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 .
DETAILED ACTION
The amendment filed 02/04/2026 has been entered. Claims 7-13, 15, 16, 22, 23, and 26-30 are cancelled. Claims 1-6, 14, 17-21, 24, and 25 are pending and under examination.
Response to Arguments
With respect to the rejection of claims 1-6, 14, 17-21, 24, and 25 under 35 USC 103, Applicant's arguments filed 02/04/2026 have been fully considered but they are not persuasive.
Applicant argues that there would be no motivation to combine the cited references, and argues that the references are from four different fields. The Examiner respectfully disagrees. All of the references are in the same field of proteomics, which is a technique well-known to those of ordinary skill. It would be obvious to one of ordinary skill that different steps may be taken from different proteomics protocols in order to optimize the protocol for the proteins being studied. The claimed invention is directed to a combination of methods that were already known in the field of proteomics at the time of filing.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The claimed method steps were already well-known to those of ordinary skill in the art at the time the claimed invention was made.
Applicant argues that the claimed invention produces unexpected results but only provides allegations without any evidence to support said results. Therefore, there is no evidence that the method steps taught in the cited references would not achieve the same result as the claimed invention.
With regard to claim 3, Applicant argues that a change in sample matrix necessitates non-transferable methodological ranges and steps but provides no evidence to support the allegation.
Claim Objections
Claim 14 is objected to because of the following informalities: the word "peptides" in line 5 is misspelled as "pedtides". Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 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 1-5, 14, 17-21, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Schenk et al., (A high confidence, manually validated human blood plasma protein reference set. BMC Medical Genomics 2008, 1:41) in view of Chen et al., (US 2006/0188956 A1), Flieger et al., (Effective phospholipid removal from plasma samples by solid phase extraction with the use of copper (II) modified silica gel cartridges. Journal of Chromatography B 1070 (2017) 1-6), and Ge et al. (Ultra-high Pressure Fast Size Exclusion Chromatography for Top-Down Proteomics. Proteomics. 2013 September; 13(17)), all of which have been previously cited.
Regarding claims 1 and 2, Schenk teaches a method of isolating proteins from human plasma (Abstract). Schenk teaches that 697 plasma proteins were identified and that some were >10-15 kDa (Figure 3). Schenk teaches that size-exclusion chromatography (SEC) is used to detect plasma proteins (p. 2, col. 1, para. 3). Schenk teaches disulfide bonds were cleaved with DTT, i.e., reduced, followed by cysteine alkylation (p. 3, col. 1, para. 1). Schenk teaches a trypsin protein digestion step (p. 3, col. 1, para. 1). Schenk teaches that proteins were identified via mass spectrometry (Abstract).
Schenk does not teach that the plasma was contacted with an extraction buffer comprising HCl/ethanol, does not teach the removal of lipids, and does not teach UHPLC combined with size exclusion chromatography.
Chen teaches a method of extracting the GPCR135 ligand from brain tissue using HCl and ethanol (para. [0189]).
Chen does not teach the removal of lipids or teach UHPLC combined with size exclusion chromatography.
Flieger teaches solid phase extraction for the removal of phospholipids (Abstract).
Flieger does not teach UHPLC combined with size exclusion chromatography.
Ge teaches ultra-high pressure-size exclusion liquid chromatography (Abstract).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to use HCl/ethanol as taught by Chen, to extract proteins from blood plasma samples as taught by Schenk, to remove lipids from plasma samples, as taught by Flieger, and to analyze proteins using UHPLC combined with size exclusion chromatography, as taught by Ge. One of ordinary skill in the art would have been motivated to do so because HCl/ethanol is a suitable extraction buffer for precipitating low molecular weight proteins, as the GPCR135 ligand has a molecular weight 4-5 kDa (Chen para. [0191]). One of ordinary skill in the art would have been motivated to remove lipids using solid phase extraction because Flieger teaches that this method may be used to remove phospholipids from human plasma (Abstract) and teaches that phospholipids are one of the most troublesome components causing difficulties in the analysis of biological samples using LCMS (Introduction, para. 1). One of ordinary skill in the art would have been motivated to use UHPLC combined with size exclusion chromatography because Ge teach that combining ultra-high pressure liquid chromatography with size exclusion chromatography allows for rapid and high-resolution separation of intact proteins for top-down proteomics (Abstract). One of ordinary skill in the art would have had a reasonable expectation of success because Schenk, Chen, Flieger, and Ge are in the same field of endeavor of protein purification methods.
Regarding claim 3, Chen teaches an HCl concentration of 0.8M. Although the concentration of Chen differs from that of the instant claim, MPEP§ 2144.05 II states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.")” The selection of a specific HCl concentration would have been a routine matter of optimization on the part of the artisan of ordinary skill, said artisan recognizing that HCl concentrations would affect extracted protein concentrations.
Regarding claim 4, Chen teaches an ethanol:HCl ratio of 3:1 (para. [0189]), i.e., ethanol is present in the extraction buffer at a ratio of approximately 75%, which is under 80%, 90% or 95%.
Regarding claim 5, Chen teaches a tissue to extraction volume ratio of 12.5% (5g in 40 mL) (para. [0189]). It would have been obvious to one of ordinary skill in the art to have used a similar ratio for Schenk’s biological samples of plasma or serum.
Regarding claim 14, Schenk teaches the use of trypsin to digest proteins (p. 3, col. 1, para. 1).
Regarding claim 17, Schenk teaches liquid chromatography tandem mass spectrometry (p. 3, col. 1, Nano-HPLC tandem mass spectrometry).
Regarding claim 18, Schenk teaches that samples were subjected to nanoelectrospray ionization (p. 3, col. 1, Nano-HPLC and mass spectrometry).
Regarding claim 19, Schenk teaches that data were acquired using data-dependent mode (p. 3, col. 2, para. 1).
Regarding claim 20, Schenk teaches that proteins were identified via mass spectrometry (Abstract).
Regarding claims 21 and 24, Schenk teaches that insulin, which is a peptide hormone, was isolated from the plasma sample (Table 3).
Regarding claim 25, Schenk teaches plasma samples with total protein concentrations of 450 µg, 750 µg, 650 µg, and 300 µg (Table 1). Therefore, the concentration of proteins less than 15 kDa would be less than 1 mg/mL.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Schenk et al. (BMC Medical Genomics 2008, 1:41), Chen et al., (US 2006/0188956 A1), Flieger et al., (Journal of Chromatography B 1070 (2017) 1-6), and Ge et al. (Proteomics. 2013 September; 13(17)) as applied to claim 1 above, and further in view of Hong et al., (A Review: Size-Exclusion Chromatography for the Analysis of Protein Biotherapeutics and Their Aggregates. Journal of Liquid Chromatography and Related Technologies, 35:2923-2950, 2012).
Schenk (p. 2, col. 1, para. 3), Chen (para. [0134], and Ge (Abstract) teach size exclusion chromatography but do not explicitly teach denaturing size exclusion chromatography.
However, Hong teaches size exclusion chromatography methods and teaches that SEC-MS methods have been developed using denaturing mobile phases (p. 2935, para. 3) i.e., denaturing size-exclusion chromatography.
It would have been obvious to one of ordinary skill in the art to have used denaturing size exclusion chromatography, as taught by Hong, as the size exclusion chromatography method as taught by modified Schenk. One of ordinary skill in the art would have been motivated to do so because Hong teaches that using non-denaturing SEC mobile phases lead to ion suppression and contamination of the mass spectrometer (p. 2935, para. 3), and teaches that using denaturing mobile phases overcomes this issue (p. 2935, para. 4).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL EMILY MARTIN whose telephone number is (703)756-1416. The examiner can normally be reached M-Th 8:30-16:00, F 8:30-10:00 EST.
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, Louise Humphrey can be reached at (571) 272-5543. 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.
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/RACHEL EMILY MARTIN/Examiner, Art Unit 1657