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 .
Claim Objections
Claim 3 is objected to because it contains grammatical errors/typo: “precursor ions peaks” should be “precursor ion peaks”;
Claims 9, 10, and 12 are objected to because they contain grammatical errors/typo: “performing a plurality analysis cycles” should be “performing a plurality of analysis cycles”;
Claim 16 is objected to because it contains grammatical errors/typo: “For each…” mid-claim capitalized;
Claim 22 is objected to because it contains multiple grammatical errors/typo:
“the analyses to be performed by in the MS2 domain” has an extra words “by”.
Claim 25 is objected to because it contains multiple grammatical errors/typo:
extra “a” in “…MS1 domain; a a second…”),
“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 13-14, 18, and 24 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 13 and 14 each recites the limitation “averaging the data from the analyses performed in the MS1 domain by the second mass analyser.” There is insufficient antecedent basis for this limitation in the claim, since both claims 13 and 14 dependent on claim 12, it is unclear whether the data to be averaged refers to data from the plurality of analysis cycles as in claim 12, or to the combined data from the MS1 analyses as in claim 1.
Claim 18 recites the limitation “each analysis cycle.” There is insufficient antecedent basis for this limitation in the claim, since claim 18 dependents on claim 8 and the term “analysis cycle” is first introduced in claim 9.
Claim 24 recites that the first mass analyser is “operated at a first dynamic range” and the second mass analyser is “operated at a second dynamic range larger than the first dynamic range.” The term “dynamic range” is indefinite because it is susceptible to multiple meanings in mass spectrometry (e.g., intrascan dynamic range, linear dynamic range, detector dynamic range, effective dynamic range under AGC/injection settings), and the claim does not specify the metric, measurement conditions, or how the dynamic range is determined for each analyser. As a result, the scope of claim 24 is unclear and the claim fails to particularly point out and distinctly claim the subject matter regarded as the invention.
For the purposes of compact prosecution, they will be interpreted as best understood in light of the specification.
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 1-9, 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 3:
Luethy in view of Norton teaches the method according to claim 1. Norton further teaches 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 (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).
Regarding Claim 4:
Luethy in view of Norton teaches the method according to claim 3. Norton further teaches 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 (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),
wherein the combined list is filtered to remove precursor ion peaks which are repeated between the first and second sets of precursor ion peaks (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).
Regarding Claim 5:
Luethy in view of Norton teaches the method according to claim 4. Norton further teaches the second set of precursor ion peaks is thresholded to remove any precursor ion peaks below a first predetermined intensity level and/or any precursor ion peaks above a second predetermined intensity level (para. [0024]: only peaks above a predetermined threshold value (e.g., by computing an average signal intensity) will be selected as the candidate peaks).
Regarding Claim 6:
Luethy in view of Norton teaches 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.
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 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 (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 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 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 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 12. 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 8. 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 by 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
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JING WANG whose telephone number is (571)272-2504. The examiner can normally be reached M-F 7:30-17:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Kim can be reached at 571-272-2293. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JING WANG/Examiner, Art Unit 2881
/ROBERT H KIM/Supervisory Patent Examiner, Art Unit 2881