DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. 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.
3. 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.
4. Claims 1-10, 14, 15 are rejected under 35 U.S.C 103 as being unpatentable over Bloomfield (US 2021/0366701 A1) in view of Yefchak (US 20090108191 A1).
Bloomfield discloses a system for calibrating the gain of an ion guide and a time-of-flight (TOF) mass analyzer of a tandem mass spectrometer in concentrating product ions with different mass-to charge ratio (m/z) values before injection into the TOF mass analyzer in comparison to not concentrating the product ions ([0044] teaches a system for operating an ion guide and a TOF mass analyzer to dynamically concentrate or not concentrate product ions with different m/z values. [0096]-[0098] teaches the gain difference (factor of 7), and the need to scale or normalize the data between the two modes), comprising: an ion source device that continuously receives and ionizes a sample containing a known compound, producing an ion beam ([0046] teaches that a sample containing a known compound is continuously received and ionized using an ion source device, producing an ion beam); an ion guide defining a guide axis that receives product ions fragmented from a known precursor ion of the known compound selected from the ion beam ([0047] teaches product ions produced from a known precursor ion of the known compound are received using an ion guide defining a guide axis);
a TOF mass analyzer downstream of the ion guide that receives the product ions ejected from the ion guide into an extraction region of the TOF mass analyzer ([0048] teaches product ions ejected from the ion guide into an extraction region are received using a TOF mass analyzer downstream of the ion guide), wherein the ion guide is adapted to provide an ion control field comprising a component for restraining movement of the product ions normal to the guide axis and comprising a component for controlling the movement of the product ions parallel to the guide axis ([0051] teaches that the ion guide adapted to provide an ion control field comprising a component for restraining movement of ions normal to the guide axis and controlling movement of the ions parallel the guide axis), wherein the ion control field has a controllable potential profile along the guide axis of the ion guide ([0051] teaches the field having a controllable potential profile along the guide axis of the guide), the profile being alternately switchable to a continuous mode where there is a continuous ejection of product ions from the ion guide to the TOF mass analyzer irrespective of the m/z values of the product ions or to a sequential mode ([0051] teaches the profile being adapted to selectively provide for either continuous release or for sequential release) where there is a sequential ejection of the product ions from the ion guide to the TOF mass analyzer according to the m/z values of the product ions ([0051] teaches sequential release of the ions from the guide according to the mass-to-charge ratios of the ions), and
wherein for the sequential mode the same ion energy is applied to the product ions over their travel through the ion guide to the extraction region irrespective of m/z value of the product ions and the product ions are sequentially released with the same ion energy from the ion guide to provide for arrival of product ions of substantially all released m/z values within the extraction region at substantially the same time ([0051] teaches the ions are sequentially released (Zeno pulsing mode) with the same ion energy from the ion guide to provide for arrival of ions of substantially all released mass-to-charge ratios within the extraction region at substantially the same time and synchronized to coincide with a Time of Flight extraction pulse of the mass analyzer);
and a processor in communication with the ion guide and the TOF mass analyzer that instructs the ion guide to eject the product ions of the known precursor ion using the sequential mode ([0119] teaches the processor initially instructs ion guide, fig. 2 element 24, to eject the product ions using the sequential mode) and instructs the TOF mass analyzer to measure the intensities of the product ions at a first group of time steps of two or more time steps ([0119] teaches that the processor instructs TOF mass analyzer to measure the intensity of the at least one known product ion at each time step of the two or more time steps), producing a sequential group of mass spectra ([0090] teaches that the intensities at time steps 1, 2, and 3 are shown plotted in a Zeno mode chromatogram, fig. 10 element 1010), instructs the ion guide to switch to the continuous mode and instructs the TOF mass analyzer to measure the intensities of the product ions at a second group of time steps of the two or more time steps ([0119] teaches that the sequential mode may then be dynamically switched to the continuous mode (normal pulsing mode). The processor instructs TOF mass analyzer to measure the m/z of the at least one known product ion at each time step of the remaining two or more time steps. [0092] teaches that at time step 4, the intensity of the product ion is measured using the normal pulsing mode), producing a continuous group of mass spectra ([0092] teaches that the intensity is plotted in normal mode chromatogram, fig. 10 element 1020).
Bloomfield fails to disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra.
Yefchak does not specifically disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra. However, Yefchak discloses determining a gain factor by measuring a ratio of the abundances of ions (as taught in abstract and [0003]. Abundances correspond to intensities. The abstract section teaches that the gain of the ion detector of a mass spectrometer is calibrated by using the ion detector to measure a ratio of the abundances of at least two ion species having a known abundance ratio. The gain of the ion detector is changed until the measured abundance ratio matches the known abundance ratio).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer (Bloomfield [0097]-[0099] teaches using normalization and combining intensities from the normal mode and Zeno pulsing mode for gain calibration. Yefchak abstract teaches measuring ratio of the abundances of at least two ion species for gain calibration of mass spectrometer). It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include calculating a gain for the sequential mode in comparison to the co--ntinuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra. Such modification would allow for more accurate gain calibration of a mass spectrometer (as taught in abstract and [0003]).
5. Regarding claim 2:
Bloomfield in view of Yefchak discloses the system of claim 1. Bloomfield in view of Yefchak does not specifically disclose that wherein the known compound comprises a known calibrant and the gain calibration is performed in a separate calibration experiment.
However, Bloomfield discloses using a known compound (as taught in [0046]) and compares measured peaks to a calibration XIC to determine quantity (as taught in [0081]). Bloomfield further discloses that calibration data is typically obtained in normal pulsing mode (as taught in [0096]). While Bloomfield does not explicitly state that the “known compound” is a calibrant run in a “separate experiment,” it would have been obvious to one of ordinary skill in the art to implement the system of Bloomfield in this manner.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include that wherein the known compound comprises a known calibrant and the gain calibration is performed in a separate calibration experiment. Such modification is a matter of routine instrument calibration and would allow establishing a calibration base line for the sample analyzed (as taught in Bloomfield [0081]).
6. Regarding claim 3:
Bloomfield in view of Yefchak discloses the system of claim 1. Bloomfield further discloses that wherein the known compound comprises a known analyte ([0047] teaches product ions produced from a known precursor ion of the know compound) and the gain calibration is performed as part of an experiment analyzing the known analyte ([0126] teaches the method operating based on the previously measured intensity of a targeted product ion).
7. Regarding claim 4:
Bloomfield in view of Yefchak discloses the system of claim 1. Bloomfield further discloses that wherein time steps of the first group of time steps are interleaved between time steps of the second groups of time steps in the two or more time steps ([0090]-[0094] teaches measuring in Zeno (steps 1-3), switching back to normal pulsing mode (steps 4-6), and switching back to Zeno (steps 7-9)).
8. Regarding claim 5:
Bloomfield in view of Yefchak discloses the system of claim 1. Bloomfield does not specifically disclose that wherein the combination of the sequential group of mass spectra comprises a spectrum calculated from one of a mean, median, or mode of the sequential group of mass spectra and the combination of the continuous group of mass spectra comprises a spectrum calculated from one of a mean, median, or mode of the continuous group of mass spectra.
However, Bloomfield discloses combining the spectra obtained in the sequential and continuous modes (as taught in [0099]). Bloomfield also discloses that the normal mode chromatogram, fig. 10 element 1020, and normalized chromatogram, fig. 10 element 1030, are added producing a combined chromatogram, fig. 10 element 1040 (as taught in [0097]). A person of ordinary skill in the art would recognize “mean”, “median”, “mode” as standard statistical method for gain calibration.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include that wherein the combination of the sequential group of mass spectra comprises a spectrum calculated from one of a mean, median, or mode of the sequential group of mass spectra and the combination of the continuous group of mass spectra comprises a spectrum calculated from one of a mean, median, or mode of the continuous group of mass spectra. Such modification would allow for normalization of the intensities and accurately calculating an XIC peak (as taught in [0099]).
9. Regarding claim 6:
Bloomfield in view of Yefchak discloses the system of claim 1. Bloomfield fails to disclose that wherein the processor further calculates a gain function, Gain_actual(m/z), from the series of ratios and corresponding m/z values of the one or more product ions that describes how the gain varies with m/z.
Yefchak does not specifically disclose that wherein the processor further calculates a gain function, Gain_actual(m/z), from the series of ratios and corresponding m/z values of the one or more product ions that describes how the gain varies with m/z. However, Yefchak discloses determining a gain factor by measuring a ratio of the abundances of ions (as taught in abstract and [0003]. Abundances correspond to intensities. The abstract section teaches that the gain of the ion detector of a mass spectrometer is calibrated by using the ion detector to measure a ratio of the abundances of at least two ion species having a known abundance ratio. The gain of the ion detector is changed until the measured abundance ratio matches the known abundance ratio).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer. It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include that wherein the processor further calculates a gain function, Gain_actual(m/z), from the series of ratios and corresponding m/z values of the one or more product ions that describes how the gain varies with m/z. Yefchak modifies Bloomfield by using ratio determined from actual experiment instead of using the theoretical formula. Such modification would allow for more accurate gain calibration of a mass spectrometer (as taught in abstract and [0003]).
10. Regarding claim 7:
Bloomfield in view of Yefchak discloses the system of claim 1.
Bloomfield does not specifically disclose that wherein the processor further calculates a single value for the gain that is a combination of the series. However, Bloomfield discloses that the gain factor depends on the m/z value and that the factor of 7 is an average Zeno pulsing gain (as taught in [0097]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include that wherein the processor further calculates a single value for the gain that is a combination of the series. Such modification would allow determining such single value for the experimentally determined gain factor.
11. Regarding claim 8:
Bloomfield in view of Yefchak discloses the system of claim 7.
Bloomfield does not disclose specifically that wherein the combination of the series of ratios comprises one of a mean, median, or mode of the series of ratios. However, Bloomfield discloses combining the spectra obtained in the sequential and continuous modes (as taught in [0099]). Bloomfield also discloses that the normal mode chromatogram, fig. 10 element 1020, and normalized chromatogram, fig. 10 element 1030, are added producing a combined chromatogram, fig. 10 element 1040 (as taught in [0097]). A person of ordinary skill in the art would recognize “mean”, “median”, “mode” as standard statistical method for gain calibration.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include that wherein the combination of the series of ratios comprises one of a mean, median, or mode of the series of ratios. Such modification would allow for normalization of the intensities and accurately calculating an XIC peak (as taught in [0099]).
12. Regarding claim 9:
Bloomfield in view of Yefchak discloses the system of claim 6. Bloomfield further discloses that wherein the processor ([0119] teaches the processor) further calculates a theoretical gain, Gain(m/z), for the known compound ([0098] teaches the formula predicting gain dependence on m/z value).
13. Regarding claim 10:
Bloomfield in view of Yefchak discloses the system of claim 9, wherein the theoretical gain is calculated according to
G
a
i
n
=
C
m
z
max
m
z
, where C is geometrical factor, (m/z)max is the largest value of m/z recorded in spectra ([0098] teaches the exact formula to calculate the theoretical gain).
14. Regarding claim 14:
A method for calibrating the gain of an ion guide and a time-of-flight (TOF) mass analyzer of a tandem mass spectrometer in concentrating product ions with different mass-to charge ratio (m/z) values before injection into the TOF mass analyzer in comparison to not concentrating the product ions ([0044] teaches a method of operating an ion guide and a TOF mass analyzer to dynamically concentrate or not concentrate product ions with different m/z values. [0096]-[0098] teaches the gain difference (factor of 7), and the need to scale or normalize the data between the two modes), comprising: continuously receiving and ionizing a sample containing a known compound using an ion source device, producing an ion beam ([0046] teaches that a sample containing a known compound is continuously received and ionized using an ion source device, producing an ion beam); receiving product ions fragmented from a known precursor ion of the known compound selected from the ion beam using an ion guide defining a guide axis ([0047] teaches product ions produced from a known precursor ion of the known compound are received using an ion guide defining a guide axis); receiving product ions ejected from the ion guide into an extraction region of a TOF mass analyzer downstream of the ion guide ([0048] teaches product ions ejected from the ion guide into an extraction region are received using a TOF mass analyzer downstream of the ion guide), wherein the ion guide is adapted to provide an ion control field comprising a component for restraining movement of the product ions normal to the guide axis and comprising a component for controlling the movement of the product ions parallel to the guide axis ([0051] teaches that the ion guide adapted to provide an ion control field comprising a component for restraining movement of ions normal to the guide axis and controlling movement of the ions parallel the guide axis), wherein the ion control field has a controllable potential profile along the guide axis of the ion guide ([0051] teaches the field having a controllable potential profile along the guide axis of the guide),
the profile being alternately switchable to a continuous mode where there is a continuous ejection of product ions from the ion guide to the TOF mass analyzer irrespective of the m/z values of the product ions or to a sequential mode ([0051] teaches the profile being adapted to selectively provide for either continuous release or for sequential release) where there is a sequential ejection of the product ions from the ion guide to the TOF mass analyzer according to the m/z values of the product ions ([0051] teaches sequential release of the ions from the guide according to the mass-to-charge ratios of the ions), and wherein for the sequential mode the same ion energy is applied to the product ions over their travel through the ion guide to the extraction region irrespective of m/z value of the product ions and the product ions are sequentially released with the same ion energy from the ion guide to provide for arrival of product ions of substantially all released m/z values within the extraction region at substantially the same time ([0051] teaches the ions are sequentially released (Zeno pulsing mode) with the same ion energy from the ion guide to provide for arrival of ions of substantially all released mass-to-charge ratios within the extraction region at substantially the same time and synchronized to coincide with a Time of Flight extraction pulse of the mass analyzer);
instructing the ion guide to eject the product ions of the known precursor ion using the sequential mode ([0119] teaches the processor initially instructs ion guide, fig. 2 element 24, to eject the product ions using the sequential mode) and instructing the TOF mass analyzer to measure the intensities of the product ions at a first group of time steps of two or more time steps using a processor ([0119] teaches that the processor instructs TOF mass analyzer to measure the intensity of the at least one known product ion at each time step of the two or more time steps), producing a sequential group of mass spectra ([0090] teaches that the intensities at time steps 1, 2, and 3 are shown plotted in a Zeno mode chromatogram, fig. 10 element 1010);
instructing the ion guide to switch to the continuous mode and instructing the TOF mass analyzer to measure the intensities of the product ions at a second group of time steps of the two or more time steps using the processor ([0119] teaches that the sequential mode may then be dynamically switched to the continuous mode (normal pulsing mode). The processor instructs TOF mass analyzer to measure the m/z of the at least one known product ion at each time step of the remaining two or more time steps. [0092] teaches that at time step 4, the intensity of the product ion is measured using the normal pulsing mode), producing a continuous group of mass spectra ([0092] teaches that the intensity is plotted in normal mode chromatogram, fig. 10 element 1020).
Bloomfield fails to disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the processor.
Yefchak does not specifically disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the processor. However, Yefchak discloses determining a gain factor by measuring a ratio of the abundances of ions (as taught in abstract and [0003]. Abundances correspond to intensities. The abstract section teaches that the gain of the ion detector of a mass spectrometer is calibrated by using the ion detector to measure a ratio of the abundances of at least two ion species having a known abundance ratio. The gain of the ion detector is changed until the measured abundance ratio matches the known abundance ratio).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer (Bloomfield [0097]-[0099] teaches using normalization and combining intensities from the normal mode and Zeno pulsing mode for gain calibration. Yefchak abstract teaches measuring ratio of the abundances of at least two ion species for gain calibration of mass spectrometer). It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the processor. Yefchak modifies Bloomfield by using ratio determined from actual experiment instead of using the theoretical formula. Such modification would allow for more accurate gain calibration of a mass spectrometer (as taught in abstract and [0003]).
15. Regarding claim 15:
A computer program product ([0044] teaches a computer program product), comprising a non-transitory tangible computer-readable storage medium whose contents include a program with instructions being executed on a processor ([0071]-[0072] teaches a computer-readable medium such as a hard disk, any other memory chip, that participates in providing instructions to processor for execution) so as to perform a method for calibrating the gain of an ion guide and a time-of-flight (TOF) mass analyzer of a tandem mass spectrometer in concentrating product ions with different mass-to-charge ratio (m/z) values before injection into the TOF mass analyzer in comparison to not concentrating the product ions ([0044] teaches a method for operating an ion guide and a TOF mass analyzer to dynamically concentrate or not concentrate product ions with different m/z values. [0096]-[0098] teaches the gain difference (factor of 7), and the need to scale or normalize the data between the two modes),
comprising: providing a system, wherein the system comprises one or more distinct software modules ([0132] teaches that this method is performed by a system that includes one or more distinct software modules), and wherein the distinct software modules comprise a control module ([0133] teaches a control module); instructing an ion guide defining a guide axis to receive product ions fragmented from a known precursor ion of a known compound selected from an ion beam using the control module ([0134] teaches that control module instructs an ion guide defining a guide axis to receive product ions fragmented from a known precursor ion of a known compound selected from an ion beam), wherein an ion source device continuously receives and ionizes a sample containing the known compound, producing the ion beam ([0046] teaches that a sample containing a known compound is continuously received and ionized using an ion source device, producing an ion beam); instructing a TOF mass analyzer downstream of the ion guide to receive product ions ejected from the ion guide into an extraction region of the TOF mass analyzer using the control module ([0135] teaches that control module instructs a TOF mass analyzer downstream of the ion guide to receive product ions ejected from the ion guide into an extraction region of the TOF mass analyzer), wherein the ion guide is adapted to provide an ion control field comprising a component for restraining movement of the product ions normal to the guide axis and comprising a component for controlling the movement of the product ions parallel to the guide axis ([0135] teaches that the ion guide is adapted to provide an ion control field comprising a component for restraining movement of the product ions normal to the guide axis and comprising a component for controlling the movement of the produce ions parallel to the guide axis),
wherein the ion control field has a controllable potential profile along the guide axis of the ion guide ([0051] teaches the field having a controllable potential profile along the guide axis of the guide), the profile being alternately switchable to a continuous mode where there is a continuous ejection of product ions from the ion guide to the TOF mass analyzer irrespective of the m/z values of the product ions or to a sequential mode ([0051] teaches the profile being adapted to selectively provide for either continuous release or for sequential release) where there is a sequential ejection of the product ions from the ion guide to the TOF mass analyzer according to the m/z values of the product ions ([0051] teaches sequential release of the ions from the guide according to the mass-to-charge ratios of the ions), and wherein for the sequential mode the same ion energy is applied to the product ions over their travel through the ion guide to the extraction region irrespective of m/z value of the product ions and the product ions are sequentially released with the same ion energy from the ion guide to provide for arrival of product ions of substantially all released m/z values within the extraction region at substantially the same time ([0051] teaches the ions are sequentially released (Zeno pulsing mode) with the same ion energy from the ion guide to provide for arrival of ions of substantially all released mass-to-charge ratios within the extraction region at substantially the same time and synchronized to coincide with a Time of Flight extraction pulse of the mass analyzer);
instructing the ion guide to eject the product ions of the known precursor ion using the sequential mode and instructing the TOF mass analyzer to measure the intensities of the product ions at a first group of time steps of two or more time steps using a control module ([0137] teaches that control module instructs the ion guide to eject the product ions of the known precursor ion using the sequential mode and instructing the TOF mass analyzer to measure the intensity of the at least one known product ion at each time step of the two or more time steps), producing a sequential group of mass spectra ([0090] teaches that the intensities at time steps 1, 2, and 3 are shown plotted in a Zeno mode chromatogram, fig. 10 element 1010);
instructing the ion guide to switch to the continuous mode and instructing the TOF mass analyzer to measure the intensities of the product ions at a second group of time steps of the two or more time steps using the control module ([0137] teaches that control module instructs the ion guide to switch to the continuous mode and instructing the TOF mass analyzer to measure the m/z of the at least one known product ion at each time step of the remaining two or more time steps. [0092] teaches that at time step 4, the intensity of the product ion is measured using the normal pulsing mode), producing a continuous group of mass spectra ([0092] teaches that the intensity is plotted in normal mode chromatogram, fig. 10 element 1020);
Bloomfield does not specifically disclose an analysis module. However, Bloomfield discloses a system that includes one or more distinct software modules (as taught in [0132]). Bloomfield also discloses that analysis is performed during the experiment ([0093] teaches that mass analysis continues in normal pulsing mode).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield to include an analysis module. Such modification would allow for subsequent stages of analysis of ions (as taught in [0006]).
Bloomfield fails to disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the analysis module.
Yefchak does not specifically disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the analysis module. However, Yefchak discloses determining a gain factor by measuring a ratio of the abundances of ions (as taught in abstract and [0003]. Abundances correspond to intensities. The abstract section teaches that the gain of the ion detector of a mass spectrometer is calibrated by using the ion detector to measure a ratio of the abundances of at least two ion species having a known abundance ratio. The gain of the ion detector is changed until the measured abundance ratio matches the known abundance ratio).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer (Bloomfield [0097]-[0099] teaches using normalization and combining intensities from the normal mode and Zeno pulsing mode for gain calibration. Yefchak abstract teaches measuring ratio of the abundances of at least two ion species for gain calibration of mass spectrometer). Yefchak modifies Bloomfield by using ratio determined from actual experiment instead of using the theoretical formula. One of ordinary skill in the art would recognize that calculating a series of ratios of product ion intensities a more accurate gain calibration than . It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the analysis module. Such modification would allow for more accurate gain calibration of a mass spectrometer (as taught in abstract and [0003]).
16. Claims 11-13 are rejected under 35 U.S.C 103 as being unpatentable over Bloomfield in view of Yefchak, further in view of Quarmby (US 2012/0032072 Al).
17. Regarding claim 11:
Bloomfield in view of Yefchak discloses the system of claim 9. Bloomfield in view of Yefchak fails to disclose that wherein the processor further calculates a percentage of the theoretical gain represented by the gain.
Quarmby does not specifically disclose that wherein the processor further calculates a percentage of the theoretical gain represented by the gain. However, Quarmby discloses a processor (as taught in [0013]) and comparing a measured (actual) gain to a target (theoretical) gain and using the comparison for gain calibration ([0037] teaches measuring the actual gain and comparing it to a target gain to determine a deviation).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer (Bloomfield [0097]-[0099] teaches using normalization and combining intensities from the normal mode and Zeno pulsing mode for gain calibration. Quarmby [0038] teaches measuring the actual gain and comparing it to a target gain to determine a deviation for gain adjustment). It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak, further in view of Quarmby, to include that wherein the processor further calculates a percentage of the theoretical gain represented by the gain. One of ordinary skill in the art would recognize that percentage is a standard mathematical way to compare two quantities. Such modification would allow comparing the measured gain with the target gain and adjusting the gain according to the deviation (as taught in Quarmby [0038]).
18. Regarding claim 12:
Bloomfield in view of Yefchak, further in view of Quarmby, discloses the system of claim 11. Bloomfield in view of Yefchak fails to disclose that wherein the percentage of the theoretical gain comprises (Gainactual(m/z)/Gain(m/z) x 100%.
Quarmby does not specifically disclose that wherein the percentage of the theoretical gain comprises (Gainactual(m/z)/Gain(m/z) x 100%. However, Quarmby discloses comparing a measured (actual) gain to a target (theoretical) gain and using the comparison for gain calibration ([0037] teaches measuring the actual gain and comparing it to a target gain to determine a deviation).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer. It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak, further in view of Quarmby, to include that wherein the percentage of the theoretical gain comprises (Gainactual(m/z)/Gain(m/z) x 100%. One of ordinary skill in the art would recognize that percentage is a standard mathematical way to compare two quantities. Such modification would allow comparing the measured gain with the target gain and adjusting the gain according to the deviation (as taught in Quarmby [0038]).
19. Regarding claim 13:
Bloomfield in view of Yefchak, further in view of Quarmby, discloses the system of claim 12. Bloomfield further discloses a memory storage for storing temporary variables or instructions to be executed by processor (as taught in [0068]). Bloomfield in view of Yefchak fails to disclose that wherein the processor further stores the percentage of the theoretical gain in a memory for the tandem mass spectrometer so that the percentage of the theoretical gain is retrieved from the memory and is used with a calculated theoretical gain in a quantitation experiment to scale intensities measured using a continuous mode and using a sequential mode and produce a quantitative measurement for the experiment where the continuous mode and the sequential mode are applied on-demand.
Quarmby does not specifically disclose that wherein the processor further stores the percentage of the theoretical gain in a memory for the tandem mass spectrometer so that the percentage of the theoretical gain is retrieved from the memory and is used with a calculated theoretical gain in a quantitation experiment to scale intensities measured using a continuous mode and using a sequential mode and produce a quantitative measurement for the experiment where the continuous mode and the sequential mode are applied on-demand. However, Quarmby discloses that comparing a measured (actual) gain to a target (theoretical) gain and using the comparison for gain calibration ([0037] teaches measuring the actual gain and comparing it to a target gain to determine a deviation). It would have been obvious to one of ordinary skill in the art to store the determined deviation in the memory of Bloomfield’s computer system and apply it as a scaling factor to the intensities in subsequent analysis.
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer. It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak, further in view of Quarmby, to include that wherein the processor further stores the percentage of the theoretical gain in a memory for the tandem mass spectrometer so that the percentage of the theoretical gain is retrieved from the memory and is used with a calculated theoretical gain in a quantitation experiment to scale intensities measured using a continuous mode and using a sequential mode and produce a quantitative measurement for the experiment where the continuous mode and the sequential mode are applied on-demand. Such modification would allow automatic gain adjustment to be made at any time and continuously based on the gain measurements (as taught in Quarmby [0037]).
20. Claims 1-10, 14, 15 are rejected under 35 U.S.C 103 as being unpatentable over Bloomfield (WO2019198010 A1) in view of Yefchak (US 20090108191 A1).
Bloomfield discloses a system for calibrating the gain of an ion guide and a time-of-flight (TOF) mass analyzer of a tandem mass spectrometer in concentrating product ions with different mass-to charge ratio (m/z) values before injection into the TOF mass analyzer in comparison to not concentrating the product ions ([0043] teaches a system for operating an ion guide and a TOF mass analyzer to dynamically concentrate or not concentrate product ions with different m/z values. [0095]-[0097] teaches the gain difference (factor of 7), and the need to scale or normalize the data between the two modes), comprising: an ion source device that continuously receives and ionizes a sample containing a known compound, producing an ion beam ([0045] teaches that a sample containing a known compound is continuously received and ionized using an ion source device, producing an ion beam); an ion guide defining a guide axis that receives product ions fragmented from a known precursor ion of the known compound selected from the ion beam ([0046] teaches product ions produced from a known precursor ion of the known compound are received using an ion guide defining a guide axis);
a TOF mass analyzer downstream of the ion guide that receives the product ions ejected from the ion guide into an extraction region of the TOF mass analyzer ([0047] teaches product ions ejected from the ion guide into an extraction region are received using a TOF mass analyzer downstream of the ion guide), wherein the ion guide is adapted to provide an ion control field comprising a component for restraining movement of the product ions normal to the guide axis and comprising a component for controlling the movement of the product ions parallel to the guide axis ([0050] teaches that the ion guide adapted to provide an ion control field comprising a component for restraining movement of ions normal to the guide axis and controlling movement of the ions parallel the guide axis), wherein the ion control field has a controllable potential profile along the guide axis of the ion guide ([0050] teaches the field having a controllable potential profile along the guide axis of the guide), the profile being alternately switchable to a continuous mode where there is a continuous ejection of product ions from the ion guide to the TOF mass analyzer irrespective of the m/z values of the product ions or to a sequential mode ([0050] teaches the profile being adapted to selectively provide for either continuous release or for sequential release) where there is a sequential ejection of the product ions from the ion guide to the TOF mass analyzer according to the m/z values of the product ions ([0050] teaches sequential release of the ions from the guide according to the mass-to-charge ratios of the ions), and
wherein for the sequential mode the same ion energy is applied to the product ions over their travel through the ion guide to the extraction region irrespective of m/z value of the product ions and the product ions are sequentially released with the same ion energy from the ion guide to provide for arrival of product ions of substantially all released m/z values within the extraction region at substantially the same time ([0050] teaches the ions are sequentially released (Zeno pulsing mode) with the same ion energy from the ion guide to provide for arrival of ions of substantially all released mass-to-charge ratios within the extraction region at substantially the same time and synchronized to coincide with a Time of Flight extraction pulse of the mass analyzer);
and a processor in communication with the ion guide and the TOF mass analyzer that instructs the ion guide to eject the product ions of the known precursor ion using the sequential mode ([0118] teaches the processor initially instructs ion guide, fig. 2 element 24, to eject the product ions using the sequential mode) and instructs the TOF mass analyzer to measure the intensities of the product ions at a first group of time steps of two or more time steps ([0118] teaches that the processor instructs TOF mass analyzer to measure the intensity of the at least one known product ion at each time step of the two or more time steps), producing a sequential group of mass spectra ([0089] teaches that the intensities at time steps 1, 2, and 3 are shown plotted in a Zeno mode chromatogram, fig. 10 element 1010), instructs the ion guide to switch to the continuous mode and instructs the TOF mass analyzer to measure the intensities of the product ions at a second group of time steps of the two or more time steps ([0118] teaches that the sequential mode may then be dynamically switched to the continuous mode (normal pulsing mode). The processor instructs TOF mass analyzer to measure the m/z of the at least one known product ion at each time step of the remaining two or more time steps. [0091] teaches that at time step 4, the intensity of the product ion is measured using the normal pulsing mode), producing a continuous group of mass spectra ([0091] teaches that the intensity is plotted in normal mode chromatogram, fig. 10 element 1020).
Bloomfield fails to disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra.
Yefchak does not specifically disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra. However, Yefchak discloses determining a gain factor by measuring a ratio of the abundances of ions (as taught in abstract and [0003]. Abundances correspond to intensities. The abstract section teaches that the gain of the ion detector of a mass spectrometer is calibrated by using the ion detector to measure a ratio of the abundances of at least two ion species having a known abundance ratio. The gain of the ion detector is changed until the measured abundance ratio matches the known abundance ratio).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer (Bloomfield [0096]-[0098] teaches using normalization and combining intensities from the normal mode and Zeno pulsing mode for gain calibration. Yefchak abstract teaches measuring ratio of the abundances of at least two ion species for gain calibration of mass spectrometer). It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include calculating a gain for the sequential mode in comparison to the co--ntinuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra. Such modification would allow for more accurate gain calibration of a mass spectrometer (as taught in abstract and [0003]).
21. Regarding claim 2:
Bloomfield in view of Yefchak discloses the system of claim 1. Bloomfield in view of Yefchak does not specifically disclose that wherein the known compound comprises a known calibrant and the gain calibration is performed in a separate calibration experiment.
However, Bloomfield discloses using a known compound (as taught in [0045]) and compares measured peaks to a calibration XIC to determine quantity (as taught in [0080]). Bloomfield further discloses that calibration data is typically obtained in normal pulsing mode (as taught in [0095]). While Bloomfield does not explicitly state that the “known compound” is a calibrant run in a “separate experiment,” it would have been obvious to one of ordinary skill in the art to implement the system of Bloomfield in this manner.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include that wherein the known compound comprises a known calibrant and the gain calibration is performed in a separate calibration experiment. Such modification is a matter of routine instrument calibration and would allow establishing a calibration base line for the sample analyzed (as taught in Bloomfield [0080]).
22. Regarding claim 3:
Bloomfield in view of Yefchak discloses the system of claim 1. Bloomfield further discloses that wherein the known compound comprises a known analyte ([0046] teaches product ions produced from a known precursor ion of the know compound) and the gain calibration is performed as part of an experiment analyzing the known analyte ([0125] teaches the method operating based on the previously measured intensity of a targeted product ion).
23. Regarding claim 4:
Bloomfield in view of Yefchak discloses the system of claim 1. Bloomfield further discloses that wherein time steps of the first group of time steps are interleaved between time steps of the second groups of time steps in the two or more time steps ([0089]-[0093] teaches measuring in Zeno (steps 1-3), switching back to normal pulsing mode (steps 4-6), and switching back to Zeno (steps 7-9)).
24. Regarding claim 5:
Bloomfield in view of Yefchak discloses the system of claim 1. Bloomfield does not specifically disclose that wherein the combination of the sequential group of mass spectra comprises a spectrum calculated from one of a mean, median, or mode of the sequential group of mass spectra and the combination of the continuous group of mass spectra comprises a spectrum calculated from one of a mean, median, or mode of the continuous group of mass spectra.
However, Bloomfield discloses combining the spectra obtained in the sequential and continuous modes (as taught in [0098]). Bloomfield also discloses that the normal mode chromatogram, fig. 10 element 1020, and normalized chromatogram, fig. 10 element 1030, are added producing a combined chromatogram, fig. 10 element 1040 (as taught in [0096]). A person of ordinary skill in the art would recognize “mean”, “median”, “mode” as standard statistical method for gain calibration.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include that wherein the combination of the sequential group of mass spectra comprises a spectrum calculated from one of a mean, median, or mode of the sequential group of mass spectra and the combination of the continuous group of mass spectra comprises a spectrum calculated from one of a mean, median, or mode of the continuous group of mass spectra. Such modification would allow for normalization of the intensities and accurately calculating an XIC peak (as taught in [0098]).
25. Regarding claim 6:
Bloomfield in view of Yefchak discloses the system of claim 1. Bloomfield fails to disclose that wherein the processor further calculates a gain function, Gain_actual(m/z), from the series of ratios and corresponding m/z values of the one or more product ions that describes how the gain varies with m/z.
Yefchak does not specifically disclose that wherein the processor further calculates a gain function, Gain_actual(m/z), from the series of ratios and corresponding m/z values of the one or more product ions that describes how the gain varies with m/z. However, Yefchak discloses determining a gain factor by measuring a ratio of the abundances of ions (as taught in abstract and [0003]. Abundances correspond to intensities. The abstract section teaches that the gain of the ion detector of a mass spectrometer is calibrated by using the ion detector to measure a ratio of the abundances of at least two ion species having a known abundance ratio. The gain of the ion detector is changed until the measured abundance ratio matches the known abundance ratio).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer. It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include that wherein the processor further calculates a gain function, Gain_actual(m/z), from the series of ratios and corresponding m/z values of the one or more product ions that describes how the gain varies with m/z. Yefchak modifies Bloomfield by using ratio determined from actual experiment instead of using the theoretical formula. Such modification would allow for more accurate gain calibration of a mass spectrometer (as taught in abstract and [0003]).
26. Regarding claim 7:
Bloomfield in view of Yefchak discloses the system of claim 1.
Bloomfield does not specifically disclose that wherein the processor further calculates a single value for the gain that is a combination of the series. However, Bloomfield discloses that the gain factor depends on the m/z value and that the factor of 7 is an average Zeno pulsing gain (as taught in [0097]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include that wherein the processor further calculates a single value for the gain that is a combination of the series. Such modification would allow determining such single value for the experimentally determined gain factor.
27. Regarding claim 8:
Bloomfield in view of Yefchak discloses the system of claim 7.
Bloomfield does not disclose specifically that wherein the combination of the series of ratios comprises one of a mean, median, or mode of the series of ratios. However, Bloomfield discloses combining the spectra obtained in the sequential and continuous modes (as taught in [0098]). Bloomfield also discloses that the normal mode chromatogram, fig. 10 element 1020, and normalized chromatogram, fig. 10 element 1030, are added producing a combined chromatogram, fig. 10 element 1040 (as taught in [0098]). A person of ordinary skill in the art would recognize “mean”, “median”, “mode” as standard statistical method for gain calibration.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include that wherein the combination of the series of ratios comprises one of a mean, median, or mode of the series of ratios. Such modification would allow for normalization of the intensities and accurately calculating an XIC peak (as taught in Bloomfield [0098]).
28. Regarding claim 9:
Bloomfield in view of Yefchak discloses the system of claim 6. Bloomfield further discloses that wherein the processor ([0118] teaches the processor) further calculates a theoretical gain, Gain(m/z), for the known compound ([0097] teaches the formula predicting gain dependence on m/z value).
29. Regarding claim 10:
Bloomfield in view of Yefchak discloses the system of claim 9, wherein the theoretical gain is calculated according to
G
a
i
n
=
C
m
z
max
m
z
, where C is geometrical factor, (m/z)max is the largest value of m/z recorded in spectra ([0097] teaches the exact formula to calculate the theoretical gain).
30. Regarding claim 14:
A method for calibrating the gain of an ion guide and a time-of-flight (TOF) mass analyzer of a tandem mass spectrometer in concentrating product ions with different mass-to charge ratio (m/z) values before injection into the TOF mass analyzer in comparison to not concentrating the product ions ([0043] teaches a method of operating an ion guide and a TOF mass analyzer to dynamically concentrate or not concentrate product ions with different m/z values. [0095]-[0097] teaches the gain difference (factor of 7), and the need to scale or normalize the data between the two modes), comprising: continuously receiving and ionizing a sample containing a known compound using an ion source device, producing an ion beam ([0045] teaches that a sample containing a known compound is continuously received and ionized using an ion source device, producing an ion beam); receiving product ions fragmented from a known precursor ion of the known compound selected from the ion beam using an ion guide defining a guide axis ([0046] teaches product ions produced from a known precursor ion of the known compound are received using an ion guide defining a guide axis); receiving product ions ejected from the ion guide into an extraction region of a TOF mass analyzer downstream of the ion guide ([0047] teaches product ions ejected from the ion guide into an extraction region are received using a TOF mass analyzer downstream of the ion guide), wherein the ion guide is adapted to provide an ion control field comprising a component for restraining movement of the product ions normal to the guide axis and comprising a component for controlling the movement of the product ions parallel to the guide axis ([0050] teaches that the ion guide adapted to provide an ion control field comprising a component for restraining movement of ions normal to the guide axis and controlling movement of the ions parallel the guide axis), wherein the ion control field has a controllable potential profile along the guide axis of the ion guide ([0050] teaches the field having a controllable potential profile along the guide axis of the guide),
the profile being alternately switchable to a continuous mode where there is a continuous ejection of product ions from the ion guide to the TOF mass analyzer irrespective of the m/z values of the product ions or to a sequential mode ([0050] teaches the profile being adapted to selectively provide for either continuous release or for sequential release) where there is a sequential ejection of the product ions from the ion guide to the TOF mass analyzer according to the m/z values of the product ions ([0050] teaches sequential release of the ions from the guide according to the mass-to-charge ratios of the ions), and wherein for the sequential mode the same ion energy is applied to the product ions over their travel through the ion guide to the extraction region irrespective of m/z value of the product ions and the product ions are sequentially released with the same ion energy from the ion guide to provide for arrival of product ions of substantially all released m/z values within the extraction region at substantially the same time ([0050] teaches the ions are sequentially released (Zeno pulsing mode) with the same ion energy from the ion guide to provide for arrival of ions of substantially all released mass-to-charge ratios within the extraction region at substantially the same time and synchronized to coincide with a Time of Flight extraction pulse of the mass analyzer);
instructing the ion guide to eject the product ions of the known precursor ion using the sequential mode ([0118] teaches the processor initially instructs ion guide, fig. 2 element 24, to eject the product ions using the sequential mode) and instructing the TOF mass analyzer to measure the intensities of the product ions at a first group of time steps of two or more time steps using a processor ([0118] teaches that the processor instructs TOF mass analyzer to measure the intensity of the at least one known product ion at each time step of the two or more time steps), producing a sequential group of mass spectra ([0089] teaches that the intensities at time steps 1, 2, and 3 are shown plotted in a Zeno mode chromatogram, fig. 10 element 1010);
instructing the ion guide to switch to the continuous mode and instructing the TOF mass analyzer to measure the intensities of the product ions at a second group of time steps of the two or more time steps using the processor ([0118] teaches that the sequential mode may then be dynamically switched to the continuous mode (normal pulsing mode). The processor instructs TOF mass analyzer to measure the m/z of the at least one known product ion at each time step of the remaining two or more time steps. [0091] teaches that at time step 4, the intensity of the product ion is measured using the normal pulsing mode), producing a continuous group of mass spectra ([0091] teaches that the intensity is plotted in normal mode chromatogram, fig. 10 element 1020).
Bloomfield fails to disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the processor.
Yefchak does not specifically disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the processor. However, Yefchak discloses determining a gain factor by measuring a ratio of the abundances of ions (as taught in abstract and [0003]. Abundances correspond to intensities. The abstract section teaches that the gain of the ion detector of a mass spectrometer is calibrated by using the ion detector to measure a ratio of the abundances of at least two ion species having a known abundance ratio. The gain of the ion detector is changed until the measured abundance ratio matches the known abundance ratio).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer (Bloomfield [0096]-[0098] teaches using normalization and combining intensities from the normal mode and Zeno pulsing mode for gain calibration. Yefchak abstract teaches measuring ratio of the abundances of at least two ion species for gain calibration of mass spectrometer). It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the processor. Yefchak modifies Bloomfield by using ratio determined from actual experiment instead of using the theoretical formula. Such modification would allow for more accurate gain calibration of a mass spectrometer (as taught in abstract and [0003]).
31. Regarding claim 15:
A computer program product ([0043] teaches a computer program product), comprising a non-transitory tangible computer-readable storage medium whose contents include a program with instructions being executed on a processor ([0070]-[0071] teaches a computer-readable medium such as a hard disk, any other memory chip, that participates in providing instructions to processor for execution) so as to perform a method for calibrating the gain of an ion guide and a time-of-flight (TOF) mass analyzer of a tandem mass spectrometer in concentrating product ions with different mass-to-charge ratio (m/z) values before injection into the TOF mass analyzer in comparison to not concentrating the product ions ([0043] teaches a method for operating an ion guide and a TOF mass analyzer to dynamically concentrate or not concentrate product ions with different m/z values. [0095]-[0097] teaches the gain difference (factor of 7), and the need to scale or normalize the data between the two modes),
comprising: providing a system, wherein the system comprises one or more distinct software modules ([0131] teaches that this method is performed by a system that includes one or more distinct software modules), and wherein the distinct software modules comprise a control module ([0132] teaches a control module); instructing an ion guide defining a guide axis to receive product ions fragmented from a known precursor ion of a known compound selected from an ion beam using the control module ([0133] teaches that control module instructs an ion guide defining a guide axis to receive product ions fragmented from a known precursor ion of a known compound selected from an ion beam), wherein an ion source device continuously receives and ionizes a sample containing the known compound, producing the ion beam ([0045] teaches that a sample containing a known compound is continuously received and ionized using an ion source device, producing an ion beam); instructing a TOF mass analyzer downstream of the ion guide to receive product ions ejected from the ion guide into an extraction region of the TOF mass analyzer using the control module ([0134] teaches that control module instructs a TOF mass analyzer downstream of the ion guide to receive product ions ejected from the ion guide into an extraction region of the TOF mass analyzer), wherein the ion guide is adapted to provide an ion control field comprising a component for restraining movement of the product ions normal to the guide axis and comprising a component for controlling the movement of the product ions parallel to the guide axis ([0134] teaches that the ion guide is adapted to provide an ion control field comprising a component for restraining movement of the product ions normal to the guide axis and comprising a component for controlling the movement of the produce ions parallel to the guide axis),
wherein the ion control field has a controllable potential profile along the guide axis of the ion guide ([0050] teaches the field having a controllable potential profile along the guide axis of the guide), the profile being alternately switchable to a continuous mode where there is a continuous ejection of product ions from the ion guide to the TOF mass analyzer irrespective of the m/z values of the product ions or to a sequential mode ([0050] teaches the profile being adapted to selectively provide for either continuous release or for sequential release) where there is a sequential ejection of the product ions from the ion guide to the TOF mass analyzer according to the m/z values of the product ions ([0050] teaches sequential release of the ions from the guide according to the mass-to-charge ratios of the ions), and wherein for the sequential mode the same ion energy is applied to the product ions over their travel through the ion guide to the extraction region irrespective of m/z value of the product ions and the product ions are sequentially released with the same ion energy from the ion guide to provide for arrival of product ions of substantially all released m/z values within the extraction region at substantially the same time ([0050] teaches the ions are sequentially released (Zeno pulsing mode) with the same ion energy from the ion guide to provide for arrival of ions of substantially all released mass-to-charge ratios within the extraction region at substantially the same time and synchronized to coincide with a Time of Flight extraction pulse of the mass analyzer);
instructing the ion guide to eject the product ions of the known precursor ion using the sequential mode and instructing the TOF mass analyzer to measure the intensities of the product ions at a first group of time steps of two or more time steps using a control module ([0136] teaches that control module instructs the ion guide to eject the product ions of the known precursor ion using the sequential mode and instructing the TOF mass analyzer to measure the intensity of the at least one known product ion at each time step of the two or more time steps), producing a sequential group of mass spectra ([0089] teaches that the intensities at time steps 1, 2, and 3 are shown plotted in a Zeno mode chromatogram, fig. 10 element 1010);
instructing the ion guide to switch to the continuous mode and instructing the TOF mass analyzer to measure the intensities of the product ions at a second group of time steps of the two or more time steps using the control module ([0136] teaches that control module instructs the ion guide to switch to the continuous mode and instructing the TOF mass analyzer to measure the m/z of the at least one known product ion at each time step of the remaining two or more time steps. [0091] teaches that at time step 4, the intensity of the product ion is measured using the normal pulsing mode), producing a continuous group of mass spectra ([0091] teaches that the intensity is plotted in normal mode chromatogram, fig. 10 element 1020);
Bloomfield does not specifically disclose an analysis module. However, Bloomfield discloses a system that includes one or more distinct software modules (as taught in [0131]). Bloomfield also discloses that analysis is performed during the experiment ([0092] teaches that mass analysis continues in normal pulsing mode).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield to include an analysis module. Such modification would allow for subsequent stages of analysis of ions (as taught in [0005]).
Bloomfield fails to disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the analysis module.
Yefchak does not specifically disclose calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the analysis module. However, Yefchak discloses determining a gain factor by measuring a ratio of the abundances of ions (as taught in abstract and [0003]. Abundances correspond to intensities. The abstract section teaches that the gain of the ion detector of a mass spectrometer is calibrated by using the ion detector to measure a ratio of the abundances of at least two ion species having a known abundance ratio. The gain of the ion detector is changed until the measured abundance ratio matches the known abundance ratio).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer (Bloomfield [0097]-[0099] teaches using normalization and combining intensities from the normal mode and Zeno pulsing mode for gain calibration. Yefchak abstract teaches measuring ratio of the abundances of at least two ion species for gain calibration of mass spectrometer). Yefchak modifies Bloomfield by using ratio determined from actual experiment instead of using the theoretical formula. One of ordinary skill in the art would recognize that calculating a series of ratios of product ion intensities a more accurate gain calibration than . It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak to include calculating a gain for the sequential mode in comparison to the continuous mode as a series of ratios of intensities of one or more product ions of the product ions obtained from a combination of the sequential group of mass spectra to corresponding intensities of the one or more product ions obtained from a combination of the continuous group of mass spectra using the analysis module. Such modification would allow for more accurate gain calibration of a mass spectrometer (as taught in abstract and [0003]).
32. Claims 11-13 are rejected under 35 U.S.C 103 as being unpatentable over Bloomfield (WO2019198010 A1) in view of Yefchak, further in view of Quarmby (US 2012/0032072 Al).
33. Regarding claim 11:
Bloomfield in view of Yefchak discloses the system of claim 9. Bloomfield in view of Yefchak fails to disclose that wherein the processor further calculates a percentage of the theoretical gain represented by the gain.
Quarmby does not specifically disclose that wherein the processor further calculates a percentage of the theoretical gain represented by the gain. However, Quarmby discloses a processor (as taught in [0013]) and comparing a measured (actual) gain to a target (theoretical) gain and using the comparison for gain calibration ([0037] teaches measuring the actual gain and comparing it to a target gain to determine a deviation).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer (Bloomfield [0096]-[0098] teaches using normalization and combining intensities from the normal mode and Zeno pulsing mode for gain calibration. Quarmby [0038] teaches measuring the actual gain and comparing it to a target gain to determine a deviation for gain adjustment). It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak, further in view of Quarmby, to include that wherein the processor further calculates a percentage of the theoretical gain represented by the gain. One of ordinary skill in the art would recognize that percentage is a standard mathematical way to compare two quantities. Such modification would allow comparing the measured gain with the target gain and adjusting the gain according to the deviation (as taught in Quarmby [0038]).
34. Regarding claim 12:
Bloomfield in view of Yefchak, further in view of Quarmby, discloses the system of claim 11. Bloomfield in view of Yefchak fails to disclose that wherein the percentage of the theoretical gain comprises (Gainactual(m/z)/Gain(m/z) x 100%.
Quarmby does not specifically disclose that wherein the percentage of the theoretical gain comprises (Gainactual(m/z)/Gain(m/z) x 100%. However, Quarmby discloses comparing a measured (actual) gain to a target (theoretical) gain and using the comparison for gain calibration ([0037] teaches measuring the actual gain and comparing it to a target gain to determine a deviation).
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer. It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak, further in view of Quarmby, to include that wherein the percentage of the theoretical gain comprises (Gainactual(m/z)/Gain(m/z) x 100%. One of ordinary skill in the art would recognize that percentage is a standard mathematical way to compare two quantities. Such modification would allow comparing the measured gain with the target gain and adjusting the gain according to the deviation (as taught in Quarmby [0038]).
35. Regarding claim 13:
Bloomfield in view of Yefchak, further in view of Quarmby, discloses the system of claim 12. Bloomfield further discloses a memory storage for storing temporary variables or instructions to be executed by processor (as taught in [0067]). Bloomfield in view of Yefchak fails to disclose that wherein the processor further stores the percentage of the theoretical gain in a memory for the tandem mass spectrometer so that the percentage of the theoretical gain is retrieved from the memory and is used with a calculated theoretical gain in a quantitation experiment to scale intensities measured using a continuous mode and using a sequential mode and produce a quantitative measurement for the experiment where the continuous mode and the sequential mode are applied on-demand.
Quarmby does not specifically disclose that wherein the processor further stores the percentage of the theoretical gain in a memory for the tandem mass spectrometer so that the percentage of the theoretical gain is retrieved from the memory and is used with a calculated theoretical gain in a quantitation experiment to scale intensities measured using a continuous mode and using a sequential mode and produce a quantitative measurement for the experiment where the continuous mode and the sequential mode are applied on-demand. However, Quarmby discloses that comparing a measured (actual) gain to a target (theoretical) gain and using the comparison for gain calibration ([0037] teaches measuring the actual gain and comparing it to a target gain to determine a deviation). It would have been obvious to one of ordinary skill in the art to store the determined deviation in the memory of Bloomfield’s computer system and apply it as a scaling factor to the intensities in subsequent analysis.
The inventions are analogous because they are directed towards improving the gain calibration of mass spectrometer. It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified Bloomfield in view of Yefchak, further in view of Quarmby, to include that wherein the processor further stores the percentage of the theoretical gain in a memory for the tandem mass spectrometer so that the percentage of the theoretical gain is retrieved from the memory and is used with a calculated theoretical gain in a quantitation experiment to scale intensities measured using a continuous mode and using a sequential mode and produce a quantitative measurement for the experiment where the continuous mode and the sequential mode are applied on-demand. Such modification would allow automatic gain adjustment to be made at any time and continuously based on the gain measurements (as taught in Quarmby [0037]).
Conclusion
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/LARRY LI/
Examiner, Art Unit 2881
/WYATT A STOFFA/Primary Examiner, Art Unit 2881