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 .
Response to Arguments
Applicant's arguments filed 3/4/26 have been fully considered but they are not persuasive.
The indefiniteness rejections of record are withdrawn in light of applicant’s amendments.
Applicant asserts that there is insufficient motivation for combining the teachings of Whitehouse and Takkis. In particular, applicant asserts that neither reference teaches delivering dopant through a second ESI source for the purpose of signal enhancement. This is not persuasive. Whitehouse describes a decades old technology wherein multiple plumes of electrospray are provided to a mixing region. Applicant assertion that Whitehouse is directed to a “fundamentally different” purpose cites to entirely different embodiments than those relied upon to reject the instant claims, and thus are irrelevant in understanding the rejection. Looking to the embodiments actually relied upon, Whitehouse provides an extremely old and well understood technique for mixing multiple ESI plumes, which is the basic step of the instant invention. What Whitehouse does not teach is placing a dopant in one of the ESI streams. Takkis adds a dopant, Ammonium Fluoride, to the eluent of a chromatograph and then ionizes said eluent via electrospray. This order of steps is accepted by the applicant at section 2b of the arguments. This sequence thus provides a dopant into the ESI stream. Applicant’s assertion that Takkis fails to add dopant to the flow stream is in error, since Takkis adds dopant to the stream upstream of the electrospray. If there is some distinguishing aspect of the instant invention’s dopant addition wherein the dopant avoids upstream addition of the dopant, such an aspect is not claimed.
Applicant argues that combining the features of Takkis and Whitehouse would require impermissible hindsight. This is not persuasive. 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). Takkis provides a clear reason to add dopant to an ESI stream, i.e., improved signal quality. Further, Takkis deals with a sample type that is specified by Whitehouse, i.e., a biological sample. The addition of the dopant of Takkis to an ESI stream of Whitehouse would only require the knowledge gleaned from these two sources.
Applicant argues that one of ordinary skill in the art would have no reasonable expectation of success in enhancing the signal of the claimed analyte of interest by adding the dopant in the mixing region This is not persuasive. The claims do not require enhancing the analyte of interest from the first ESI by adding a dopant from the second ESI. Rather, they require :forming a mixture.” Further, the rejection does not propose enhancing the signal of the first ESI by adding dopant to the second ESI. Clearly the mechanism of Takkis is intended to enhance detection of analyte from the stream of the ESI to which the dopant is added. Applicant is arguing against a combination that was neither proposed nor claimed.
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.
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 1-9, 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over US 2006/0255261 A1 [Whitehouse] in view of Takkis, Kalev, et al. "A sensitive method for the simultaneous UHPLC-MS/MS analysis of milrinone and dobutamine in blood plasma using NH4F as the eluent additive and ascorbic acid as a stabilizer." Clinical Mass Spectrometry 12 (2019): 23-29 [hereinafter Takkis].
Regarding Claim 1:
Whitehouse teaches a method for determining the presence or the level of an analyte of interest in a sample (para 2) comprising the following steps:
a) providing a first electrospray ionization source for a first analytical flow stream comprising the analyte of interest (Fig. 6 (185), para 67),
b) providing a second electrospray ionization source for a second analytical flow stream, wherein each of the first analytical flow stream and the second analytical flow stream is comprised in gaseous form or aerosol (Fig. 6 (186, 187), para 67),
c) intermixing the first and the second analytical flow stream for forming a mixture (Fig. 6 (188)), wherein the mixture comprises the analyte of interest (para 67), and
d) determining the presence or the level of an analyte of interest in the sample using mass spectrometry (para 75, claim 1).
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However, Whitehouse fails to teach that the second analytical flow stream comprises a dopand, or that the mixture comprises the dopand
Takkis teaches adding Ammonium Fluoride to a sample to provide significant MS signal enhancement. Section 1- last paragraph, Section 4.1. Furthermore, Takkis uses electrospray ionization per section 2.5, which is the same ionization technique used by Whitehouse and the instant application. Adding the Ammonium Fluoride of Takkis to one of the supplementary ESI streams of Whitehouse, i.e., the streams corresponding to (186) and (187), would result in said stream entering the mixing zone (188) of Whitehouse. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective time of filing to add the Ammonium Fluoride of Takkis to a supplementary stream of Whitehouse, thus achieving the above noted limitations. One would have been motivated to do so in order to provide enhanced signals at the MS.
Regarding Claim 2:
The above modified invention teaches the method of claim 1, wherein the method is performed for enhancing the mass spectrometric signal of the analyte of interest. Takkis Section 1- last paragraph, Section 4.1.
Regarding Claim 3:
The above modified invention teaches the method of claim 1, wherein the first analytical flow stream is intermixed with the second analytical flow stream after leaving the first and the second electrospray ionization source. Whitehouse Fig. 6 (188).
Regarding Claim 4:
The above modified invention teaches the method of claim 1, wherein the first electrospray ionization source and the second electrospray ionization source are arranged at least 10° to 180° according to a plan view over the two electrospray ionization sources and at least 10° to 180° according to a front view for the electrospray ionization sources.
Whitehouse Figs. 5 and 6 show the plans at issue. Furthermore, Whitehouse paras 67 amd 70 note that the ESI are angled to spray into a common mixing region. Optimizing such an angle to be within the claimed range is well within the bounds of normal experimentation. See MPEP 2144.05 II (A). “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to dis-cover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Furthermore, “[a] particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). In the case at hand, Whitehouse teaches that angles of the ESI probes need to be chosen such that their respective sprays reach the mixing zone. As such, Whitehouse identifies these angles as a variable which achieves a recognized result. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective time of filing to optimize the angles to meet the claims ranges since it is not inventive to dis-cover the optimum or workable ranges by routine experimentation.
Regarding Claim 5:
The above modified invention teaches the method of claim 1, wherein the dopand is DMSO or NH4F. Takkis - Ammonium Fluoride.
Regarding Claim 6:
The above modified invention teaches the method of claim 1, but fails to specify that the second flow stream comprises a concentration of the dopand or a concentration of the derivatization reagent in the range of 5 to 35% (v/v).
Optimizing the concentration of elements in the flow stream is well within the bounds of normal experimentation. See MPEP 2144.05 II (A). “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to dis-cover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Furthermore, “[a] particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). In the case at hand, Takkis teaches various concentrations depending upon experimental conditions. Sections 2.2., 2.4, 2.6. As such, Takkis identifies concentration as a result-effective variable which achieves the recognized result of adjusting signal. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective time of filing to optimize the concentration of the stream to meet the above limitation since it is not inventive to dis-cover the optimum or workable ranges by routine experimentation.
Regarding Claims 7-8 and 16-17:
The above modified invention teaches that a dopand is used, and as such also makes obvious the alternative embodiments discussed in claims 7-8 and 16-17.
Regarding Claim 9:
The above modified invention teaches the method of claim 1, wherein the analyte of interest is selected from the group consisting of nucleic acid, amino acid, peptide, protein, metabolite, hormones, fatty acid, lipid, carbohydrate, steroid, ketosteroid, secosteroid, a molecule characteristic of a certain modification of another molecule, a substance that has been internalized by the organism, a metabolite of such a substance and combination thereof. Whitehouse para 74, Takkis abstract.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over US 2006/0255261 A1 [Whitehouse] in view of Takkis, Kalev, et al. "A sensitive method for the simultaneous UHPLC-MS/MS analysis of milrinone and dobutamine in blood plasma using NH4F as the eluent additive and ascorbic acid as a stabilizer." Clinical Mass Spectrometry 12 (2019): 23-29 [hereinafter Takkis] as applied to claim 1, and further in view of US 2002/0146743 A1 [Chen].
Regarding Claim 18:
The above modified invention teaches the method of claim 1, wherein the analyte of interest is a peptide. Whitehouse para 74. However, the above modified invention does not specify that the peptide is exhibiting free —NH2 and/or —COOH groups.
Chen teaches a mass spectrometry method (claim 1) including determining the presence of C-terminus peptides. Para 5, et al. It would have been obvious to one of ordinary skill in the art before the effective time of filing to use the above modified invention to determine the presence or the level of a c-terminus peptide, or even of multiple c-termini peptides. This is simply because such peptides are well-known, and analyzing samples to determine the presence or the level of such peptides is a fundamental use of mass spectrometry.
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 WYATT A STOFFA whose telephone number is (571)270-1782. The examiner can normally be reached M-F 0700-1600 EST.
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WYATT STOFFA
Primary Examiner
Art Unit 2881
/WYATT A STOFFA/Primary Examiner, Art Unit 2881