DETAILED ACTION
This Office action is in response to the amendment filed on July 16th, 2026. Claims 1, 3-12, and 14-20 are pending.
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 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) 1, 3-12, and 14-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0269048 (Jarvis et al.) in view of US 2018/0144918 (Geromanos et al.).
Regarding claim 1, Jarvis et al. discloses a method for analyzing ions comprising:
determining intensities and mass-to-charge ratios (m/z) of a population of analyte ions, wherein the population of analyte ions is transmitted through a differential mobility spectrometry device operating in transmission mode prior to being mass analyzed (“In the second mode of operation, DMS device 200 is off, the SV is set to zero and ions 250 are simply transported from entrance opening 260 to exit opening 280. This is, for example, the disabled or transparent mode of DMS device 200.” P 43);
applying a separation voltage (SV) and a compensation voltage (COV) to the differential mobility spectrometry device to enable filtering mode on the differential mobility spectrometry device (“In the first mode, DMS device 200 is on, SV and CoV voltages are applied, and ions are separated. This is, for example, the enabled mode.” P 42); and
iteratively, performing the following steps:
(a) transmitting a plurality of ions through the enabled differential mobility spectrometry device having a SV-COV combination applied thereto so as to select a set of precursor ions based on their differential mobility (“In various alternative embodiments, the one or more DMS parameters necessary to enable DMS device 510 for the corresponding compound of interest of the user-defined MS/MS scan comprise a separation voltage (SV) parameter and a compensation voltage (CoV) parameter.” P 72);
(b) fragmenting at least a portion of the set of precursor ions so as to form a set of product ions (“During the MS/MS scan step, one or more user-defined MS/MS scans of a plurality of user-defined MS/MS scans are performed that correspond to compounds of interest found in the precursor ion mass spectrum.” P 67);
(c) obtaining a product ion scan identifying intensities and m/z of at least a portion of the set of product ions (“During an IDA method, the user-defined full product ion MS/MS scan can be performed producing a measured product ion spectrum.” P 61); and
(d) adjusting at least one of the SV and COV applied to the enabled differential mobility spectrometry device (“During the MS/MS scan step, one or more user-defined MS/MS scans of a plurality of user-defined MS/MS scans are performed that correspond to compounds of interest found in the precursor ion mass spectrum.” P 79, wherein “one or more” implies the option of a second set).
Jarvis et al. does not disclose identifying which of the population of analyte ions, if any, are present in each of the plurality of product ion scans obtained at different SV-COV combinations, by correlating the determined m/z of the population of analyte ions with the m/z of the population of analyte ions with the m/z of the product ion scan at each SV-COV combination. Germanos et al. discloses a method for analyzing ions including a step of identifying which precursor ions, if any, are present in product ion scans (“The fragmentation filtering process according to some embodiments determines the residual precursor ion cluster in the product ion spectrum” P 60), by correlating the determined m/z of the population of analyte ions with the m/z of the product ion scan (“ratio of the residual ion intensity/precursor ion intensity” P 59). It would have been obvious to a person having ordinary skill in the art at the time the application was filed to modify the method of Jarvis et al. to include the step of identifying which of the population of analyte ions, if any, are present in each of the plurality of product ion scans obtained at different SV-COV combinations, using the correlation process in Germanos et al., in order to determine fragmentation efficiency and therefore analysis sensitivity, as discussed in Germanos et al. (“In some embodiments, fragmentation efficiency may be determined as 1 minus the ratio of the residual ion intensity/precursor ion intensity. In various embodiments, sensitivity as a function of qualitative analysis directly relates to fragmentation efficiency.” P 59).
Regarding claim 3, Jarvis et al. in view of Germanos et al. disclose the method of claim 1, wherein correlating the determined m/z of the population of analyte ions with the m/z if the product ion scan at each SV-COV comprises multiplying a value indicative of the intensity at each determined m/z of the population of analyte ions by a value indicative of the intensity at each corresponding m/z of the product ion scan (“ratio of the residual ion intensity/precursor ion intensity” P 59).
Regarding claim 4, Jarvis et al. in view of Germanos et al. disclose the method of claim 3, wherein the value indicative of the intensity at each determined m/z of the population of analyte ions comprises the determined intensity (“ratio of the residual ion intensity/precursor ion intensity” P 59).
Regarding claim 5, Jarvis et al. in view of Germanos et al. disclose the claimed method except for multiplying by a value determined based relative to a threshold. Thresholding is well-known in the art, and it would have been obvious to a person having ordinary skill in the art at the time the application was filed to base the value on a threshold so that only signal peaks are found, and noise is not erroneously identified as a precursor ion.
Regarding claim 6, Jarvis et al. in view of Germanos et al. disclose the method of claim 5, wherein the value indicative of the intensity at each m/z of the product ion scan is assigned one of two binary values based on the intensity at each m/z of the product ion scan relative to the threshold (obvious for the reasons discussed with regard to claim 5).
Regarding claim 7, Jarvis et al. in view of Germanos et al. disclose the method of claim 1, wherein obtaining the product ion scan further comprises: mass filtering the set of precursor ions to select a subset of precursor ions; and subjecting the subset of precursor ions to fragmentation (“During the MS/MS scan step, one or more user-defined MS/MS scans of a plurality of user-defined MS/MS scans are performed that correspond to compounds of interest found in the precursor ion mass spectrum.” P 79, wherein “MS/MS” implies mass filtering prior to fragmentation).
Regarding claim 8, Jarvis et al. in view of Germanos et al. disclose the method of claim 7, wherein the subset of precursor ions comprises ions of the set of precursor ions having about 50 m/z or greater (obvious to set the filter to 50 m/z or greater as a matter of routine optimization or experimentation).
Regarding claim 9, Jarvis et al. in view of Germanos et al. disclose the method of claim 1, further comprising performing liquid chromatography on a sample and obtaining the population of analyte ions and each set of precursor ions from the sample at approximately the same elution time (“Ion source 505 ionizes a sample producing an ion beam. System 500 can also include a sample introduction device (not shown) that presents the sample to the ion source. The sample introduction device can provide a sample to ion source 505 using one of a variety of techniques. These techniques include, but are not limited to, gas chromatography (GC), liquid chromatography (LC), capillary electrophoresis (CE), or flow injection analysis (FIA).” P 64, where it would have been obvious to use elution time range in which a composition of the liquid chromatography sample is substantially identical because otherwise the spectrums would not be of the same sample and not comparable).
Regarding claim 10, Jarvis et al. in view of Germanos et al. disclose the method of claim 1, further comprising performing liquid chromatography on a sample and obtaining the population of analyte ions and each set of precursor ions from the sample during a first elution time range in which a composition of the sample is substantially identical (“Ion source 505 ionizes a sample producing an ion beam. System 500 can also include a sample introduction device (not shown) that presents the sample to the ion source. The sample introduction device can provide a sample to ion source 505 using one of a variety of techniques. These techniques include, but are not limited to, gas chromatography (GC), liquid chromatography (LC), capillary electrophoresis (CE), or flow injection analysis (FIA).” P 64, where it would have been obvious to use elution time range in which a composition of the liquid chromatography sample is substantially identical because otherwise the spectrums would not be of the same sample and not comparable).
Regarding claim 11, Jarvis et al. in view of Germanos et al. disclose the method of claim 10, further comprising: obtaining a second population of analyte ions and a second plurality of sets of precursor ions from the sample during a second elution time range in which the composition of the sample differs from the composition of the sample during the first elution time range; and identifying which of the second population of analyte ions are present in each of a second plurality of product ion scans obtained at a plurality of SV-COV combinations from the second plurality of sets of precursor ions (“Ion source 505 ionizes a sample producing an ion beam. System 500 can also include a sample introduction device (not shown) that presents the sample to the ion source. The sample introduction device can provide a sample to ion source 505 using one of a variety of techniques. These techniques include, but are not limited to, gas chromatography (GC), liquid chromatography (LC), capillary electrophoresis (CE), or flow injection analysis (FIA).” P 64, where it would have been obvious to perform multiple cycles with multiple compositions if analysis of multiple compositions was desired).
Regarding claim 12, Jarvis et al. discloses a system for analyzing ions, comprising:
a differential mobility spectrometry device for separating ions based on their differential mobilities (fig. 4, element 510);
a tandem mass spectrometer for receiving ions transmitted from the differential mobility spectrometry device (fig. 4, element 520), comprising:
a mass filter (“Mass spectrometer 520 is a tandem mass spectrometer and can include one or more physical mass filters” P 66);
a fragmentation device (“In such an instrument a precursor ion is selected in a mass filter, fragmented, and the product ions are analyzed in a mass analyzer.” P 2); and
a mass analyzer (“A mass analyzer of mass spectrometer 520 can include, but is not limited to, a time-of-flight (TOF), quadrupole, an ion trap, a linear ion trap, an orbitrap, or a Fourier transform mass analyzer.” P 66);
a control system operatively coupled to the differential mobility spectrometry device and the tandem mass spectrometer, the control system comprising:
a processor (fig. 1, element 104);
a memory (fig. 1, elements 106, 108, and 110) including program code configured to, when executed, cause the processor to:
determining intensities and mass-to-charge ratios (m/z) of a population of analyte ions, wherein the population of analyte ions is transmitted through a differential mobility spectrometry device operating in transmission mode prior to being mass analyzed (“In the second mode of operation, DMS device 200 is off, the SV is set to zero and ions 250 are simply transported from entrance opening 260 to exit opening 280. This is, for example, the disabled or transparent mode of DMS device 200.” P 43);
applying a separation voltage (SV) and a compensation voltage (COV) to the differential mobility spectrometry device to enable filtering mode on the differential mobility spectrometry device (“In the first mode, DMS device 200 is on, SV and CoV voltages are applied, and ions are separated. This is, for example, the enabled mode.” P 42); and
iteratively, performing the following steps:
(a) transmitting a plurality of ions through the enabled differential mobility spectrometry device having a SV-COV combination applied thereto so as to select a set of precursor ions based on their differential mobility (“In various alternative embodiments, the one or more DMS parameters necessary to enable DMS device 510 for the corresponding compound of interest of the user-defined MS/MS scan comprise a separation voltage (SV) parameter and a compensation voltage (CoV) parameter.” P 72);
(b) fragmenting at least a portion of the set of precursor ions so as to form a set of product ions (“During the MS/MS scan step, one or more user-defined MS/MS scans of a plurality of user-defined MS/MS scans are performed that correspond to compounds of interest found in the precursor ion mass spectrum.” P 67);
(c) obtaining a product ion scan identifying intensities and m/z of at least a portion of the set of product ions (“During an IDA method, the user-defined full product ion MS/MS scan can be performed producing a measured product ion spectrum.” P 61); and
(d) adjusting at least one of the SV and COV applied to the enabled differential mobility spectrometry device (“During the MS/MS scan step, one or more user-defined MS/MS scans of a plurality of user-defined MS/MS scans are performed that correspond to compounds of interest found in the precursor ion mass spectrum.” P 79, wherein “one or more” implies the option of a second set).
Jarvis et al. does not disclose identifying which of the population of analyte ions, if any, are present in each of the plurality of product ion scans obtained at different SV-COV combinations, by correlating the determined m/z of the population of analyte ions with the m/z of the product ion scan at each SV-COV combination. Germanos et al. discloses a method for analyzing ions including a step of identifying which precursor ions, if any, are present in product ion scans (“The fragmentation filtering process according to some embodiments determines the residual precursor ion cluster in the product ion spectrum” P 60), by correlating the determined m/z of the population of analyte ions with m/z of the product ion scan (“ratio of the residual ion intensity/precursor ion intensity” P 59). It would have been obvious to a person having ordinary skill in the art at the time the application was filed to modify the method of Jarvis et al. to include the step of identifying which of the population of analyte ions, if any, are present in each of the plurality of product ion scans obtained at different SV-COV combinations, using the correlation process in Germanos et al., in order to determine fragmentation efficiency and therefore analysis sensitivity, as discussed in Germanos et al. (“In some embodiments, fragmentation efficiency may be determined as 1 minus the ratio of the residual ion intensity/precursor ion intensity. In various embodiments, sensitivity as a function of qualitative analysis directly relates to fragmentation efficiency.” P 59).
Regarding claim 14, Jarvis et al. in view of Germanos et al. disclose the system of claim 12, wherein the correlating the determined m/z of the population of analyte ions with the m/z of the product ion scan at each SV-COV combination comprises multiplying a value indicative of the intensity at each determined m/z of the population of analyte ions by a value indicative of the intensity at each corresponding m/z of the product ion scan (“ratio of the residual ion intensity/precursor ion intensity” P 59).
Regarding claim 15, Jarvis et al. in view of Germanos et al. disclose the system of claim 14, wherein the value indicative of the intensity at each determined m/z of the population of analyte ions comprises the determined intensity (“ratio of the residual ion intensity/precursor ion intensity” P 59).
Regarding claim 16, Jarvis et al. in view of Germanos et al. disclose the claimed invention except for multiplying by a value determined based relative to a threshold. Thresholding is well-known in the art, and it would have been obvious to a person having ordinary skill in the art at the time the application was filed to base the value on a threshold so that only signal peaks are found, and noise is not erroneously identified as a precursor ion.
Regarding claim 17, Jarvis et al. in view of Germanos et al. disclose the system of claim 16, wherein the value indicative of the intensity at each m/z of the product ion scan is assigned one of two binary values based on the intensity at each m/z of the product ion scan relative to the threshold (obvious for the reasons discussed with regard to claim 16).
Regarding claim 18, Jarvis et al. in view of Germanos et al. disclose the system of claim 12, wherein the at least a portion of the set of precursor ions that are fragmented comprise a subset of precursor ions mass filtered by the mass analyzer (intended use).
Regarding claim 19, Jarvis et al. in view of Germanos et al. disclose the system of claim 18, wherein the subset of precursor ions comprises ions of the set of precursor ions having about 50 m/z or greater (intended use).
Regarding claim 20, Jarvis et al. in view of Germanos et al. disclose the system of claim 12, wherein the population of analyte ions and each set of precursor ions are obtained from a liquid chromatography sample at approximately the same elution time (intended use).
Response to Arguments
Applicant's arguments filed July 16th, 2026 have been fully considered but they are not persuasive.
Regarding the 103 rejections over Jarvis in view of Germanos, applicant argues that it would not have been obvious to a person having ordinary skill in the art at the time the application was filed to modify Jarvis to include the step of identifying which of the population of analyte ions, if any, are present in each of the plurality of product ion scans obtained at different SV-COV combinations, by correlating the determined m/z of the population of analyte ions with the m/z of the product ion scan at each SV-COV combination because Jarvis looks for ions of interest identified in a survey scan and therefore the ions are already identified.
Identifying ions as of interest is not the same as identifying which analyte ions are present in the product scan. An ion of interest may be fully fragmented, in which case it would not be in the product scan, or it may be fragmented only partially, in which case it would be present in the product scan. Knowing which analyte ions you are interested in does not tell you anything about the fragmentation efficiency of those ions.
Applicant further argues that Germanos fails to teach or suggest of identifying which of the population of analyte ions, if any, are present in each of the plurality of product ion scans obtained at different SV-COV combinations, by correlating the determined m/z of the population of analyte ions with the m/z of the product ion scan at each SV-COV combination because the analyte ions of Geromanos were not transmitted through a differential mobility spectrometry device in transmission mode prior to being mass analyzed.
If the differential mobility spectrometry device is operating in transmission mode the mobility filter is turned off and has no effect (see applicant’s specification, “Certain aspects of the present teachings provide a method for analyzing ions, comprising determining intensities and mass-to-charge ratios (m/z) of a population of analyte ions transmitted through a differential mobility spectrometry device operating in a transmission mode in which ion mobility filtering is disabled prior to the transmitted ions being mass analyzed.”). Hence, this is equivalent to not having a DMS at all, which Germanos certainly does disclose, as the presence of an ion mobility spectrometer is disclosed as optional in Germanos.
More importantly, the actual creation of the spectra, including a spectrum taken in transmission mode as well as the spectra taken in DMS filtering enabled mode at various SV-COV combinations, is found in Jarvis. Germanos teaches identifying which of the population of analyte ions, if any, are present in product ion scans, by correlating the determined m/z of the population of analyte ions with the m/z of the product ion scans, which is a data analysis step performed on the completed spectra by correlating the m/z values at which peaks appear. The situation is equivalent to applicant’s figure 8, reproduced below, where Jarvis discloses the creation of the spectra shown in fig. 8B (product scan) and fig. 8C (transmission mode spectra) and Germanos discloses correlating the two to form the correlation spectra shown in fig. 8D.
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The correlation method can be performed on any two spectra to identify which population of ions, if any, are present in both scans. Of course, the identification of correlated peaks only has meaning as a measure of fragmentation efficiency if the precursor ions fragmented to create the product spectrum are chosen from within the analyte ions data set. It would be meaningless to correlate a spectrum taken in DMS enabled mode at one SV-COV setting with a product ion scan where the precursor ions are chosen at a different SV-COV setting, for example, because different ions would be selected for downstream mass analysis and fragmentation.
However, in this case the correlation is between a spectrum taken in a transmission mode, in which all sample ions pass to the mass analyzer, and a product ion scan where a smaller subset of those analyte ions pass through the DMS filter and are later fragmented. Because the precursor ions comprise is subset of the original set of analyte ions, all the peaks in the product ion scan are either fragments of those analyte/precursor ions or unfragmented precursor ions that correlate to one of the analyte ions in the transmission spectrum, therefore the spectra of Jarvis can be correlated using the method of Geromanos to determine many much of the precursor ions remain unfragmented.
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 ELIZA W OSENBAUGH-STEWART whose telephone number is (571)270-5782. The examiner can normally be reached 10am - 6pm Pacific Time M-F.
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/ELIZA W OSENBAUGH-STEWART/Primary Examiner, Art Unit 2881
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