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 Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea (i.e., mental processes for recognizing known markers from collected data and associating marker identity with time to make a calibration relationship), and the claims do not recite additional elements that integrate the abstract idea into a practical application or amount to significantly more than the judicial exception.
Step 2A, Prong One – Judicial exception (Abstract Idea)
The courts consider a mental process (thinking) that “can be performed in the human mind, or by a human using a pen and paper” to be an abstract idea. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d 1690, 1695 (Fed. Cir. 2011). As the Federal Circuit explained, “methods which can be performed mentally, or which are the equivalent of human mental work, are unpatentable abstract ideas the ‘basic tools of scientific and technological work’ that are open to all.’” 654 F.3d at 1371, 99 USPQ2d at 1694 (citing Gottschalk v. Benson, 409 U.S. 63, 175 USPQ 673 (1972)). See also Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 ("‘[M]ental processes[] and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work’" (quoting Benson, 409 U.S. at 67, 175 USPQ at 675)); Parker v. Flook, 437 U.S. 584, 589, 198 USPQ 193, 197 (1978) (same). Further, the courts do not distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, "[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person’s mind." Versata Dev. Group v. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015). See also Intellectual Ventures I LLC v. Symantec Corp., 838 F.3d 1307, 1318, 120 USPQ2d 1353, 1360 (Fed. Cir. 2016) (‘‘[W]ith the exception of generic computer-implemented steps, there is nothing in the claims themselves that foreclose them from being performed by a human, mentally or with pen and paper.’’); Mortgage Grader, Inc. v. First Choice Loan Servs. Inc., 811 F.3d 1314, 1324, 117 USPQ2d 1693, 1699 (Fed. Cir. 2016) (holding that computer-implemented method for "anonymous loan shopping" was an abstract idea because it could be "performed by humans without a computer").
In the instant case, the independent claims recite limitations that, when considered in their broadest reasonable interpretation, fall within the abstract idea of a mental process (concepts formed in the human mind such as observation, evaluation, and judgment). For instance, the independent claim 1 recites (independent claims 10 and 18 each recites similar limitations):
generating an output that includes one or more pI markers associated with a sample from MS data performed on the sample;
identifying the one or more pI markers in the output;
identifying one or more of an isotope or a charge state associated with the one or more pI markers; and
correlating time values to the identified one or more pI markers based on the identified isotope or charge state.
These limitations collectively recite an abstract idea. In particular, they are directed to the abstract idea of identifying known calibration markers in analytical data and correlating detected time values to the known markers based on associated isotope or charge state information. These steps are acts of observation, recognition, classification, and correlation of information. The specification confirms that “[c]onventional methods for converting a time scale to a pI scale in Capillary Isoelectric Focusing (CiEF) assays with MS detection rely on a manual search for pI markers on an MS electropherogram, followed by the construction of a calibration curve” (see Spec. para. [047]). Thus, the claimed methods merely automate a marker-identification and calibration process that could be performed by a person viewing analytical data.
Step 2A, Prong Two – Integration into a Practical Application
The claims are not integrated into a practical application because in practice, executing all of the steps is indistinguishable from: (i) mere data acquisition from a conventional instrument environment, and (ii) generic computer implementation of the abstract analysis. That is to say that integration into a practical application is lacking where, as here, the abstract idea has no effect on the material world or the execution of the process.
Although the claims include additional elements, e.g., “mass spectrometer”, CiEF, etc., the claims do not recite an improvement to the operation of the mass spectrometer, the CiEF separation, ion generation, ion detection, or any other instrument component. Rather, the claimed “generating…identifying…and…correlating” steps are recited functionally and use conventional MS output as data for the abstract calibration process.
Therefore, the claims as a whole are directed to an abstract idea.
Step 2B– Significant More (Inventive Concept)
The claims do not include additional elements, either individually or as an ordered combination, that amount to significant more than the abstract idea. The additional elements, including MS analysis, pI or compound markers, isotope or charge state information, are used in their ordinary capacities to collect, process, and correlate analytical data. The ordered combination does not transform the nature of the claims into a patent-eligible application. Instead, the claims merely automate the previously manual process of identifying marker peaks and constructing a calibrating relationship using generic computer and conventional MS data.
Dependent claims 2 and 11 recite spiking the sample with markers or reference compound; and claims 16 and 17 limit the method to CiEF-MS or CE-MS devices. These limitations merely provide a laboratory context or field of use for the abstract calibration process. Dependent claims 3, 13 and 19 merely generate or display graphical information, which is presentation of information or insignificant post-solution activity. Claims 4-9, 12 and 20 add XIC extraction, correlating peaks, identifying overlapping or aligned peaks, removing out of alignment peaks, and removing outlier calibration points. These limitations make the data analysis more specific, but they still amount to selecting, evaluating, filtering, and correlating analytical data to identifying calibration marker peaks. They improve the abstract calibration analysis itself, not the operation of the MS, CiEF-MS, or CE-MS device.
Taken alone or as ordered combination, claims 1-20 fail to recite patent eligible subject matter.
Claim Objections
Claim 12 is objected to because of the following informalities: Claim 12 recites “one or more outlier” which should be “one or more outliers”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11, and 13-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 11 and 13 each recites “The method of claim 1…the compound makers…”. There is insufficient antecedent basis for this limitation in the claim since claim 1 does not provide antecedent basis for “compound markers”. For prosecution purpose, these claims are interpreted as being dependent on claim 10.
Claim 14 recites “wherein the list of compound...” There is insufficient antecedent basis for this limitation in the claim.
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 1-5, and 10-19 are rejected under 35 U.S.C. 103 as being unpatentable over Xu, T., et al., (2022 January 28). An improved capillary isoelectric focusing-mass spectrometry method for high-resolution characterization of monoclonal antibody charge variants. Analytical Methods, 14(4), 383–393 [hereinafter Xu] in view of Egertson, J. D., et al., (2015). Multiplexed peptide analysis using data-independent acquisition and Skyline. Nature Protocols, 10(6), 887–903 [hereinafter Egertson].
Regarding Claim 1:
Xu teaches a method for performing calibration of isoelectric point (pI) markers in mass spectrometry (MS) detection (Abstract: an improved clEF-MS method of determining pIs of mAb charge variants by analyzing PI markers), the method comprising:
generating an output that includes one or more pI markers associated with a sample from MS data performed on the sample (Pages 1 and 10: samples with “Five peptide markers with pI values of 4.1, 5.5, 7.0, 9.8, 10.0 were obtained” and “The cIEF electropherograms and MS data were analyzed”, generating output as shown in Figs. 7A/B, which shows “Extracted ion electropherograms of five pI markers”, each plotted against migration time);
identifying the one or more pI markers in the output (Page 10: the PI marker peaks in the extracted ion electropherograms are identified. Figs. 7A/B labels pI marker peaks by known pI values, including pI 4.05, 5,52, 7.00, 9.50);
identifying one or more of [m/z values] associated with the one or more pI markers (Page 10: Fig. 7 shows each of the pI marker is associated with an identified m/z value, for example, “pI 9.99, m/z 624.3; pI 9.50, m/z 950.4; pI 7.00, m/z 627.3; pI 5.52, m/z 471.2; pI 4.05, m/z 591.2”); and
correlating time values to the identified one or more pI markers based on the identified [m/z values] (Page 9: “Fig. 7. Linear regression of pI values of pI markers versus mobilization times exhibited a good correlation coefficient (
R
2
=
0.999
)
with the wide range ampholyte (pI 3–10).” Figs. 7C/D shows correlation between time values and the pI markers. That is, Xu uses each marker’s identified m/z to extract its ion signal extract migration time, and the peak time of that m/z trace is then correlated with that marker’ s known pI value).
However, Xu does not specifically note that identify one or more of an isotope or a charge state of the pI markers and the correlation of time to pI markers are based on the identified one or more of an isotope or a charge state.
Egertson teaches that, for peptide detection in MS data, the expected traces can be selected based on precursor charges states (Page 3: “To detect and quantify a peptide, mass chromatograms (m/z-specific signal intensity over time) are extracted for a set of likely precursor charge states (e.g. +2, +3, +4 for tryptic ions2, peptides) and their associated fragment”).
As such, in the modified system, Xu’s cIEF-MS pI calibration method is modified to identify the pI marker signals using Egertson’s charge-state-specific extracted chromatograms. Specifically, for each of Xu’s peptide pI markers, the combined system identifies a charge states associated with the marker, extracts an m/z specific chromatogram corresponding to that charge state, determines the migration time of the marker peak from the extracted chromatogram, and then uses Xu’s pI/time calibration method to correlate the determined migration time with the known pI value of the marker based on the identified charge state, as recited in claim 1.
Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to modify Xu’s cIEF-MS pI-marker calibration method to identify the pI marker signals using Egertson’s charge-state-specific extracted chromatograms, because Xu’s pI markers are peptide markers detected from MS data and Egertson teaches a known MS technique for reliably detecting peptide signals over time based on likely precursor charge state, and using charge-state-specific chromatograms would improve the reliability of Xu’s pI marker identification since a single m/z signal may include interference from unrelated ions, whereas charge state information provides additional conformation that the extracted signal corresponds to the intended peptide pI marker.
Regarding Claim 10:
Xu in view of Egertson teaches claim 1, which recites steps of claim 10 including generating an output that includes one or more compound markers associated with the sample; identifying the one or more compound markers in the output; identifying one or more of an isotope or a charge state associated with the one or more compound markers; and correlating time values to the identified one or more compound markers based on the identified isotope or charge state.
Xu further teaches performing MS analysis on a sample as Xu teaches analyzing the “cIEF electropherograms and MS data”.
In addition, Xu teaches a method for performing calibration of pI markers in MS, which is narrower than the broad compound marker calibration recited in claim 10.
As such, Xu in view of Egertson also teaches claim 10.
Regarding Claim 18:
Xu teaches an “improved capillary isoelectric focusing-mass spectrometry method,” where “cIEF-MS was successfully used for accurately determining the isoelectric points (pIs) of mAb1 charge variants via analyzing the pI markers and spiking in a standard protein (cytochrome c) to samples for migration time normalization” (Abstract). Since a cIEF-MS device necessarily includes a control circuitry and operating such a device to perform said method requires activate cIEF and MS to perform their analysis accordingly, Xu teaches a capillary isoelectric focusing-mass spectrometry (CiEF-MS) device coupled to a processing system for performing calibration of isoelectric point (pI) markers, the device comprising: control circuitry configured to: activate the CiEF to perform analysis on a sample; activate the MS to perform MS analysis on a sample, as recited in claim 18.
Rest of claim 18 recites substantially identical elements as in claim 1. Since Xu in view of Egertson teaches claim 1, the combined references also teach claim 18.
Regarding Claim 2 and 11:
Xu in view of Egertson teaches the method of claim 1 and claim 10, respectively. Xu further teaches spiking the sample with the one or more pI markers associated with one or more reference compounds (Abstract: “determining the isoelectric points (pIs) of mAb1 charge variants via analyzing the pI markers and spiking in a standard protein (cytochrome c) to samples for migration time normalization”).
Regarding Claim 3:
Xu in view of Egertson teaches the method of claim 1. Xu further teaches extracted ion electropherograms of pI markers as intensity vs. migration time (Figs. 7A/B) and also teaches a calibration curve correlating marker migration time with known pI (Figs. 7C/D). Thus, it would be obvious to display the marker intensity data vs. calibrated pI rather than migration time, as recited in claim 3, because Xu’s calibration curve provides the direct conversion from migration pI, and displaying the data on a pI axis would facilitate interpretation of the pI-separated species.
Regarding Claim 13:
Xu in view of Egertson teaches the method of claim 1. As discussed in claim 3, the combined system could display pI marker vs migration time and identify charge state of the pI markers. Thus, the modified system also could display the identified charge state associated with the identified pI markers, as recited in claim 13.
Regarding Claim 19:
Xu in view of Egertson teaches the device of claim 18. Since claim 19 recites substantially same elements as in claim 13, the combined references also teach claim 19.
Regarding Claim 4:
Xu in view of Egertson teaches the method of claim 1. The combined references further teach wherein identifying the one or more of the isotope or the charge state associated with the one or more pI markers further comprises extracting XIC values for the isotope or the charge state (Egertson teaches extracting mass chromatograms traces for likely precursor charge stages. Xu teaches extracts ion electropherogram’s for marker m/z values. Thus, the combined system extracts charge state specific traces for Xu’s pI marker peptide).
Regarding Claim 5:
Xu in view of Egertson teaches the method of claim 1. The combined references further correlating a plurality of peaks in MS analysis data with one or more of the identified isotope or the charge state with one or more of the time values (Xu teaches correlates marker peak migration times with known pI values. Egertson teaches using charge state associated chromatograms to identify peaks over time. Thus, the combined system correlates peaks with the identified charge with time values).
Regarding Claim 12:
Xu in view of Egertson teaches the method of claim 1. Xu teaches evaluating the linearity of a pI marker calibration curve generated from pI marker migration times (Figs. 7C/D). Xu also teaches “Distortion of linearity at acidic pH range was observed…[while] it still maintained excellent linearity in the basic range,” and “the linear regression equation (y =5.6x +111.4) in Fig. 7D achieved from the analysis of pI markers was used for determining the pIs of mAb1 charge variants.” As such, in light Xu’s teaching, it would be obvious to identify and remove outlier calibration points that deviate from the regression relationship so that the remaining marker points provide a more accurate pI vs. time calibration.
Regarding Claim 14:
Xu in view of Egertson teaches the method of claim 1. Xu further teaches wherein the list of compound markers or the list of one or more pI markers comprises one or more calibration peptides (Xu teaches using “peptide markers Five peptide markers with pI values of 4.1, 5.5, 7.0, 9.8, 10.0”).
Regarding Claim 15:
Xu in view of Egertson teaches the method of claim 1. Xu further teaches wherein the sample contains one or more proteins (Xu teaches “characterization of monoclonal antibody (mAb) charge variants”, which is a specific protein).
Regarding Claim 16:
Xu in view of Egertson teaches the method of claim 1. Xu further teaches wherein the method employs a capillary isoelectric focusing-mass spectrometry (CiEF-MS) device (Xu expressly uses cIEF-MS).
Regarding Claim 17:
Xu in view of Egertson teaches the method of claim 1. Xu further teaches wherein the method employs a Capillary electrophoresis-mass spectrometry (CE-MS) device (Xu expressly uses cIEF-MS, which is a narrower category than CE-MS).
Claims 6-9 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Xu in view of Egertson, further in view of US 2018/0136220A1 [hereinafter Grote].
Regarding Claims 6 and 20:
Xu in view of Egertson teach the method of claim 1 and the device of claim 18, respectively.
Xu teaches extracted ion electropherograms of five pI markers, where each marker is shown as a peak at a migration time, as shown in Figs. A/B. Thus, the combined references teach wherein the pI marker corresponds to a peak of a trace associated with a compound.
However, the combined references do not specifically teach the pI marker corresponds to an overlapping peak of one or more traces associated with a compound.
Grote teaches that MS data are searched against a peptide library, allowing “a set number of transition ion chromatograms to be extracted for a peptide within the window of its predicted RT…The peak groups are scored according to several factors intended to discriminate a “true” peptide target from non-specific noise” (paras. [0011 and 0103]).
As such, in a combined system, Xu’s pI marker peptide is identified not merely by one extracted ion electropherogram peak, but by the peak group (“overlapping peak”) formed from one or more marker-associated extracted traces, as recited in claims 6 and 20, because the marker peptide is represented by corresponding peak signals in the extracted traces associated with the peptide.
Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to identify Xu’s peptide pI markers using the peak group approach of Grote, because Xu’s calibration requires accurate marker migration time, and Grote teaches a known MS technique for distinguishing true peptide targets from noise using extracted chromatograms and peak groups. The combined method would thus improve confidence that the selected peak corresponds to the intended pI marker and reduce calibration error from interfering peaks.
Regarding Claim 7:
Xu in view of Egertson teach the method of claim 6.
Xu teaches that pI markers show up as extracted ion electropherogram peaks and using the migration times of those pI marker peaks to build the pI vs time calibration curve.
Grote further teaches that “peak groups are scored according to several factors intended to discriminate a ‘true’ peptide target from non-specific noise”, and “OpenSWATH firstly identified the peak groups … and aligned them … based on the clustering behaviors of retention time in each run … only those peptide peak groups that deviate within 3 standard deviations from the retention time were reported and considered for alignment” (paras. [0103, 0332]).
As such, the combined references further teach claim 7. In the modified system, one or more peaks associated with Xu’s pI marker peptide are identified as an aligned peak group with other peaks, and the pI marker is identified based on the time or intensity of that aligned peak group.
Regarding Claim 8:
Xu in view of Egertson teach the method of claim 7.
Xu teaches using pI marker migration times to generate a pI vs time calibration. Grote teaches scoring peak groups to distinguish a true peptide target from non-specific noise and using cutoffs/FDR to exclude bad peak groups (paras. [0103, 0332]).
As such, the combined references further teach claim 8. In the combined system, peaks or peak groups associated with Xu’s pI marker that are out of alignment with the marker-associated traces are identified as false/noise peak groups and removed from the marker output before the marker migration time is used for pI calibration.
Regarding Claim 9:
Xu in view of Egertson teach the method of claim 8.
Grote further teaches evaluating peptide-associated transition peaks using signal intensity, co-elution with other transitions from the same peptide, peak shape, and correlation between measured transition amount (paras. [0103, 0298]).
As such, the combined references further teach claim 9. In the combined system, Xu’s marker-associated peaks are considered aligned/valid when their intensity-bearing transition traces co-elute and satisfy intensity/correlation/peak quality criteria; interfering or misshapen peaks are excluded.
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.
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/JING WANG/Examiner, Art Unit 2881
/MICHAEL J LOGIE/ Primary Examiner, Art Unit 2881
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