DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claims 10-11 are objected to because of the following informalities:
Claim 10 lists “(iv) quadruply charged ions; and (iv) more than quadruply charged ions.” The second “(iv)” should be “(v).”
Claim 11 recites “... ions of an internal standard are detected a mass analysis scan,” which should be “detected in a mass analysis scan.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 17 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 17 recites that the width Δmz satisfies a formula including the terms “m/z” and “z.” However, the claim does not define what value of “m/z” is used in the formula, e.g., whether it refers to the center m/z of the isolation window, an instantaneous m/z value along the scanned curve, or some other m/z value. The claim also does not provide antecedent basis for “z” or otherwise identify what “z” represents. Although “z” appears to refer to an ion charge state, claim 17 does not expressly recite that meaning or identify which ions’ charge state is used. Accordingly, the scope of claim 17 are unclear.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-10, 12-16, and 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0153140 A1 [hereinafter Makarov] in view of US 2017/0299550 A1 [hereinafter Wang].
Regarding Claim 1:
Makarov teaches a method of operating an analytical instrument (Abstract: method of operating a mobility spectrometer) that comprises an ion mobility separator, a mass filter arranged downstream of the ion mobility separator, and a mass analyser arranged downstream of the mass filter (para. [0098]: “The IMS/MS/MS combinations are preferably any: IMS/Q/Trap or IMS/Q/Orbitrap, where Trap denotes an ion trap, Q denotes a quadrupole mass filter and Orbitrap denotes an Orbitrap mass analyser”), the method comprising:
the ion mobility separator (Fig. 7 -IMS) performing a plurality of ion mobility separation scans, wherein in each ion mobility separation scan the ion mobility separator receives ions and separates them according to their ion mobility (Fig. 7 and para. [0099]: “The ions introduced from the source into the IMS are separated by the IMS as described herein, e.g. according to either the low resolution or high resolution modes”);
the mass filter (Fig. 7- Q) filtering separated ions using an isolation window (para. [0099]: after IMS, ions “then are passed into the quadrupole mass filter (Q) which may be operated either as a mass filter,” a quadrupole mass filter inherently filters by an m/z transmission window), and
during each ion mobility separation scan: (i) scanning a centre mass to charge ratio (m/z) of the isolation window (para. [0103]: “In this linked-scan method, a mass filter, such as the quadrupole mass filter in FIG. 7 for example, is rapidly scanned simultaneously with the mobility scanning by the IMS so that only ions of defined mobility/ mass ratio or lying on a defined curve on a mobility/mass diagram are passed into a subsequent mass analyser”), and
However, Makarov does not specifically note that during each ion mobility separation scan: (ii) controlling a width Δmz of the isolation window such that during the ion mobility separation scan, ions emerging from the ion mobility separator within an ion mobility arrival time range ΔT are transmitted by the mass filter; and wherein each mass analysis scan has a duration T, and wherein ΔT<T.
Wang teaches during each ion mobility separation scan: (ii) controlling a width Δmz of the isolation window such that during the ion mobility separation scan, ions emerging from the ion mobility separator within an ion mobility arrival time range ΔT are transmitted by the mass filter (para. [0011]: “a wideband isolation window to be applied by the mass filter to the ions produced from the sample...determining a window width of the wideband isolation window, wherein the window width is an m/z sub-range... each window position is defined by a drift time value along the IM drift time spectrum and an m/z value along the m/z spectrum... the window width and the sequence of window positions are determined such that the wideband isolation window when moved through the sequence of window positions transmits ions in the determined region of interest”).
Makarov teaches “the whole scan should take 50 to 1000 ms” (para. [0103]). Wang teaches selecting an IM trace/region by selecting a drift time range and m/z range and an example of zooming/working with “a narrower drift-time range (25 to 36.5 ms)” (para. [0072]) Thus, in the modified system, the ion mobility arrival time range ΔT (25 to 36.5 ms) is less than the Orbitrap scan during T (50-1000ms), as claimed.
Makarov teaches that selecting only ions of interest in a linked mobility/mass scan improves dynamic range and avoids analyzing unwanted ions. Wang teaches that defining the mass-filter window width and drift-time/m/z positions allows the isolation window to capture a selected IM trace/region and produce a simpler, more selective data set with reduced interference. Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to modify Makarov’s linked IMS/quadrupole scan with Wang’s drift-time/m/z window-control method, to allow Makarov’s selected mobility/mass curve to be implemented as a finite, controlled IM-MS trace, so the mass filter transmits ions within the desired drift-time/m/z region while excluding ions outside that region. This would reduce ion-signal interference and prevent trap capacity from being consumed by unwanted ions before Orbitrap analysis, thereby improving selectivity and dynamic range while maintaining the IMS-resolved information for downstream high-resolution mass analysis.
Regarding Claim 2:
Makarov in view of Wang teaches the method of claim 1. As discussed in claim 1, Makarov teaches “One or more scans can be taken at different mobility/mass ratios or along different curves on a mobility/mass diagram” such that “a high resolution mass spectrum… can be obtained which will include only ions of interest” (para. [0057]); Wang teaches “each window position is defined by a drift time value along the IM drift time spectrum and an m/z value along the m/z spectrum... the window width and the sequence of window positions are determined such that the wideband isolation window when moved through the sequence of window positions transmits ions in the determined region of interest” (para. [0011]). As such, in the modified system, during the first/second ion mobility separation scan, the centre m/z of the isolation window along the first/second curve are scanned such that ions having a first charge state are transmitted by the mass filter, as claimed.
Regarding Claim 3:
Makarov in view of Wang teaches the method of claim 2.
Wang teaches “the all-ions data set comprising a collection of data points spanning an IM drift time spectrum, an m/z spectrum correlated with the IM drift time spectrum ...the all-ions data set comprises two or more IM traces, and the IM traces comprise respective sub-collections of data points that map onto the all-ions data set such that the IM traces diverge from each other” (para. [0012]).
Thus, in the modified system, the first and second curves taught in Makarov can be implemented in drift-time/m-z space using window positions defined by drift time and m/z and thus diverged from each other by a shift in ion mobility drift time, as taught in Wang.
Regarding Claim 4:
Makarov in view of Wang teaches the method of claim 3. The combined references further teach wherein the shift in ion mobility arrival time corresponds to the ion mobility arrival time range ΔT (Makarov teaches using multiple linked scans along different mobility/mass curves to select ions of interest. Wang teaches defining the moving mass-isolation window by drift-time/m/z positions and transmitting ions in a selected IM trace/region, i.e., a selected drift-time/m/z strip. In the modified system, each linked scan selects one drift-time strip having arrival-time range ΔT. The second curve is shifted from the first curve by the same ΔT so that the second scan selects the next adjacent drift-time strip of the same selected ion class, rather than re-scanning the same strip or leaving a gap).
Regarding Claim 5:
Makarov in view of Wang teaches the method of claim 2. Wang further teaches wherein the second curve or second set of curve segments has substantially the same shape in the ion mobility arrival time-m/z space as the first curve or first set of curve segments (paras. [0061, 0063]: “Each isolation window position is defined by the drift time position and the m/z position of the centroid of the isolation window... the centroid of an isolation window may follow a curved path, a straight path, or a path comprising both curved and straight sections... the rate of change (slope) of a linear path, or the radius of curvature of a curved path, may be constant ... as needed to capture all of the desired data points”).
Regarding Claim 6:
Makarov in view of Wang teaches the method of claim 1. The combined references further teach wherein the plurality of ion mobility separation scans comprises a first set of K ion mobility separation scans, and wherein the method comprises: during each of the K ion mobility separation scans: scanning the centre mass to charge ratio of the isolation window along a respective curve or set of curve segments in ion mobility arrival time-m/z space such that ions having a first charge state are transmitted by the mass filter; wherein for each of the K respective curves or sets of curve segments, most or all of the curve or set of curve segments is separated from an adjacent curve or set of curve segments by a shift in ion mobility arrival time (claim 6 comprises essentially same limitations recited in claims 2 and 3 except implemented for K scans instead of previous claimed 2 scans. Since Makarov teaches “one or more scans can be taken … along different curves”, including more than 2 scans, the combined references also teach claim 6).
Regarding Claim 7:
Makarov in view of Wang teaches the method of claim 6. The combined references further teaches wherein: the shift in ion mobility arrival time corresponds to the ion mobility arrival time range ΔT; and/or most or all of the K curves or sets of curve segments have substantially the same shape in the ion mobility arrival time-m/z space (claim 7 comprises essentially same limitations recited in claims 4-5 except implemented for K scans instead of previous claimed 2 scans. Since Makarov teaches “one or more scans can be taken … along different curves”, including more than 2 scans, the combined references also teach claim 7).
Regarding Claim 8:
Makarov in view of Wang teaches the method of claim 6. Makarov further teaches wherein a product (K×ΔT) is less than the duration T of each mass analysis scan (para. [0103]: “one or more subsequent scans can be taken at different mobility/mass ratios...To match the repetition rate of the Orbitrap analyser, the whole scan should take 50 to 1000 ms depending on required resolutions in IMS and quadrupole,” indicating selecting K strips so that K×ΔT<T is the natural timing condition for fitting those K selected arrival-time strips within one Orbitrap mass-analysis cycle).
Regarding Claim 9:
Makarov in view of Wang teaches the method of claim 6.
Makarov teaches “In this so-called linked-scan method, it allows selection only of ions of certain type(s), e.g. of selected charge states,” and “One or more scans can be taken at different mobility/mass ratios or along different curves on a mobility/mass diagram” (paras. [0057,0103]). As such, the combined references teach the ion mobility separation scans comprise a second set of ion mobility separations cans separated ions having a second different charge state can be transmitted by the mass filter. In the modified system, the first set of K scans targets a first charge-state band, e.g., 2+ ions, and the second set of K₂ scans targets a second different charge-state band, e.g., 3+ ions. During each K₂ scan, the center m/z is scanned along a respective drift-time/m/z curve for the second charge state, and adjacent K₂ curves are shifted in ion mobility arrival time to cover different portions of that second charge-state band, as recited in claim 9.
Regarding Claim 10:
Makarov in view of Wang teaches the method of claim 9. Makarov further teaches wherein: the first charge state is one of (i) singly charged ions; (ii) doubly charged ions; (iii) triply charged ions; (iv) quadruply charged ions; and (iv) more than quadruply charged ions; and/or the second charge state is one of (i) singly charged ions; (ii) doubly charged ions; (iii) triply charged ions; (iv) quadruply charged ions; and (iv) more than quadruply charged ions, and the second charge state is a different charge state to the first charge state (para. [0058]: “In such an operation, a high-resolution mass spectrum, such as obtained using an Orbitrap™ analyser, can be obtained which will include only ions of interest (e.g. 2- or 3-charged ions, or glycopeptides only, etc.), i.e., the first/second charge state can be doubly charged ions or triply charged ions).
Regarding Claim 12:
Makarov in view of Wang teaches the method of claim 1.
Makarov further teaches scanning the quadrupole/mass filter with the IMS scan so that ions lying on a selected mobility/mass curve are transmitted, and the selected ions may be ions of selected charge states, e.g., 2- or 3-charged ions.
Wang further teaches that IM traces may be formed by charge state trends, and that the wideband isolation acquisition may capture two or more selected IM traces.
In the modified system, the centre m/z of the isolation window is scanned through drift-time/m/z positions to capture multiple selected charge-state traces for the same analyte, e.g., the 2+ and 3+ charge-state traces of the same peptide/protein analyte. Thus, ions of the same analyte having plural different charge states are transmitted by the mass filter, as recited in claim 12.
Regarding Claim 13:
Makarov in view of Wang teaches the method of claim 1. Makarov further teaches during one or more or each ion mobility separation scan: (i) scanning the centre m/z of the isolation window across a m/z range of interest (para. [0113]: “an overview broad mass range spectrum could be used to select m/z of interest”);
wherein the m/z range of interest is continuous (para. [0057]: “and “One or more scans can be taken ...along different curves on a mobility/mass diagram,” i.e., “continuous”); or wherein the m/z range of interest comprises a set of distinct and separated m/z sub-ranges.
Regarding Claim 14:
Makarov in view of Wang teaches the method of claim 13. Wang further teaches during one or more or each ion mobility separation scan: (i) substantially smoothly and/or substantially continuously and/or bijectively scanning the centre m/z of the isolation window across the m/z range of interest (para. [0067]: “In the scanned operation mode, the isolation window is moved from one position to another in a gradual manner, i.e., in finely stepped iterations, which may entail a significant degree of overlap. As one example of a scanned operation mode, an isolation window of width Δm/z=50 may move through the following positions: 50 m/z to 99 m/z, then 55 m/z to 104 m/z, then 60 m/z to 109 m/z, as so on”).
Regarding Claim 15:
Makarov in view of Wang teaches the method of claim 13. The combined references teach during one or more or each ion mobility separation scan: (ii) controlling the width Δmz of the isolation window such that during the ion mobility separation scan, ions emerging from the ion mobility separator within an ion mobility arrival time range ΔT are transmitted by the mass filter, as discussed in claim 1.
Makarov teaches during the ion mobility separation scan, the isolation window centre m/z is being scanned across the m/z range of interest, as discussed in claim 13.
Regarding Claim 16:
Makarov in view of Wang teaches the method of claim 13. Wang further teaches during one or more or each ion mobility separation scan: (ii) controlling the width Δmz of the isolation window such that when the isolation window centre m/z is being scanned across the m/z range of interest, the window width Δmz can be held substantially constant or varied (para. [0090]: “wherein determining the window width comprises determining the window width such that the window width is constant at each window position, or such that the window width at one or more of the window positions is different from the window width at the other window positions”).
In the modified system, as discussed for claim 1, the controlled width Δmz corresponds to the ion mobility arrival-time range ΔT transmitted by the mass filter. Therefore, a constant window width teaches ΔT held substantially constant, and a different window width at different positions teaches ΔT varied during the scan.
Regarding Claim 19:
Makarov in view of Wang teaches the method of claim 1. Makarov further teaches wherein: the duration T is (i)≥1 ms; (ii)≥2 ms; (iii)≥5 ms; (iv)≥10 ms; (v)≥50 ms; or (vi)≥100 ms (para. [0103]: “the whole scan should take 50 to 1000 ms”); and/or the ion mobility arrival time range ΔT is (i)≤0.5 ms; (ii)≤1 ms; (iii)≤2 ms; (iv)≤5 ms; (v)≤10 ms; or (vi)≤50 ms.
Regarding Claim 20:
Makarov in view of Wang teaches the method of claim 1. Makarov further teaches wherein the mass analyser is a Fourier Transform (FT) mass analyser or a multi-reflection time-of-flight (mrTOF) mass analyser (para. [0057]: the mass analyser may be “an FT mass analyser that measures the frequency of oscillation induced by a potential that varies harmonically in one direction (e.g. an Orbitrap™ mass analyser) or a TOF mass analyser”).
Regarding Claim 21:
Makarov in view of Wang teaches the method of claim 1. Wang further teaches a control system for an analytical instrument, the control system configured to cause the analytical instrument to perform the method of claim 1 (para. [0013]: “a controller configured to control acquisition of a wideband-isolated data set from a sample, by controlling the mass filter to apply a wideband isolation window to ions produced from the sample such that the wideband isolation window moves through a sequence of window positions effective to capture IM-MS data limited to a region of interest in an all-ions data set”).
Regarding Claim 22:
Makarov in view of Wang teaches the method of claim 21. Makarov further teaches an analytical instrument (including IMS, mass filter and mass analyser as discussed in claim 1), comprising the control system of claim 21.
Regarding Claim 23:
Makarov in view of Wang teaches the method of claim 21. Makarov further teaches a mass spectrometer, comprising the control system of claim 21 (para. [0036]: “the present invention provides filtering of ions according to ion mobility and coupling of the filtered ions to a further ion separation and/or identification device, preferably a mass spectrometer”).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Makarov in view of Wang, further in view of US 2019/0310264 A1 [hereinafter Everley].
Regarding Claim 11:
Makarov in view of Wang teaches the method of claim 1. Makarov further teaches adding one or more internal standard(s) of one or more target analytes to a sample; ionising the sample and internal standard(s) to produce ions (para. [0037]: rapid transfer without mobility separation may be used “in combination with mobility separation, e.g. for adding internal calibrants to mobility-selected species”). However, the combined references do not specifically note that during the first ion mobility separation scan: (i) scanning a centre mass to charge ratio (m/z) of the isolation window such that ions of the internal standard(s) are transmitted by the mass filter, and (ii) determining whether ions of an internal standard are detected in a mass analysis scan, wherein, when it is determined that ions of an internal standard are detected a mass analysis scan, the method further comprises performing one or more target scans each having a target isolation window including an m/z representative of the target analyte.
Everley teaches:
during the first ion mobility separation scan: (i) scanning a centre mass to charge ratio (m/z) of the isolation window such that ions of the internal standard(s) are transmitted by the mass filter, and (ii) determining whether ions of an internal standard are detected in a mass analysis scan (para. [0025]: “by including peptides engineered to act as a mass spectrometer trigger, the proper size and placement of an isolation window may be determined... this approach may allow the mass spectrometer to examine peptides injected into the mass spectrometer only when trigger peptides are identified; when they are not detected, the mass spectrometer may thereby perform less monitoring and/or analysis”);
wherein, when it is determined that ions of an internal standard are detected a mass analysis scan, the method further comprises performing one or more target scans each having a target isolation window including an m/z representative of the target analyte (para. [0042]: “the mass spectrometer may be configured to identify the peptide samples 122 by identifying the trigger peptide in the mass spectrometer data and then using the known offset to identify an isolation window in which the corresponding peptide samples are expected to appear”).
Everley teaches adding engineered trigger peptides that are detected first and then used, through a known mass offset, to determine the target peptide’s isolation window for targeted MS analysis. Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to use the trigger-peptide/internal-standard targeting method in the modified Makarov/Wang system to avoid wasting IM-MS/Orbitrap scan time on target analytes that are not actually present or not eluting. Once the internal standard/trigger peptide is detected, the system can use its known relationship to the target analyte to set the target isolation window and perform targeted scans only when the corresponding analyte is expected, improving throughput, selectivity, and efficiency while reducing unnecessary monitoring.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Makarov in view of Wang, further in view of US 2020/0357627A1 [hereinafter Peterson].
Regarding Claim 18:
Makarov in view of Wang teaches the method of claim 1. However, the combined references do not specifically note that during an ion mobility separation scan of the plurality of ion mobility separation scans: adjusting an intensity of ions transmitted by the mass filter based on an expected intensity for the ions.
Peterson teaches during an ion mobility separation scan of the plurality of ion mobility separation scans: adjusting an intensity of ions transmitted by the mass filter based on an expected intensity for the ions (paras. [0017, 0223-0224]: “The method is intended to control... the number of ions accumulated at the ion trap... Ions traverse the ion path over a transmission time period and can be received at the ion trap... the transmission time period can be terminated once the total number of ions received at the ion detector exceeds a predetermined amount”).
The modified Makarov/Wang system teaches selectively transmits a desired IM-MS region. Peterson teaches controlling the number of ions accumulated in an ion trap by controlling the transmission time period based on detected ions. Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to incorporate Peterson’s ion-current control into the modified Makarov/Wang system to further regulate how much of that selected ion population is accumulated for analysis, preventing the selected ions transmitted by the mass filter from overfilling the downstream trap/Orbitrap path, and improving the combined system by keeping the accumulated ion population near a desired amount.
Allowable Subject Matter
Claim 17 would be allowable if rewritten to overcome the rejection (s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office Action and to include all the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JING WANG whose telephone number is (571)272-2504. The examiner can normally be reached M-F 7:30-17:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Kim can be reached at 571-272-2293. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JING WANG/Examiner, Art Unit 2881 /MICHAEL J LOGIE/ Primary Examiner, Art Unit 2881
Prosecution Insights