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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/02/2026 has been entered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or
under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims priority of foreign application EUROPEAN PATENT OFFICE (EPO) 19209516.4 filed 11/15/2019. Based on the filing receipt, the effective filing date of this application is November 15, 2019 which is the filing date of foreign application EPO 19209516.4 from which the benefit of priority is claimed.
Information Disclosure Statement
The Information Disclosure Statement filed 03/03/2026 has been considered by the office.
Status of Claims
Claims 2-7, 11-15, 23 have been cancelled by the Applicant.
Claims 1, 8-10, and 16-22, and 24-27 are pending and examined herein.
Withdrawn Rejections
The rejection of claims 1-3, 6-10, and 17-27 on the grounds of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, has been withdrawn, necessitated by amendments filed 03/02/2026, which limit the invention to nucleophilic derivatization reagents reduced to practice, namely propylamine, butylamine, and pentylamine.
The rejection of claims 1, 4, 6, 8-10, 16-22, and 25-27 on the grounds of 35 U.S.C. 103 over Holthoon (cited below) and Fischer (cited below) has been withdrawn, necessitated by amendments filed 03/02/2026.
The rejection of claims 2-3 and 23-24 on the grounds of 35 U.S.C. 103 over Holthoon (cited below), Fischer (cited below), and Brans (cited below) has been withdrawn, necessitated by amendments filed 03/02/2026.
New prior art rejections, necessitated by amendments filed 03/02/2026, are discussed below.
The double patenting rejections below have been modified, necessitated by amendments filed 03/02/2026.
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.
Claims 1, 8-10, 16-22, and 24-27 are rejected under 35 U.S.C. 103 as being unpatentable over Holthoon, et al. (“Quantitative analysis of penicillins in porcine tissues, milk and animal feed using derivatisation with piperidine and stable isotope dilution liquid chromatography tandem mass spectrometry”, published 2010-02-26, cited in PTO-892 dated 05/21/2025) in view of Fischer, et al. (“Automated Enrichment of Sulfanilamide in Milk Matrices by Utilization of Aptamer-Linked Magnetic Particles”, published 2016-11-09, cited in PTO-892 dated 11/28/2025) and Brans (US 20140243241 A1, published 2014-08-28, cited in PTO-892 dated 05/21/2025) as evidenced by the National Center for Biotechnology Information (PubChem Compound Summary for CID 8007, Butylamine, https://pubchem.ncbi.nlm.nih.gov/compound/Butylamine, cited in PTO-892 dated 05/21/2025).
Holthoon teaches a method of determining the amount or concentration of a derivatized antibiotic analyte in an obtained sample comprising pre-treating the sample with a nucleophilic derivatization reagent, wherein the nucleophilic derivatization reagent comprises an amine group; and determining the amount or concentration of the one or more antibiotic analytes in the sample by using LC/MS, wherein the one or more antibiotic analytes are derivatized with a nucleophilic derivatization reagent to stabilize the antibiotic analyte, as in claim 1 (see, e.g., determining amount or concentration of a derivatized antibiotic analyte by LC/MS – p. 3027, col. 1, under “Abstract”: “The penicillin piperidine derivatives were determined by LC–MS/MS”; derivatized with a nucleophilic derivatization reagent to stabilize the antibiotic analyte – p. 3029, col. 1, under “Introduction”: “In this study, the use of piperidine (PIP) to stabilise penicillin residues in matrix by the formation of penicillin–piperidine derivatives is presented”). Holthoon teaches the sample is pre-treated with a nucleophilic derivatization reagent, specifically piperidine, after the sample is obtained, as in claims 8 and 25 (see, e.g., p. 3031, col. 1, under “Sample preparation: milk”). While Holthoon does not explicitly state that the sample is pre-treated “immediately” after the sample is obtained, it would have been obvious to an artisan of ordinary skill before the claimed invention was filed to have immediately pre-treated the sample because Holthoon recites, “To prevent degradation of penicillin residues during workup, a derivatization procedure was developed, by which penicillins were converted to stable piperidine derivatives”, which means the pre-treatment needs to be executed as soon as possible to maximize the benefit of the pre-treatment (see, e.g., p. 3027, col. 1, under “Abstract”). Holthoon teaches the sample obtained after the pre-treatment step comprises antibiotic analytes derivatized with the nucleophilic derivatization reagent, as in claims 9 and 26 (see, e.g., p. 3027, col. 1, under “Abstract”: Penicillin residues were derivatised in the crude extract with piperidine and isolated using solid-phase extraction. The penicillin piperidine derivatives were determined by LC–MS/MS”). Holthoon teaches the sample is pre-treated with a nucleophilic derivatization reagent after the sample is obtained, as in claim 17 (see, e.g., p. 3031, col. 1, under “Sample preparation: milk”). The examiner understands that it would be obvious to complete the method used to pre-treat the milk sample in less than 10 minutes, as in claim 17, because Holthoon recites, “To prevent degradation of penicillin residues during workup, a derivatization procedure was developed, by which penicillins were converted to stable piperidine derivatives”, which means the pre-treatment needs to be executed as soon as possible to maximize the benefit of the pre-treatment (see, e.g., p. 3027, col. 1, under “Abstract”). Holthoon teaches the nucleophilic derivatization reagent prevents hydrolyzation of the antibiotic during determining step b) of claim 1, as in claim 18 (see, e.g., p. 3027, col. 1, under “Abstract”). Holthoon teaches the nucleophilic derivatization reagent prevents hydrolyzation of the antibiotic during determining step c) of claim 1, as in claim 19 (see, e.g., p. 3027, col. 1, under “Abstract”). Holthoon teaches the nucleophilic derivatization reagent stabilizes the antibiotic by forming a covalent adduct of the antibiotic analyte and the nucleophilic derivatization reagent, as in claims 20 and 21 (see, e.g., stabilizes the antibiotic - p. 3027, col. 1, under “Abstract”; covalent adduct of antibiotic analyte and the nucleophilic derivatization reagent – p. 3032, col. 2, under “Synthesis of penicillin–piperidine derivatives”: “the corresponding piperidine derivative was formed by addition to the β-lactam carbonyl group”). Holthoon teaches the nucleophilic derivatization reagent stabilizes the antibiotic for more than 2 hours, as in claim 22 (see, e.g., p. 3029, col. 2, under “Synthesis of penicillin–piperidine derivatives”: “The derivatised penicillins were stable for 1 year when kept at −20 °C”). Holthoon teaches the nucleophilic derivatization reagent prevents hydrolyzation of the antibiotic during determining step c) of claim 1, as in claim 24 (see, e.g., p. 3027, col. 1, under “Abstract”).
Holthoon fails to teach enriching the sample with an enrichment workflow by the addition of magnetic beads carrying analyte-selective groups to the pretreated sample, as in claims 1, 10, and 27.
However, in a journal article on antibiotic enrichment utilizing magnetic particles, Fischer rectifies this deficiency. Fischer teaches the enrichment of antibiotic analytes by utilizing analyte-selective magnetic beads, as in claims 1, 10, and 27 (see, e.g., antibiotic analyte – p. 9246, under “ABSTRACT:”; enrichment utilizing analyte-selective magnetic beads - p. 9248, under “Figure 1.”).
Holthoon and Fischer teach as set forth above, but these references fail to teach measuring piperacillin and meropenem, as in claim 1.
However, Brans teaches the examples of beta-lactam antibiotics to be measured include penicillin G, nafcillin, cloxacillin, dicloxacillin, piperacillin, and meropenem, as in 1 (see, e.g., p. 3, col. 2, para. [0058]).
Holthoon and Fischer are analogous to the field of the claimed invention because they are both in the field of antibiotic detection. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the antibiotic enrichment of Fischer into the method of Holthoon. An artisan would have been motivated to do so because Fischer discloses that “[t]o analyze low-abundant residues or contaminants, in most cases a cleanup or enrichment is necessary” (see p. 9246, col. 1, under “Introduction”, para. 1). Fischer further discloses that by using their enrichment method, “[e]nrichment factors up to 8-fold could be achieved” (see p. 9246, under “ABSTRACT:”). The artisan would have a reasonable expectation of success based on the given disclosures.
While Holthoon does not explicitly teach derivatizing and measuring piperacillin or meropenem, it would have been prima facie obvious to the person of ordinary skill in the art to make and use the claimed invention from the disclosures of Holthoon, Fischer, and Brans. Holthoon teaches testing eight species of penicillin by derivatizing the penicillin with a nucleophilic derivatization reagent (see, e.g., p. 3036, under “Table 3”). Holthoon discloses, “For the penicillins studied, a single compound was produced in high yield. In all cases, the corresponding piperidine derivative was formed by addition to the ß-lactam carbonyl group, followed by ring opening” (see, e.g., p. 3032, col. 2, para.1). Using piperacillin, a species of penicillin, or meropenem in the method of Holthoon as modified by Fischer would have been considered a simple substitution of equivalent elements as Holthoon and Fischer teach measuring penicillins, which are beta-lactam antibiotics and Brans teaches that piperacillin and meropenem are also species of beta-lactam antibiotics (see, e.g., Brans, para. [0058]). As is stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)." The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Holthoon also fails to explicitly teach the nucleophilic derivatization reagent is primary linear butylamine, as in claims 1 and 16. However, Holthoon teaches “Penicillins do not only react quickly with piperidine but also with other primary (e.g., methylamine, aminoethanol) and secondary amines” (see p. 3032, col. 2, under “Method development”, para. 1). The National Center for Biotechnology Information discloses that primary linear butylamine, as in claims 1 and 16, is a primary amine (see, e.g., p. 2, under “Description”: “Butan-1-amine [a.k.a. butylamine] is a primary aliphatic amine that is Butane substituted by an amino group at position 1”).
It would have been prima facie obvious to the person of ordinary skill in the art to make and use the claimed invention from the disclosures of Holthoon, Fischer, and Brans. Such would have been considered a simple substitution of equivalent elements as Holthoon teaches, “Penicillins do not only react quickly with piperidine but also with other primary (e.g., methylamine, aminoethanol) and secondary amines” (see, p. 3032, col. 2, under “Method development”), and butylamine is another species of primary amine as evidenced by the National Center for Biotechnology Information. As is stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)." The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of this prior art reference.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 8-10, 16-22, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 18, 19, 21, and 22 of copending Application No. 17/745,367 (referred to as ‘367 going forward). Although the claims at issue are not identical, they are not patentably distinct from each other because they are rendered obvious in view of Holthoon (cited above) and Fischer (cited above). The rejection of claims 1, 8-10, 16-22, and 24 on the grounds of nonstatutory double patenting as being unpatentable over claims 15, 18, 19, 21, and 22 of copending Application No. 17/745,367 is modified, necessitated by amendment filed 03/02/2026.
‘367 teaches a method of producing a stabilized antibiotic derivative by derivatizing with a nucleophilic derivatization reagent comprising a primary amine group, as in claims 1, 8, 9, 17-21, and 25-26 (see, e.g., claim 15 of ‘367). The examiner understands that the disclosure of ‘367, particularly claims 15 and 19 of ‘367, would lead an artisan of ordinary skill to understand that the antibiotic should be immediately treated with the nucleophilic derivatization reagent because the treatment stabilizes the antibiotic, which means the treatment needs to be executed as soon as possible to maximize the benefit of the treatment. ’367 teaches that a stabilized antibiotic derivative will not undergo hydrolysis, as in claims 18, 19, and 24 (see, e.g., claim 21 of ‘367). ’367 also teaches the antibiotic is Meropenem or Piperacillin, as in claim 1 (see, e.g., claim 18 of ‘367). ‘367 also defines the nucleophilic derivatization reagent to be a primary linear butylamine, as in claims 1 and 16 (see, e.g., Specification of ‘367, p. 13, para. 1). ‘367 teaches the antibiotic is stabilized for more than 2 hours, as in claim 22 (see, e.g., claim 22 of ‘367).
‘367 fails to teach a method for measuring derivatized antibiotic analytes in an obtained sample by pretreating the sample with magnetic beads and measuring the analytes with an immunological assay, as in claim 1. ‘367 fails to teach an enrichment step comprising at least one enrichment workflow, as in claims 10 and 27.
However, Holthoon rectifies the deficiency of ‘367 regarding measuring the antibiotic analyte in a journal article on measuring antibiotics in a sample. Holthoon teaches a method of determining the amount or concentration of a derivatized antibiotic analyte in an obtained sample comprising pre-treating the sample with a nucleophilic derivatization reagent, wherein the nucleophilic derivatization reagent comprises a primary amine group; and determining the amount or concentration of the one or more antibiotic analytes in the sample by using LC/MS, wherein the one or more antibiotic analytes are derivatized with a nucleophilic derivatization reagent to stabilize the antibiotic analyte, as in claim 1 (see, e.g., determining amount or concentration of a derivatized antibiotic analyte by LC/MS – p. 3027, col. 1, under “Abstract”: “The penicillin piperidine derivatives were determined by LC–MS/MS”; the nucleophilic derivatization reagent comprises a primary amine group – p. 3032, col. 2, under “Method development”: “Penicillins do not only react quickly with piperidine but also with other primary (e.g., methylamine, aminoethanol) and secondary amines”; derivatized with a nucleophilic derivatization reagent to stabilize the antibiotic analyte – p. 3029, col. 1, under “Introduction”: “In this study, the use of piperidine (PIP) to stabilise penicillin residues in matrix by the formation of penicillin–piperidine derivatives is presented”).
Also, in a journal article on antibiotic enrichment utilizing magnetic particles, Fischer rectifies the deficiency of ‘367 regarding enriching the antibiotic analyte. Fischer teaches the enrichment of antibiotic analytes by utilizing analyte-selective magnetic beads, as in claims 1, 10, and 27 (see, e.g., antibiotic analyte – p. 9246, under “ABSTRACT:”; enrichment utilizing analyte-selective magnetic beads - p. 9248, under “Figure 1.”).
‘367, Holthoon, and Fischer are analogous to the field of the claimed invention because they are both in the field of antibiotic detection. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the antibiotic enrichment of Fischer and measurement method of Holthoon into ‘367. An artisan would have been motivated to do so because Fischer discloses that “[t]o analyze low-abundant residues or contaminants, in most cases a cleanup or enrichment is necessary” (see p. 9246, col. 1, under “Introduction”, para. 1). Fischer further discloses that by using their enrichment method, “[e]nrichment factors up to 8-fold could be achieved” (see p. 9246, under “ABSTRACT:”). The artisan would have a reasonable expectation of success based on the given disclosures.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 9, 10 and 16 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 19, and 20 of copending Application No. 18/312,442 (referred to as ‘442 going forward). Although the claims at issue are not identical, they are not patentably distinct from each other because an artisan would have seen how the analytes defined in the specification of ‘442 would be incorporated into the claims of ‘442. The rejection of claims 1, 9, 10 and 16 on the grounds of nonstatutory double patenting as being unpatentable over claims 1, 10, 19, and 20 of copending Application No. 18/312,442 is modified, necessitated by amendment filed 03/02/2026.
‘442 teaches a method for determining the presence or level of an analyte of interest having a molar mass of smaller than 200 Da in a sample comprising the steps of derivatizing the analyte of interest with a nucleophilic derivatization reagent for forming a derivatized analyte of interest, and determining the presence or level of the derivatized analyte of interest in the sample using immunological assay or mass spectrometry (MS), and enriching the sample using magnetic beads, as in claims 1, 9, and 10 (see, e.g., claims 1, 10, and 20 of ‘442). The specification of ‘442 defines the analyte of interest as an antibiotic analyte, as in claims 1 (see, e.g., Specification of ‘442, p. 18, para. 5). ’442 teaches the nucleophilic derivatization reagent comprises primary linear butylamine, as in claims 1 and 16 (see, e.g., claim 19 of ‘442).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 23 and 27 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 19, and 20 of ‘442, as applied to claims 1, 4, 9, 10 and 16 above. Although the claims at issue are not identical, they are not patentably distinct from each other because they are rendered obvious in view of Brans (cited above). The rejection of claims 23 and 27 on the grounds of nonstatutory double patenting as being unpatentable over claims 1, 10, 19, and 20 of ‘442 in view of Brans is modified, necessitated by amendment filed 03/02/2026.
’442 teaches the enrichment workflow of claim 27 (see, e.g., claims 10 and 20 of ‘442). However, ‘442 fails to teach measuring the β-lactam antibiotics, piperacillin and meropenem, as in claim 23. However, Brans rectifies this deficiency in a patent on a method for measuring beta-lactam antibiotics (see, e.g., cover page, title). Bran teaches the examples of beta-lactam antibiotics to be measured include piperacillin and meropenem, as in claim 23 (see, e.g., p. 3, col. 2, para. [0058]).
It would have been prima facie obvious to the person of ordinary skill in the art to make and use the claimed invention from the disclosures of ‘442 and Brans. Such would have been considered a simple substitution of equivalent elements as ‘442 teaches measuring antibiotics, in general, and Brans teaches that piperacillin and meropenem are examples of antibiotics, specifically, β-lactam antibiotics. As stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)." The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these references.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 8, 17-22, and 24-26 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 19, and 20 of ‘442, as applied to claims 1, 9, 10, and 16 above. Although the claims at issue are not identical, they are not patentably distinct from each other because they are rendered obvious in view of Holthoon, et al. (cited above) as evidenced by Ashenhurst (cited above). The rejection of claims 8, 17-22, and 24-26 on the grounds of nonstatutory double patenting as being unpatentable over claims 1, 10, 19, and 20 of ‘442 in view of Holthoon and Ashenhurst is modified, necessitated by amendment filed 03/06/2026.
‘442 teaches as set forth above, but fails to teach the sample is pre-treated with a nucleophilic derivatization reagent immediately after the sample is obtained, as in claims 8 and 25. ‘442 fails to teach the sample is pre-treated with a nucleophilic derivatization reagent within less than 10 minutes after the sample is obtained, as in claim 17. ‘442 fails to teach the nucleophilic derivatization reagent prevents hydrolyzation of the antibiotic during determining step b) of claim 1, as in claims 18 and 24. ‘442 fails to teach the nucleophilic derivatization reagent prevents hydrolyzation of the antibiotic during determining step c) of claim 1, as in claim 19. ‘442 fails to teach the nucleophilic derivatization reagent stabilizes the antibiotic by forming a covalent adduct of the antibiotic analyte and the nucleophilic derivatization reagent, as in claims 20, 21, and 26. ‘442 fails to teach the nucleophilic derivatization reagent stabilizes the antibiotic for more than 2 hours, as in claim 22.
Holthoon rectifies these deficiencies in a journal article that utilizes antibiotic derivatives for analysis of antibiotics in samples (see, e.g., p. 3027, col. 1, under “Abstract”). Holthoon teaches the sample is pre-treated with a nucleophilic derivatization reagent, specifically piperidine, after the sample is obtained, as in claims 8 and 25 (see, e.g., p. 3031, col. 1, under “Sample preparation: milk”). The instant specification discloses that nucleophilic derivatization reagents are reagents comprising a nucleophile, which is a chemical species that donates an electron pair to form a chemical bond (see, e.g., p. 18, lines 17-22). Piperidine is a nucleophile as evidenced by Ashenhurst (see, e.g., p. 14, para. 1). While Holthoon does not explicitly state that the sample is pre-treated “immediately” after the sample is obtained, it would have been obvious to an artisan of ordinary skill before the claimed invention was filed to have immediately pre-treated the sample because Holthoon recites, “To prevent degradation of penicillin residues during workup, a derivatization procedure was developed, by which penicillins were converted to stable piperidine derivatives“, which means the pre-treatment needs to be executed as soon as possible to maximize the benefit of the pre-treatment (see, e.g., p. 3027, col. 1, under “Abstract”). Holthoon teaches the sample is pre-treated with a nucleophilic derivatization reagent after the sample is obtained, as in claim 17 (see, e.g., p. 3031, col. 1, under “Sample preparation: milk”). The examiner understands that it would be obvious to complete the method used to pre-treat the milk sample in less than 10 minutes, as in claim 17. Holthoon teaches the nucleophilic derivatization reagent prevents hydrolyzation of the antibiotic during determining step b) of claim 1, as in claims 18 and 24 (see, e.g., p. 3027, col. 1, under “Abstract”). Holthoon teaches the nucleophilic derivatization reagent prevents hydrolyzation of the antibiotic during determining step c) of claim 1, as in claim 19 (see, e.g., p. 3027, col. 1, under “Abstract”). Holthoon teaches the nucleophilic derivatization reagent stabilizes the antibiotic by forming a covalent adduct of the antibiotic analyte and the nucleophilic derivatization reagent, as in claims 20, 21, and 26 (see, e.g., stabilizes the antibiotic - p. 3027, col. 1, under “Abstract”; covalent adduct of antibiotic analyte and the nucleophilic derivatization reagent – p. 3032, col. 2, under “Synthesis of penicillin–piperidine derivatives”: “the corresponding piperidine derivative was formed by addition to the β-lactam carbonyl group”). Holthoon teaches the nucleophilic derivatization reagent stabilizes the antibiotic for more than 2 hours, as in claim 22 (see, e.g., p. 3029, col. 2, under “Synthesis of penicillin–piperidine derivatives”: “The derivatised penicillins were stable for 1 year when kept at −20 °C”).
‘442 and Holthoon are analogous to the field of the claimed invention because they are both in the field of biochemistry. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to substitute the nucleophilic derivatization reagent of ‘442 with the nucleophilic derivatization reagent of Holthoon. The artisan would have been motivated to substitute these reagents “to prevent degradation of penicillin residues during workup” (see, e.g., p. 3027, col. 1, under “Abstract”). An artisan would have had reasonable expectation of success considering the cumulative disclosure of these references.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The applicant’s arguments, filed 03/02/2026, have been considered but have been found not persuasive for the reasons discussed below.
Claim Rejections – 35 U.S.C. 112
The applicant’s arguments regarding 35 U.S.C. 112(a), filed 03/02/2026, have been considered and have been found persuasive for the reasons discussed below, due to amendments filed 03/02/2026.
The applicant argues the following:
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The office agrees with the assertion and has withdrawn the 35 U.S.C. 112(a) rejection, necessitated by amendments filed 03/02/2026.
Claim Rejections – 35 U.S.C. 103
While the applicant’s arguments regarding the 35 U.S.C. 103 rejections of claims 1-4, 6, 8-10, and 16-27 have been considered, they are either moot due to claim amendments filed 03/02/2026 or unpersuasive for reasons discussed below.
The applicant argues on p. 8-9 of the remarks filed 03/02/2026:
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While Holthoon does not explicitly state that the derivatizing reagent is a primary amine, Holthoon discloses, “Penicillins do not only react quickly with piperidine but also with other primary (e.g., methylamine, aminoethanol) and secondary amines” (see, p. 3032, col. 2, under “Method development”). In the context of Holthoon’s disclosure, a person of ordinary skill in the art would understand that primary amines would function well as derivatization reagents.
The applicant argues, without evidence, that a person of ordinary skill in the art would not expect the longer-chain primary amines to behave in the same manner as methylamine. However, Holthoon’s disclosure would lead an artisan to have a reasonable expectation of success. Firstly, Holthoon’s discloses that that primary amines in general react quickly with penicillins and names methylamine and aminoethanol as examples of primary amines. Also, while the longer alkyl chain affects the nucleophilicity of primary linear amines, methylamine, propylamine, butylamine, and pentylamine are all primary amines that an artisan would reasonably expect to react with penicillins due to the disclosure of Holthoon and the nucleophilicity of all primary amines. For the Simple Substitution of One Known Element for Another To Obtain Predictable Results rationale to be used, the Office personnel must articulate: “a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable”. See MPEP 2143. The results of the substitution of one primary amine for another would have been predictable.
The applicant continues on p. 9 of the remarks:
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While the results of Figures 6 and 7 of the applicant’s specification may be materially different, the results do not undermine the office’s simple substitution rationale. As discussed above, for the Simple Substitution of One Known Element for Another To Obtain Predictable Results rationale to be used, the Office personnel must articulate: “a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable”. See MPEP 2143. The results of the substitution do not have to be equivalent, only predictable. Nothing about the results of Figures 6 and 7 suggest unpredictability regarding the substitution of primary amines when considering the disclosure of Holthoon (cited above), Fischer (cited above), and Brans (cited above) as evidenced by the National Center for Biotechnology Information (cited above). Figure 6 shows the measured peak-areas of meropenem derivatized with propylamine, butylamine, and pentylamine under different reaction conditions. Although under optimal conditions meropenem derivatized with butylamine gives the highest peak-area compared to the pentylamine and propylamine counterparts, the optimal reaction conditions for meropenem derivatized with propylamine produces measured peak areas that are only slightly lower. Furthermore, the optimal reaction conditions for meropenem derivatized with pentylamine and propylamine produce peak-areas that are orders of magnitude higher than the worst performing conditions for butylamine derivatized meropenem. Figure 7 shows the measured peak-areas of piperacillin derivatized with propylamine, butylamine, and pentylamine under different reaction conditions. Although under optimal conditions pentylamine gives the highest peak-area compared to butylamine and propylamine, the optimal conditions for meropenem derivatized with butylamine and propylamine produce peak-areas that are orders of magnitude higher than the worst performing conditions for pentylamine derivatized piperacillin. Figures 6 and 7 provides evidence that piperacillin and meropenem are effectively derivatized by all three of propylamine, butylamine, and pentylamine under optimal conditions, albeit to different extents depending on the reaction conditions.
The applicant continues arguments on p. 9-10 of the remarks:
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Emphasis added.
The applicant quotes Holthoon’s disclosure that cephalosporins are not suited to the methods of Holthoon. Holthoon’s discloses, “The derivatisation with piperidine was also tested on the other important group of ß-lactam antibiotics, the cephalosporins” (see, p. 3039, col. 1, para. 3). Holthoon is not discussing β-lactam antibiotics broadly; Holthoon discusses cephalosporins and clavulanate specifically. In any case, piperacillin is a penicillin and meropenem is a carbapenem, neither are cephalosporins. Holthoon is describing the reaction of penicillins with piperidine (a secondary amine) as straightforward. Because piperacillin is a penicillin, a person of ordinary skill in the art would have had a reasonable expectation that piperacillin would react with primary amines in a similar manner as the penicillins tested by Holthoon.
The applicant continues arguments on p. 11 of the remarks filed 03/02/2026:
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Emphasis added.
The double derivatization is not a limitation of the claimed invention. The scope of the claims covers all derivatizations. Holthoon’s disclosure of derivatization at the β-lactam carbonyl group would have led a person of ordinary skill in the art to expect β-lactam antibiotics to be compatible with derivatization with nucleophiles, like primary and secondary amines, because of the shared β-lactam ring.
The applicant continues arguments on p. 12 of the remarks filed 03/02/2026:
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Holthoon does not express that its result may not be transferable to other β-lactam antibiotics. Holthoon, as discussed above, specifically discloses that experiments clavulanate and cephalosporins have not thus far proved successful. Also, the deviations among tested penicillins by Holthoon do not negate the fact-pattern of successful derivatization of the tested penicillins by Holthoon. While a person of ordinary skill in the art would not know which of the β-lactams from Brans’ list to select, that artisan would have understood that they are all β-lactam and the results from derivatizing the listed β-lactams with primary amines would be predictable, given their shared β-lactam ring.
The applicant continues arguments on p. 12 of the remarks filed 03/02/2026:
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The office agrees that Fischer does not disclose the derivatization reagent and antibiotic analytes of the claimed invention. Fischer is cited to rectify Holthoon’s deficiencies regarding an enrichment workflow.
The applicant continues arguments on p. 13 of the remarks filed 03/02/2026:
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The applicant argues that a person of ordinary skill in the art would have had no reasonable expectation of success when considering using the technique of Holthoon on piperacillin or meropenem using butylamine, pentylamine, or propylamine. However, a person of ordinary skill in the art would have had an understanding based on the state of the art, including the disclosure of Holthoon and Brans, that primary amines, such as butylamine, pentylamine, and propylamine, react quickly with the β-lactam ring of penicillins (see, e.g., Holthoon, p. 3032, col. 2, para. 1, and p. 3032, col. 2, under “Method development”, para. 1). A person of ordinary skill in the art would have had expected the results of derivatizing other penicillins, such as piperacillin, or β-lactam antibiotics more broadly, such as meropenem, with primary amines, such as butylamine, pentylamine, and propylamine, to be predictable. In addition, the deviations in results of penicillins tested by Holthoon is not evidence of unpredictable results regarding derivatization of penicillins and other β-lactam antibiotics. Again, the longer alkyl-chain of butylamine, propylamine, and pentylamine compared to methylamine would not have led a person of ordinary skill in the art to consider the reagents incompatible with derivatizing β-lactam antibiotics because all of the listed primary amines will remain nucleophilic. Also, Holthoon disclosed that primary amines generally react quickly with penicillins, and they only gave methylamine as one example of a primary amine.
The applicant continues arguments on p. 13-14 of the remarks filed 03/02/2026:
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Emphasis added.
The applicant’s arguments that the derivatized piperacillin is more stable than the native piperacillin is not an unexpected result, in view of Holthoon’s disclosure: “The derivatised penicillins were stable for 1 year when kept at −20 °C” (see, e.g., p. 3029, col. 2, under “Synthesis of penicillin–piperidine derivatives”).
The applicant continues arguments by stating that a person of ordinary skill in the art would not have predicted that no residual native compound is found in the eluate, showing that the derivatization reaction is quantitative, and that the addition of the nucleophile does not catalyze hydrolyzation. However, only the quantitative component of the above assertion is relevant to the scope of the claimed invention and Holthoon’s disclosure is also quantitative, therefore, that result is predictable.
Again, while the results of Figures 6 and 7 of the applicant’s specification may be materially different, the results do not undermine the office’s simple substitution rationale. As discussed above, for the Simple Substitution of One Known Element for Another To Obtain Predictable Results rationale to be used, the Office personnel must articulate: “a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable”. See MPEP 2143. The results of the substitution do not have to be equivalent, only predictable. Nothing about the results of Figures 6 and 7 show unpredictability regarding the substitution of derivatization reagents or antibiotic analytes, when considering the disclosure of Holthoon (cited above), Fischer (cited above), and Brans (cited above) as evidenced by the National Center for Biotechnology Information (cited above). Figure 6 shows the measured peak-areas of meropenem derivatized with propylamine, butylamine, and pentylamine under different reaction conditions. Although under optimal conditions meropenem derivatized with butylamine gives the highest peak-area compared to the pentylamine and propylamine counterparts, the optimal reaction conditions for meropenem derivatized with propylamine produces a measured peak-area that is only slightly lower. Furthermore, the optimal reaction conditions for meropenem derivatized with pentylamine and propylamine produce peak-areas that are orders of magnitude higher than the worst performing conditions for butylamine derivatized meropenem. Figure 7 shows the measured peak-areas of piperacillin derivatized with propylamine, butylamine, and pentylamine under different reaction conditions. Although under optimal conditions pentylamine gives the highest peak-area compared to butylamine and propylamine, the optimal conditions for meropenem derivatized with butylamine and propylamine produce peak-areas that are orders of magnitude higher than the worst performing conditions for pentylamine derivatized piperacillin. Figures 6 and 7 provides evidence that piperacillin and meropenem are effectively derivatized by all three of propylamine, butylamine, and pentylamine under optimal conditions, albeit to different extents depending on the reaction conditions. A similar fact pattern holds comparing the results between Figure 6 and Figure 7. While the optimal reagent and reaction conditions produce peak-areas of approximately 2E7 and 3E6 for meropenem derivatized with butylamine and piperacillin derivatized with pentylamine, respectively, many reaction conditions for piperacillin derivatized with butylamine produce higher measured peak-areas than some of the less-than-optimal reaction conditions for meropenem derivatized with butylamine. The difference in measured peak-areas offered as alleged evidence of unexpected results are highly affected by the reaction conditions (i.e., specific amounts of reagents, temperature, etc.) that are not commensurate in scope with the claims. See MPEP 716.02(d).
For all of the reasons discussed above, the arguments of the applicant are found unpersuasive.
Double Patenting
The applicant states that they will consider the filing of a terminal disclaimer upon indication that the claims are otherwise in condition for allowance. Because a terminal disclaimer has not been filed at this time, the claims stand rejected on grounds of obviousness-type double patenting.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The National Center for Biotechnology Information (PubChem Compound Summary for CID 8007, Butylamine, https://pubchem.ncbi.nlm.nih.gov/compound/Butylamine) discloses that butylamine is equivalent to primary linear butylamine. Ashenhurst (“Nucleophilicity of Amines”) discloses that piperidine is a nucleophile. The section on Amine Function Group from chemistrysteps.com (https://www.chemistrysteps.com/amine-functional-group/), which recites “The amine functional group is a fundamental building block in both organic and biological chemistry. The lone pair of electrons on the nitrogen atom makes amines basic, nucleophilic, and highly versatile, allowing them to participate in a wide range of reactions” (see p. 21, under “Summary of Amines”).
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/MICHAEL CAMERON SVEIVEN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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