DETAILED ACTION
The amendment filed on 05/26/2026 has been entered and fully considered. Claim 6-8 and 16-19 are canceled. Claims 1-5, 9-12 and 20-21 are pending, of which claim 1 and 11 are amended.
Response to Amendment
In response to amendment, the examiner modifies rejection over the prior art established in the previous 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 .
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 3-6, 9-12 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Joo et al. (Journal of Chromatography B, 2013) (Joo) in view of Maslov et al. (International Journal of Molecular Sciences, 2019, IDS) (Maslov) and Yan et al. (RSC Advances, 2015) (Yan).
Regarding claim 1, Joo teaches A method for determining the presence or level of an analyte of interest having a molar mass of smaller than 200 Da (valproic acid) in a sample (abstract), comprising the steps of
a) providing the sample comprising the analyte of interest, wherein the analyte of interest comprises a carboxylic acid group (page 36, par 6),
b) activating the analyte of interest by the addition of at least one activation reagent (TPP, DTTP) (page 36, par 6),
c) derivatizing the analyte of interest provided by step a) orb) with a nucleophilic derivatization reagent (PA) for forming a derivatized analyte of interest (Fig. 1, page 36, par 6), and
d) determining the presence or level of the derivatized analyte of interest in the sample using mass spectrometry (MS) (page 37, par 1).
Joo does not specifically teach that wherein the nucleophilic derivatization reagent is selected from the group consisting of propylamine, butylamine, or pentylamine. However, Maslov teaches alkylamines, including n-butylamine, to improve mass spectrometry detection of small metabolite analytes (page 3, par 2). Maslov teaches that “The use of n-butylamine showed the greatest superiority in global coverage of sample metabolomic composition in ESI(-) compared with other selected additives.” (page 3, par 2). It would have been obvious to one of ordinary skill in the art to select any of the closely-related primary alkylamines recited in Claim 7 to achieve the same predictable result taught by Maslov, in order to improve MS performance.
Joo does not specifically teach that wherein the at least one activation reagent is a first activation reagent and a second activation reagent,
wherein the first activation reagent is selected from the group consisting of NHydroxysuccinimid (OHSu), N-Hydroxysulfosuccinimide (sulfo-OSu), Hydroxybenzotriazole (HOBt) and salts of these compounds, and
wherein the second activation reagent is selected from the group consisting of Dicyclohexylcarbodiimid (DIC), l-Ethyl-3-(3-dimethylaminopropyl)carbodiimid (EDC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide, Cyclohexyl-N' -(2-morpholinoethyl )carbodiimide N,N'-Dicyclohexylcarbodiimide, Nmethyl-p-toluenesulfonate, 1,3-Bis( trimethylsilyl)carbodiimide and N,N' -Methanetetraylbis[ 4-methyl ]benzenamine.
However, Yan teaches EDC/NHS activation of carboxylic acids as a widely used approach to form amides. Yan teaches that ““Amide bond formation (or amidation) from carboxylic acid by carbodiimide activation with the assistance of additives such as NHS… is so broadly used… that it would be difficult to overstate its importance.” (page 69939, par 1). Yan further identifies EDC and NHS explicitly “Taking one of the most common activation recipes as an example, namely EDC and an additive of NHS with carboxylic acid…” (page 69939, par 1), and reiterates EDC/NHS activation “efficiently forms an amide with an amine…” (page 69939, par 1). Thus, Yan teaches the exact activation reagent pair recited in Claim 8. It would have been an obvious design choice to select any well-known activation reagent, such as EDC with NHS, to activate the carboxylic acid in Joo prior to amine coupling, because Yan teaches that EDC/NHS is among the most common activation systems for this exact transformation (page 69939, par 1).
Regarding claim 2, the Courts have held that to provide a mechanical or automatic means to replace manual activity, which accomplishes the same result, is within the ambit of a person of ordinary skill in the art. (See In re Venner, 120 USPQ 192 CCPA 1958) (see MPEP section 2144.04). Therefore, it would have been obvious to one of ordinary skill in the art to automate the procedure.
Nevertheless, Joo teaches autosampler (page 36, par 8) to automate the sampling process.
Regarding claim 3, Joo teaches that wherein the analyte of interest (VPA) has a molar mass of 150 Da or less (page 36, par 6).
Regarding claim 4, Joo teaches that wherein the analyte of interest is valproic acid (page 36, par 6).
Regarding claim 5, Joo teaches that wherein in step c) an amide of the derivatized analyte of interest is formed (Fig. 1).
Regarding claim 9, Joo teaches that wherein the analyte of interest is free of a nucleophilic functional group, which could react with the carboxylic acid group of the analyte of interest (abstract).
Regarding claim 10, Joo teaches that wherein the said method comprises an additional step:
e) enriching the sample (centrifuge and dry) (page 36, par 6).
Regarding claim 11, Joo teaches an analytical system adapted to perform the method of claim 1 (page 36, par 6, page 37, par 1),
wherein the analytical system comprises
a sample preparation station for the automated preparation of samples comprising analytes of interest (page 36, par 6);
a liquid chromatography (LC) separation station (page 36, par 8); and
a mass spectrometer (MS) (page 37, par 1).
Regarding claim 12, Joo teaches a sampling tube for collecting a patient sample comprising a nucleophilic derivatization reagent for forming a derivatized analyte of interest in a sample (page 36, par 6), wherein the one or more analytes of interest is a carboxylic acid having a molar mass of smaller than 200 Da (page 36, par 6).
The claim requires a sampling tube comprising a nucleophilic derivatization reagent, but does not require any particular timing by which the nucleophilic derivatization reagent is placed into the tube.
Regarding claim 21, Joo teaches that wherein the one or more analytes of interest is valproic acid or salicylic acid (page 36, par 6).
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Joo in view of Maslov and Yan as applied to claims 1, 3-6, 9-12 and 21 above, and further in view of Vondenhoff et al. (WO 2019/141779, IDS) (Vondenhoff).
Regarding claim 20, Joo does not teach that wherein in step e) the sample is enriched using magnetic beads. However, Vondenhoof teaches that the sample is enriched using magnetic beads (page 36, line 18-23). It would have been obvious to one of ordinary skill in the art to select magnetic beads for the enrichment of analytes, because the selection is based on its suitability for the intended use.
Response to Arguments
Applicant's arguments filed 05/26/2026 have been fully considered but they are not persuasive.
With respect to the rejection of claim 1 under 35 U.S.C. § 102 over Joo, Applicant argues that Joo does not disclose the newly recited nucleophilic derivatization reagent selected from propylamine, butylamine, or pentylamine, and does not disclose the newly recited activation reagent combination including a first activation reagent selected from OHSu, sulfo-OSu, HOBt, or salts thereof and a second activation reagent selected from the recited carbodiimide group. This argument is persuasive to the extent that Joo alone does not expressly disclose the newly added Markush groups. Accordingly, the anticipation rejection of claim 1 over Joo alone is withdrawn.
However, the amended claim remains unpatentable under 35 U.S.C. § 103 over Joo in view of Maslov and Yan.
Joo teaches the core method of determining the presence or level of a low molecular weight carboxylic acid analyte, valproic acid, in a biological sample by derivatizing the carboxylic acid with an amine reagent to form an amide derivative and detecting the derivative by UPLC-MS/MS. Joo therefore establishes that amine derivatization of valproic acid for MS detection was known.
Applicant argues that Maslov does not teach n-butylamine as a covalent derivatization reagent, but instead teaches n-butylamine only as an ionization additive (remark, page 12). This argument is not persuasive because the rejection does not rely on Maslov as teaching the entire derivatization reaction of claim 1. Rather, Maslov is relied upon for its teaching that n-butylamine is useful in MS analysis of low-molecular-weight metabolites and improves MS detection performance. One of ordinary skill in the art, starting from Joo’s amine-derivatization method and seeking to optimize MS detection of low molecular weight metabolites, would have found it obvious to use a closely related primary alkylamine such as butylamine as the amine reagent because such substitution involves selection among known amine reagents for the predictable purpose of modifying MS response and analytical performance.
Applicant further argues that Maslov teaches drawbacks of alkylamines due to MS source contamination (remark, page 12). This argument is not persuasive because a reference does not teach away merely by recognizing a manageable disadvantage. Maslov still teaches that n-butylamine is effective for improving MS analysis and further provides a decontamination procedure to address the contamination issue. Thus, Maslov would not have discouraged one of ordinary skill in the art from using n-butylamine; rather, it teaches both its benefit and a way to manage its known drawback.
Applicant also argues that Yan does not teach predictable EDC/NHS activation of small carboxylic acids and that Yan’s mechanistic discussion shows substrate-dependent behavior (remark, page 13). This argument is not persuasive. Yan expressly teaches that amide bond formation from carboxylic acid by carbodiimide activation with additives such as NHS is broadly used, and further identifies EDC/NHS activation as one of the most common activation recipes for converting carboxylic acids to activated intermediates that form amides with amines. Although Yan discusses mechanistic details and substrate-dependent intermediate formation, Yan still confirms that EDC/NHS activation is a known and commonly used activation system for carboxylic acid amidation. Obviousness does not require absolute predictability, only a reasonable expectation of success. In view of Joo’s successful amine derivatization of valproic acid and Yan’s teaching of common EDC/NHS carboxylic acid activation for amide formation, one of ordinary skill in the art would have had a reasonable expectation of success in using the recited carbodiimide/NHS-type activation system to activate a carboxylic acid analyte prior to reaction with an amine.
Applicant argues that Joo uses a TPP/DTTP activation system and that neither Joo nor Yan expressly suggests replacing it with EDC/NHS (remark, page 14). This argument is not persuasive. The obviousness inquiry is not limited to bodily incorporating one reference into another. Joo teaches the desirability of forming an amide derivative of valproic acid for MS detection. Yan teaches a well-known alternative activation chemistry for forming amides from carboxylic acids using EDC/NHS or related carbodiimide/additive systems. Substituting one known carboxylic acid activation system for another known carboxylic acid activation system to perform the same amide-forming function represents the use of a known technique to improve or modify a similar method and would have been within the ordinary skill in the art.
Applicant further argues that the Office’s position requires improper hindsight because the combination involves both replacing Joo’s 2-picolylamine with an alkylamine and replacing Joo’s TPP/DTTP activation system with a carbodiimide/NHS-type system (remark, page 15). This argument is not persuasive. The motivation is not derived from Applicant’s disclosure. Joo itself provides the reason to derivatize valproic acid with an amine for improved MS detection. Maslov provides the reason to use n-butylamine in MS analysis of low-molecular-weight metabolites. Yan provides the reason to use EDC/NHS-type activation for carboxylic acid amidation. The proposed combination therefore follows from the express teachings of the references and the ordinary goal of improving derivatization and MS detection of low molecular weight carboxylic acid analytes.
Finely, applicant argues that claim 12 requires a sampling tube containing the nucleophilic derivatization reagent at the time of sample collection, such that the derivatization reagent contacts the sample upon collection (remark, page 9-10). This argument is not persuasive.
Claim 12 does not recite that the nucleophilic derivatization reagent must be present in the sampling tube before or at the time of sample collection. Rather, claim 12 recites only “[a] sampling tube for collecting a patient sample comprising a nucleophilic derivatization reagent for forming a derivatized analyte of interest in a sample.” Thus, the claim requires a sampling tube comprising a nucleophilic derivatization reagent, but does not require any particular timing by which the nucleophilic derivatization reagent is placed into the tube.
Applicant’s reliance on the specification is not commensurate with the scope of the claim. Limitations from the specification, such as collecting a sample into a tube that already contains the reagent, cannot be imported into the claim where the claim language does not recite such a limitation.
Joo teaches adding 2-picolylamine, a nucleophilic derivatization reagent, to sample material during sample preparation for forming a derivatized analyte of interest. Joo further teaches that the derivatization reaction mixture is held in vials/tubes during the derivatization step. Therefore, Joo teaches a sample-containing vessel comprising a nucleophilic derivatization reagent for forming a derivatized analyte of interest in a sample, as broadly claimed.
Accordingly, Applicant’s argument is not persuasive, and the rejection of claim 12 is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797
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