DETAILED ACTION
In application filed on 02/15/2023, Claims 1-10 are pending. The claim set submitted on 02/25/2023 is considered because this is the most recent claim set. Claims 1-10 are considered in the current office 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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/23/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because certain reference characters in figures, not limited to Figures 2A-C are not legible.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term “Evotip and Evosep One” (See specification, Para 0097), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Further, the disclosure is objected to because of the following informalities:
It appears that the recited “NISTmAb” is an abbreviation. Applicant should provide the unabbreviated form of this recitation.
Appropriate correction is required.
Claim Objections
Claims 1 and 5-10 are objected to because of the following informalities:
Claim 1 recites “digested peptides” in line 3 of the Claim but earlier recited “digested peptide” in line 1 of the claim (preamble).
Consistent language should be used and for the purpose of expedited prosecution, Examiner interprets “digested peptides” in line 3 of the Claim as “digested peptide”.
Appropriate correction is required.
In addition, Claim 1 recites “a predicted amino acid sequence of a digested peptide of said protein of interest” in lines 6-7 of the claim but earlier recited “an amino acid sequence of a digested peptide of said protein of interest” in lines 1-2 of the claim.
It appears that this limitation should be recited as “a predicted amino acid sequence of a digested peptide of said protein of interest” in lines 6-7 of the claim should be recited as “the amino acid sequence of the digested peptide of said protein of interest”.
Consistent language should be used and for the purpose of expedited prosecution, Examiner interprets “a predicted amino acid sequence of a digested peptide of said protein of interest” in lines 6-7 of the claim as “the amino acid sequence of the digested peptide of said protein of interest”.
Appropriate correction is required.
Further, Claim 1 recites “a protein of interest” in line 3 of the Claim but earlier recited “a protein of interest” in lines 1-2 of the claim (preamble).
Is this “a protein of interest” in lines 1-2 same as the “a protein of interest” in line 3 of Claim?
Consistent language should be used and for the purpose of expedited prosecution, Examiner interprets “a protein of interest” in line 3 as “the protein of interest”.
Appropriate correction is required.
In addition, Claim 1 recites “a digested peptide” in lines 6-7 and 12. Further the Claims recites “said digested peptides” in line 10.
Consistent language should be used and for the purpose of expedited prosecution, Examiner interprets “a digested peptide” in lines 6-7 and 12 as “the digested peptide”. Also Examiner interprets “said digested peptides” in line 10 as “said digested peptide”.
Appropriate correction is required.
Claim 5 recites “the chromatography step” in lines 1 of the Claim but earlier recited “subjecting said mixture to analysis using liquid chromatography-mass spectrometry” in line 8 of claim 1.
Consistent language should be used and for the purpose of expedited prosecution, Examiner interprets “the chromatography step” in line 1 of claim 5 as “the step of subjecting said mixture to analysis using liquid chromatography-mass spectrometry”.
Appropriate correction is required.
Claim 6 recites the limitations "said mass spectrometer" in line 1 but earlier recited “liquid chromatography-mass spectrometry” in line 8 of claim 1.
Consistent language should be used and for the purpose of expedited prosecution, Examiner interprets "said mass spectrometer" as "a mass spectrometer of the liquid chromatography-mass spectrometry”.
Further, Applicant recites “said mass spectrometer is coupled to said liquid chromatography system”.
Consistent language should also be used and for the purpose of expedited prosecution, Examiner interprets “said mass spectrometer is coupled to said liquid chromatography system” as “said mass spectrometer is coupled to liquid chromatography system” of “the liquid chromatography-mass spectrometry”.
Appropriate correction is required.
Claims 7-9 recites “a digested peptide”. It appears that this limitation should be recited as “the digested peptide” in light of the recited “a digested peptide” in Claim 1.
Consistent language should be used and for the purpose of expedited prosecution, Examiner interprets “a digested peptide” in Claims 7-9 as “the digested peptide”
Appropriate correction is required.
Claims 8-9 recites “the heavy isotopes”. It appears that this limitation should be recited as “the heavy isotope at or near each peptide terminus” in light of the recited “a heavy isotope at or near each peptide terminus” in Claim 1.
Consistent language should be used and for the purpose of expedited prosecution, Examiner interprets “the heavy isotopes” as “each of the heavy isotope at or near each peptide terminus”.
Appropriate correction is required.
Further, Claims 8-9 recites “the added mass”. It appears that this limitation should be recited as “an added mass” as it is a property of the structure of the heavy isotopes.
For the purpose of expedited prosecution, Examiner interprets “the added mass” as “ an added mass”
Appropriate correction is required.
Claim 10 recites “said heavy peptide standard”. It appears this limitation should be recited as “said at least one heavy peptide standard”.
Consistent language should be used and for the purpose of expedited prosecution, Examiner interprets “said heavy peptide standard” as “said at least one heavy peptide standard”.
Appropriate correction is required.
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 1-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims have been analyzed for eligibility in accordance with their broadest reasonable interpretation. All claims are directed to statutory categories, i.e., a method (Claims1-10) (Step 1: YES).
Analysis:
Claim 1: Ineligible.
Claim 1 recites a method for identifying an amino acid sequence of a digested peptide of a protein of interest. Thus, the claim is directed to a method, which is one of the statutory categories of invention (Step 1: YES).
Claim 1 recites “(c) comparing a retention time and/or at least one mass spectrum of said at least one heavy peptide standard to a retention time and/or at least one mass spectrum of said digested peptides; and (d) using the comparison of (c) to identify the amino acid sequence of a digested peptide of said protein of interest”. Therefore, the claim is directed towards an abstract idea, and more specifically to the abstract idea group of a math or mental process since claim 1 relates to using a math or mental process to “(c) compare a retention time and/or at least one mass spectrum of said at least one heavy peptide standard to a retention time and/or at least one mass spectrum of said digested peptides; and (d) using the comparison of (c) to identify the amino acid sequence of a digested peptide of said protein of interest”. (Step 2A, Prong 1: YES).
Step 2A, Prong 2:
This judicial exception is not integrated into a practical application.
Once the using of the comparison to identify the amino acid sequence of the digested peptide of the said protein of interest is made, then no further action is taken, so no particular practical application. (Step 2A, Prong 2: NO).
Step 2B:
Furthermore, the courts have found that limitations adding insignificant extrasolution activity to the judicial exception, such as mere data gathering in conjunction with a law of nature or abstract idea, are limitations found not to be enough to qualify as ‘significantly more’ when recited in a claim with a judicial exception (see the 2014 Interim Guidance on Patent Subject Matter Eligibility of the Federal Register dated December 16, 2014; and MPEP 2106.05(I)(A)). Note that mere data gathering is not significantly more than the abstract idea. See MPEP 2106.05(g).
Here, it appears that “that the analysis using liquid chromatography mass spectrometry is data gathering and therefore an insignificant extra solution activity. See MPEP 2106.05(g).
Further here, there are no additional elements which are significantly more than the abstract idea in independent Claim 1. The steps of “(a) combining a peptide digest having digested peptides of a protein of interest with at least one heavy peptide standard to form a mixture, wherein said at least one heavy peptide standard includes a heavy isotope at or near each peptide terminus, and an amino acid sequence of said at least one heavy peptide standard is a predicted amino acid sequence of a digested peptide of said protein of interest; (b) subjecting said mixture to analysis using liquid chromatography-mass spectrometry” appears to be well-understood, routine, and conventional (WURC) in the field of proteomics, as evidenced by Ranish et al. (US20100261279A1).(Step 2B: NO).
Therefore, Claim 1 is ineligible.
Moreover, Claims 2-10 are rejected by virtue of dependency on Claim 1.
Claims 2-3: Ineligible.
Step 2A, Prong One and Prong Two: Claims 2-3 provides general properties of the amino acid sequence. The claims do not provide any practical application.
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claims 2-3 are ineligible.
Moreover, Claim 3 is rejected by virtue of dependency on Claim 2.
Claim 4: Ineligible.
Step 2A, Prong One and Prong Two: Claim 4 provides the type of the protein of interest. The claims do not provide any practical application.
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claim 4 is ineligible.
Claim 5-6: Ineligible.
Step 2A, Prong One and Prong Two: Claims 5-6 further define the data gathering steps which appear to be generic and WURC.
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claims 2 and 3 are ineligible.
Claim 7: Ineligible.
Claim 7 recites “…determining whether a retention time of said at least one heavy peptide standard aligns with a retention time of a digested peptide”. Therefore, the claim is directed towards an abstract idea, and more specifically to the abstract idea group of a math or mental process since claim 7 relates to using a math or mental process to “…determine whether a retention time of said at least one heavy peptide standard aligns with a retention time of a digested peptide”. (Step 2A, Prong 1: YES).
Step 2A, Prong 2:
This judicial exception is not integrated into a practical application.
Once the evaluation is made then no action is taken, so no particular practical application.(Step 2A, Prong 2: NO).
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claim 7 is ineligible.
Claim 8: Ineligible.
Claim 8 recites “determining whether MS1 spectrum peaks of said at least one heavy peptide are shifted by the added mass of the heavy isotopes relative to MS' spectrum peaks of a digested peptide.”. Therefore, the claim is directed towards an abstract idea, and more specifically to the abstract idea group of a math or mental process since claim 8 relates to using a math or mental process to “…“determine whether MS1 spectrum peaks of said at least one heavy peptide are shifted by the added mass of the heavy isotopes relative to MS' spectrum peaks of a digested peptide.””. (Step 2A, Prong 1: YES).
Step 2A, Prong 2:
This judicial exception is not integrated into a practical application.
Once the evaluation is made then no action is taken, so no particular practical application.(Step 2A, Prong 2: NO).
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claim 8 is ineligible.
Claim 9: Ineligible.
Claim 8 recites “determining whether MS2 spectrum peaks of said at least one heavy peptide are shifted by the added mass of one of the heavy isotopes relative to MS2 spectrum peaks of a digested peptide.” Therefore, the claim is directed towards an abstract idea, and more specifically to the abstract idea group of a math or mental process since claim 9 relates to using a math or mental process to “…“determine whether MS2 spectrum peaks of said at least one heavy peptide are shifted by the added mass of one of the heavy isotopes relative to MS2 spectrum peaks of a digested peptide”. (Step 2A, Prong 1: YES).
Step 2A, Prong 2:
This judicial exception is not integrated into a practical application.
Once the evaluation is made then no action is taken, so no particular practical application.(Step 2A, Prong 2: NO).
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claim 9 is ineligible.
Claim 10: Ineligible.
Step 2A, Prong One and Prong Two: Claim 10 provides general properties of the peptide digest and heavy peptide standard. The claims do not provide any practical application.
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claim 10 is ineligible.
Claim Rejections - 35 USC § 102
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 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 and 5-6 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Ranish et al. (US20100261279A1).
Regarding Claim 1, Ranish teaches a method for identifying an amino acid sequence of a digested peptide of a protein of interest, comprising:
(a) combining (See Para 0062…addition of C-terminal tags before or after digestion of protein, thereby teaching “combining”) a peptide digest (See Para 0061…one or more peptides of interest) having digested peptides of a protein of interest (‘protein samples’) (See Para 0061…proteins samples digested to generate one or more peptides of interest) with at least one heavy peptide standard (See Para 0062… containing isotopically heavy or light amino acids, such as lysine and arginine, or heavy variants thereof. The C-terminal tags may be incorporated before or after digestion of the protein samples, thereby teaching “at least one heavy peptide”) to form a mixture (See Para 0063… the internal standard is added at an amount equal to that of the modified peptide of interest; The addition of the internal standard to the modified peptide of interest forms “a mixture”),
wherein said at least one heavy peptide standard (See Para 0062… containing isotopically heavy or light amino acids, such as lysine and arginine, or heavy variants thereof) includes a heavy isotope at or near each peptide terminus (See Para 0062…C-terminal tags or the N-terminal tags) , and an amino acid sequence of said at least one heavy peptide standard (‘sequence of the internal standard’) is a predicted amino acid sequence of a digested peptide of said protein of interest (‘sequence of the modified peptide of interest’) ; Further See Para 0015…The internal standard is identical to the modified peptide of interest in terms of its sequence…);
(b) subjecting said mixture to analysis using liquid chromatography-mass spectrometry (See Para 0063…The mixture is analyzed by nanoLC-MS/MS using an LTQ-Orbitrap™ instrument (Thermo Scientific) or it may be fractionated by strong cation exchange chromatography prior to LC-MS analysis);
(c) comparing (‘determination from ratios’) a retention time and/or at least one mass spectrum (See Para 0016…fragmentation pattern) of said at least one heavy peptide standard (See Para 0015… The internal standard) to a retention time and/or at least one mass spectrum (See Para 0016…fragmentation pattern) of said digested peptides (See Para 0015… modified peptide of interest). Further See Para 0016…the relative amount of the modified peptide of interest and the internal standard is determined from the ratios of the intensities of the ions in the fragment ion pairs, as each fragment pair consists of a fragment ion from each isobaric pair member, thereby teaching “comparing….”); Examiner submits that the claimed “a retention time” is interpreted as optional due to the recited “and/or” ; and
(d) using the comparison of (c) to identify the amino acid sequence of a digested peptide of said protein of interest (‘the sequence of the peptide of interest’) (See Para 0016…The fragmentation pattern is also used to identify the sequence of the peptide of interest, as each peptide can fragment along the peptide backbone and produce corresponding fragment ions, thereby teaching “using the comparison to identify…”).
Regarding Claim 5, Ranish teaches wherein said chromatography step comprises reversed phase liquid chromatography, ion exchange chromatography, size exclusion chromatography, affinity chromatography, hydrophobic interaction chromatography, hydrophilic interaction chromatography, mixed-mode chromatography, or a combination thereof (See Para 0063… strong cation exchange chromatography, thereby teaching “ion exchange chromatography”).
Regarding Claim 6, Ranish teaches wherein said mass spectrometer (See Para 0063…LTQ-Orbitrap™ instrument (Thermo Scientific)) is an electrospray ionization mass spectrometer, nano-electrospray ionization mass spectrometer, or an Orbitrap-based mass spectrometer (See Para 0063…LTQ-Orbitrap™ instrument (Thermo Scientific)), wherein said mass spectrometer is coupled to said liquid chromatography system (See Para 0063…Analysis by Liquid Chromatography-Mass Spectrometry; See Para 0064…Alternatively, peptide samples are analyzed by reversed phase HPLC (Agilent 1100 series) electro-spray ionization LC-MS using the LTQ Orbitrap).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Ranish et al. (US20100261279A1) as applied to claim 1 above, and further in view of Koll et al. (US20120322093A1).
Regarding Claim 2, Ranish does not explicitly teach that the said amino acid sequence is a sequence variant.
In the analogous art of a method for determining amino acid sequence mutations in a produced polypeptide, Koll teaches that the said amino acid sequence (See Para 0007…amino acid sequence, of a polypeptide) is a sequence variant (See Para 0007… determination of amino acid sequence variants, i.e. mutations in the amino acid sequence, of a polypeptide. Indirectly therewith also nucleic acid sequence variants can be determined).
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 the method of Ranish to incorporate that the said amino acid sequence is a sequence variant, as taught by Koll for the benefit of determining amino acid sequence mutations in a produced polypeptide (Koll, Abstract, Para 0007), allowing for the provision of a method providing high sensitivity to find and identify potential sequence variants to confirm product homogeneity and consistency during cell line development processes (Koll, Abstract, Para 0005).
Regarding Claim 4, Ranish does not teach that said protein of interest is an antibody, a bispecific antibody, a monoclonal antibody, a fusion protein, an antibody-drug conjugate, an antibody fragment, a host cell protein, or a protein pharmaceutical product.
In the analogous art of a method for determining amino acid sequence mutations in a produced polypeptide, Koll teaches that said protein of interest is an antibody, a bispecific antibody, a monoclonal antibody, a fusion protein, an antibody-drug conjugate, an antibody fragment, a host cell protein, or a protein pharmaceutical product (See Para 0040…. Therapeutic proteins, e.g. produced by recombinant methods, may be a mixture of molecules with slightly different amino acid sequences,…thereby teaching “protein pharmaceutical product”).
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 the method of Ranish to incorporate that said protein of interest is an antibody, a bispecific antibody, a monoclonal antibody, a fusion protein, an antibody-drug conjugate, an antibody fragment, a host cell protein, or a protein pharmaceutical product, as taught by Koll for the benefit of detecting the amino acid sequence mutations (variations) that may be present within therapeutic proteins when produced by recombinant methods (Koll, Para 0040), allowing for the provision of a method providing high sensitivity to find and identify potential sequence variants to confirm product homogeneity and consistency during cell line development processes (Koll, Abstract, Para 0005).
Claims 3 is rejected under 35 U.S.C. 103 as being unpatentable over Ranish et al. (US20100261279A1) in view of Koll et al. (US20120322093A1) as applied to claim 2 above, and further in view of Zhang et al. ("Streamlined sequence variant analysis (SVA) for in-depth characterization of biotherapeutics.").
Regarding Claim 3, the method of claim 2 is obvious over Ranish in view of Koll.
The combination of Ranish and Koll does not teach that said sequence variant is a critical quality attribute.
In the analogous art of peptide mapping analysis, Zhang teaches that said sequence variant is a critical quality attribute (See Page 3, Identifying SVs….SVs are considered impurities in protein-based therapeutics. …For this reason, they have to be minimized during the development of biotherapeutics and if they are present in final products they are often classified as critical quality attributes (CQA) requiring careful monitoring).
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 the method of the combination of Ranish and Koll to incorporate that said sequence variant is a critical quality attribute, as taught by Zhang for the benefit of disclosing the need for carefully monitoring the sequence variants as they are considered impurities in protein-based therapeutics (Zhang, Page 3, Identifying SVs), allowing for the development of a sensitive liquid chromatography-mass spectrometry (LC-MS) workflow along with efficient data analysis software to identify SVs is critical for correct detection and characterization in biopharmaceutical laboratories (Zhang, Page 1, Identifying SVs).
Claims 7 is rejected under 35 U.S.C. 103 as being unpatentable over Ranish et al. (US20100261279A1) as applied to claim 1 above, and further in view of Thomas et al. (US20140349881A1).
Regarding Claim 7, Ranish does not teach that said comparing step comprises determining whether a retention time of said at least one heavy peptide standard aligns with a retention time of a digested peptide.
In the analogous art of targeted protein quantitation, Thomas teaches that said comparing step (See Para 0465… The MASSterclass® readout is defined by the ratio between the area under the peak specific for the analyte and the area under the peak specific for the synthetic isotopically labelled analogue (internal standard), thereby teaching the “comparing step”) comprises determining whether a retention time of said at least one heavy peptide standard (‘isotopically labelled synthetic peptide (internal standard)’) aligns with a retention time of a digested peptide (See Para 0465… Both the endogenous peptide (analyte) and its corresponding isotopically labelled synthetic peptide (internal standard) elute at the same retention time).
Thomas further teaches that the peptides samples are obtained from proteins subjected to tryptic digest (Para 0457).
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 the method of Ranish to incorporate that said comparing step comprises determining whether a retention time of said at least one heavy peptide standard aligns with a retention time of a digested peptide, as taught by Thomas for the benefit of determining the original concentration of the protein in the sample (Thomas, Para 0465), allowing for the provision of new test panels comprising biomarkers and clinical parameters, for the prediction, diagnosis, prognosis and/or monitoring of hypertensive disorders of pregnancy and particularly preeclampsia (Thomas, Abstract).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Ranish et al. (US20100261279A1) as applied to claim 1 above, and further in view of Pappireddi et al. ("A review on quantitative multiplexed proteomics." Chembiochem 20.10 (2019): 1210-1224.).
Regarding Claim 8, Ranish does not teach that the said comparing step comprises determining whether MS1 spectrum peaks of said at least one heavy peptide are shifted by the added mass of the heavy isotopes relative to MS1 spectrum peaks of a digested peptide.
In the analogous art of quantitative multiplexed proteomics, Pappireddi teaches that said comparing step (See Fig. 2E…using the ratios between peak sizes) comprises determining whether MS1 spectrum peaks of said at least one heavy peptide (referred to as peptides in the heavy sample [See Fig. 2E]) are shifted by the added mass of the heavy isotopes relative to MS1 spectrum peaks of a digested peptide (‘amino acids with naturally occurring isotopes (light)’) (See Fig. 2E…. Peptides in the heavy sample are shifted to the right on the MS1 spectrum compared to those from the light sample. . Ratios between peak sizes within one spectrum can thus be used for relative quantification.)
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 the method of Ranish to incorporate that the said comparing step comprises determining whether MS1 spectrum peaks of said at least one heavy peptide are shifted by the added mass of the heavy isotopes relative to MS1 spectrum peaks of a digested peptide, as taught by Pappireddi for the benefit of conducting peptide analysis using MS1 based quantification via heavy isotope labeling, which inherently leads to much higher reproducibility (i.e., higher measurement precision) (Pappireddi, Section 1.4), demonstrating the use of mass spectrometry-based proteomics which is becoming an increasingly powerful tool that is now able to routinely detect and quantify thousands of proteins ((Pappireddi, Abstract).
Claims 9 is rejected under 35 U.S.C. 103 as being unpatentable over Ranish et al. (US20100261279A1) as applied to claim 1 above, and further in view of Parker et al. ("Quantitative analysis of SILAC data sets using spectral counting." Proteomics 10.7 (2010): 1408-1415”).
Regarding Claim 9, Ranish does not teach that the said comparing step comprises determining whether MS2 spectrum peaks of said at least one heavy peptide are shifted by the added mass of one of the heavy isotopes relative to MS2 spectrum peaks of a digested peptide.
In the analogous art of a new quantitative proteomics approach that combines the best aspects of stable isotope labeling of amino acids in cell culture (SILAC) labeling and spectral counting, Parker teaches that the said comparing step (See Section 3.1… Overlay of selected MS/MS fragmentation spectra of heavy and light peptides) comprises determining whether MS2 spectrum peaks (referred to as MS/MS fragmentation spectra [Section 3.1]) of said at least one heavy peptide (See Section 3.1… MS/MS fragmentation spectra of heavy, referring to the “heavy peptide/labeled peptides”) are shifted by the added mass (See Section 3.1… the expected 10Da mass shift of y ions) of one of the heavy isotopes relative to MS2 spectrum peaks of a digested peptide (Section 3.1… MS/MS fragmentation spectra of…light peptides/unlabeled peptides).
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 the method of Ranish to incorporate that the said comparing step comprises determining whether MS2 spectrum peaks of said at least one heavy peptide are shifted by the added mass of one of the heavy isotopes relative to MS2 spectrum peaks of a digested peptide, as taught by Parker for the benefit of correctly identifying labeled and unlabeled peptides (Parker, Section 3.1), allowing for demonstration of the use of SPeCtRA that is a protein quantification technique that is accurate and sensitive as well as easy to automate and apply to high-throughput analysis of complex biological samples (Parker, Abstract).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Ranish et al. (US20100261279A1) as applied to claim 1 above, and further in view of Zhou et al. ("Performance metrics for evaluating system suitability in liquid chromatography—Mass spectrometry peptide mass mapping of protein therapeutics and monoclonal antibodies." MAbs. Vol. 7. No. 6. Taylor & Francis, 2015.).
Regarding Claim 10, Ranish does not teach that a molar ratio of said peptide digest to said heavy peptide standard is between about 1:50 and about 1:200, or about 1:100.
In the analogous art of the use of liquid chromatography – mass spectrometry (LC-MS) for the characterization of proteins, Zhou teaches that a molar ratio of said peptide digest (referred to as unlabeled (light ) peptide [Page 1106 , left column, results]) to said heavy peptide standard (referred to as labeled (heavy) peptide [Page 1106 , left column, results]) is between about 1:50 and about 1:200, or about 1:100 (See Results…Each unlabeled (light) peptide in the 4 intra-scan peptide pair was spiked at signal normalized concentrations of 0.1%, 1%, 10%, or 100% of the corresponding labeled (heavy) peptide concentration).
Examiner submits that the exemplary teaching of Zhou results in effective unlabeled (light); labeled (heavy) peptide molar ratios of 0.001:1(1:1000), 0.01:1(1:100), 0. 1:1(1:10) and 1:1 for the unlabeled (light) peptide to the heavy standards.
In addition, Examiner submits that the limitation “about 1:50 and about 1:200” is optional in light of the recited “or” in the claim.
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 the method of Ranish to incorporate that a molar ratio of said peptide digest to said heavy peptide standard is between about 1:50 and about 1:200, or about 1:100, as taught by Zhou for the benefit of developing the proper LC-MS system suitability metrics for the characterization of proteins (Zhou, Abstract), which allows for fulfilling the regulatory requirements for specific applications specific to the product of interest (Zhou, Page 1105, right column),
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OYELEYE ALEXANDER ALABI whose telephone number is (571)272-1678. The examiner can normally be reached on M-F 7:30am-5:30pm.
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/OYELEYE ALEXANDER ALABI/ Examiner, Art Unit 1797