m/z range to 12 segments and perform MS scan over each m/z segment).
Luethy teaches an LTQ-FT duty cycle where a FT MS1 scan runs in parallel with an ion-trap (IT) MS scan and several IT MS/MS scans, with precursor selection based on the preceding FT and IT scans. Kang teaches segmented (windowed) SIM-stitching and performing many segment scans per cycle. Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to apply Kang’s segmented/windowed MS1 acquisition to Luethy’s second-analyser survey operation because Kang explicitly teaches that segmenting and stitching yields higher S/N and higher sensitivity/dynamic range across a wide m/z range than a single wide scan, which directly addresses the practical limitation in Luethy’s cycle that IT surveys performed under tight time budgets can miss or poorly measure low-abundance precursors.
Regarding Claim 11:
Luethy in view of Norton, and further in view of Kang teaches the method according to claim 10. Kang further teaches:
each cycle comprises: performing a plurality of analyses in the MS1 domain for each m/z subrange of interest using the second mass analyser (Abstract, Fig. 1, and Pages 6 and 17: perform multiple scans, each scan applies a linear ion trap (LIT)-based stitching method, where the m/z ranges are divided to segments with different widths perform MS scans over each segment, for example, fig. 1 shows divide a full m/z range to 12 segments and perform MS scan each m/z segment), and
for each m/z subrange of interest averaging the data from the MS1 analyses performed by the second mass analyser (Pages 15 and 20: “The scans were averaged using Xcalibur 3.0.63”).
Regarding Claim 12:
Luethy in view of Norton teaches the method according to claim 1. Luethy further teaches performing a plurality analysis cycles using the tandem mass spectrometer, wherein each cycle comprises performing a single analysis across the m/z range of interest in the MS1 domain using the first mass analyse; and performing analyses of some of the precursor ions in the MS2 domain using the second mass analyser (as discussed in claim 1).
However, the combined references do not specifically note that performing a plurality of analyses across the m/z range of interest in the MS1 domain using the second mass analyser
Kang further teaches performing a plurality of analyses across the m/z range of interest in the MS1 domain using the second mass analyser (Abstract, Fig. 1, and Pages 6 and 17: teaches a linear ion trap (LIT)-based stitching method, and performs a plurality of MS scans over a plurality of segments of the m/z range).
Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to apply Kang’s segmented/windowed MS1 acquisition and averaging to Luethy’s second-analyser survey operation, so the combined method would perform multiple analyses across the m/z range. Since Luethy already runs multiple second-analyser events during the FT MS1 transient, incorporating multiple short segment MS1 surveys (with averaging per segment) is a predictable use of the available parallel window to improve precursor measurement quality while preserving the overall duty cycle.
Regarding Claim 13:
Luethy in view of Norton, and further in view of Kang teaches the method according to claim 12. Kang further teaches for each analysis cycle, averaging the data from the analyses performed in the MS1 domain for that cycle by the second mass analyser (Pages 15 and 20: “The scans were averaged using Xcalibur 3.0.63”).
Regarding Claim 14:
Luethy in view of Norton, and further in view of Kang teaches the method according to claim 13. Luethy further teaches averaging the data from the analyses performed in the MS1 domain comprises thresholding the data to remove precursor ion peaks below a third intensity level (Page 5: “discard peaks whose best isotope envelope score is less than 4× the noise floor score,” where the noise floor score is a peak-quality metric derived from the spectrum signal (i.., from the measured signal magnitude”).
Regarding Claim 15:
Luethy in view of Norton, and further in view of Kang teaches the method according to claim 12.
Luethy further teaches wherein a single cycle analysis performed in the MS1 domain by the second mass analyser are interleaved with the analyses performed in the MS2 domain by the second mass analyser (Luethy says the cycle includes “an IT MS scan and several IT MS/MS scans” (all on the IT/second analyser)).
Kang further teaches the plurality of analyses performed in the MS1 domain by the second mass analyser (teaches multiple segment/subrange MS1 surveys (e.g., “30 different 100 m/z segments” / “12 segments … per cycle”).
As such, substitute Luethy’s single analyzer-2 MS1 survey scan with Kang’s plural segmented/windowed MS1 survey approach would yield a scan queue for which the MS1 segment analyses are interleaved with the MS2 analyses on the second analyser by inserting a segment MS1 scan after every fixed group of MS2 scans (and repeating for successive segments).
Regarding Claim 16:
Luethy in view of Norton, and further in view of Kang teaches the method according to claim 15. Kang further teaches wherein for each analysis cycle, at least 3, 5, or 7 analyses are performed in the MS1 domain by the second mass analyser (as an example, Kang teaches divide the m/z range to 21 segments and scan each segment accordingly).
Regarding Claim 17:
Luethy in view of Norton, and further in view of Kang teaches the method according to claim 15.
Kang further teaches wherein the analyses performed in the MS1 domain (Kang further teaches distributing the segment acquisitions over time to reduce time-dependent effects, e.g., “We iteratively rotated the acquisition of the segments, to minimize the effects of any … instability or sample composition stratification”),
Luethy further teaches a duration of the analysis performed in the MS1 domain by the first mass analyser (teaches the first analyser performs an FT MS scan in each cycle, i.e., a first-analyser MS1 acquisition interval (“a cycle consists of an FT MS scan…”)
As such, Luethy in view of Kang teaches “the analyses performed in the MS1 domain are interleaved evenly throughout the duration of the analysis performed in the MS1 domain by the first mass analyser,” since substituting Luethy’s single analyser-2 MS1 survey with Kang’s plural segment-MS1 surveys and executing them within Luethy’s FT-scan parallel window entails scheduling the segment-MS1 surveys using a fixed spacing rule (e.g., after every fixed number of analyser-2 MS/MS events), which distributes them across the entire FT-MS1 duration and therefore yields the claimed “interleaved evenly throughout the duration.”
Regarding Claim 18:
Luethy in view of Norton teaches the method according to claim 9. However, the combined references do not specifically note limitations recited in claim 18.
Kang teaches:
wherein each analysis cycle further comprises performing a gain control analysis using the first mass analyser or the second mass analyser (Page 8- Section 3.1: peforms AGC (Automatic Gain Control) target optimization ““with increasing AGC targets …” and that “we chose ... as the AGC target value throughout this study …”),
wherein an injection time for each of the MS1 analyses performed by the first and/or second mass analysers is adjusted based on the gain control analysis (Pages 4-5: Section 2.2.1: injection time varies as a function of the AGC target selection: “AGC targets … were selected … Ion injection times were 25, 50, 100, and 500 ms for AGC targets … respectively”).
Luethy teaches an LTQ-FT workflow that performs parallel MS scans and MS/MS scans in the hybrid instrument, i.e., a tandem MS method where scan timing/throughput matters. Kang teaches performing gain control via AGC target selection/optimization and explicitly teaches that ion injection time is set to different values depending on AGC target. Therefore, it would have been ordinary for an ordinary skilled person in the art, before the effective time of filing, to incorporate Kang’s AGC-based injection-time adjustment into Luethy’s tandem MS workflow so that the injection time for MS1 analyses is adjusted based on gain control analysis. A POSITA would be motivated to do so because AGC-based injection-time control is used to achieve the desired ion population/measurement quality without unnecessary accumulation time, improving MS1 data quality and efficiency in the tandem MS cycle.
Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Luethy in view of Norton, and further in view of CA 2763261A1 [hereinafter Senko].
Regarding Claim 21:
Luethy in view of Norton teaches the method according to claim 20. However, the combined references do not specifically note data from the MS1 analyses performed by the first and second mass analysers is used to identify a chromatographic peak eluting from the chromatographic separation apparatus
Senko teaches data from the MS1 analyses performed by the first and second mass analysers is used to identify a chromatographic peak eluting from the chromatographic separation apparatus (Abstract, paras. [0037, 0052]: “taking a series of mass spectral scans of a sample that has eluted from the liquid chromatography (LC) column.” “An extracted ion chromatogram (XIC) is created for each m/z data point of mass spectral scans,” “the current weighted intensities for each of the different m/ z data points within the reconstructed weighted mass spectrum give an indication of...a chromatographic elution peak of the precursor ions exists”).
Luethy teaches acquiring MS1 information in a hybrid LTQ-FT workflow using both analyzers’ MS-level data streams. Senko teaches using MS1 data collected over time from LC elution to identify a chromatographic elution peak by generating an extracted ion chromatogram (XIC) from the MS data and using the resulting peak-state information (e.g., whether a peak exists / is approaching / has passed). Therefore, it would have been obvious to apply Senko’s XIC/peak-identification approach to the MS1 data available in Luethy to identify a chromatographic peak eluting from the chromatographic separation. A POSITA would be motivated to do so because identification via XIC/peak-state analysis enables downstream acquisition decisions based on whether the chromatographic peak is present/near apex, improving the quality of subsequent tandem analysis compared with acting on MS1 information without chromatographic-peak identification
Regarding Claim 22:
Luethy in view of Norton, and further in view of Senko teaches the method according to claim 21. Senko further teaches the analyses to be performed in the MS2 domain by the second mass analyser are selected based on the identified chromatographic peak eluting from the mass spectrometer (para. [0054]: a precursor can be selected based on the comparison between current vs previous weighted spectrum, and then “tandem mass spectrometry is performed on the precursor ion near the apex of the chromatographic peak containing the precursor ion”).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/JING WANG/Examiner, Art Unit 2881
/DAVID E SMITH/Examiner, Art Unit 2881
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