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 .
Priority
Applicant’s claim for the benefit of a prior-filed application (has PRO 63414437, filed on October 07, 2022) under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6-10, 12-13, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over EPA Method 8327 (Per-and Polyfluoroalkyl Substances (PFAS) by Liquid Chromatography/Tandem Mass Spectrometry (LC/MS/MS), 2021, hereinafter EPA) in view of ZELECHONOK (US11307181B1).
Regarding Claim 1, EPA discloses a method for analyzing per- and polyfluoroalkyl substances (PFAS) using a liquid chromatography/tandem mass spectrometry (LC/MS/MS) system (Title, §1.1).
In particular, precautionary measures are employed to minimize problems with measurement precision and bias, including using LC/MS-grade solvents, verifying supplies/reagents and LC-system materials to reduce PFAS contamination, using appropriate containers to avoid analyte loss, placing an isolator column upstream of the sample injection valve to delay contaminants to the analytical column, and following labware cleaning to minimize carryover (§4.3; §4.3.1–§4.3.6).
Consistent with these contamination-control measures, the equipment includes a liquid chromatograph (LC) system described as a UPLC, analytical LC columns including phenyl-hexyl and C18 reversed-phase columns, isolator columns specified as C18 columns, and a tandem mass spectrometry (MS/MS) detector capable of MS/MS analysis, including an example triple quadrupole mass spectrometer with an electrospray ionization source (§6.0–§6.1).
Samples and standards are analyzed under the same LC/MS/MS conditions, including injection volume, consistent with introducing a liquid sample via an injection device (§11.3.2; §11.5.1). Target analytes are qualitatively identified by comparing primary and secondary product ion responses to standards and by comparing retention time in a sample to the isotopically labeled surrogate in the same sample and/or to the target analyte in standards (§11.6). Once a target compound has been identified, the compound is quantified based on the integrated abundance of the primary product ion unless interference problems are observed (§11.7).
However, EPA does not explicitly disclose “the isolator column comprises a stationary phase material comprising a mixed mode with anion exchange surface chemistry.”
ZELECHONOK discloses a high-pressure liquid chromatography system using multiple mixed-mode columns connected to a switching valve (Col. 1, Lns. 30–33).
The high-pressure liquid chromatography system avoids interference from contaminants by initially passing mobile phase containing unwanted material through the first-dimension column as a cleaning column before the second-dimension analytical column. The mixed-mode columns have reverse phase and ion-exchange characteristics to combine sample cleaning and analyte separation in one automated process (Col. 2, Lns. 7–43).
FIG. 1 is a schematic representation of a stationary phase with a ligand structure that performs as mixed-mode chromatography material with anion exchange properties (Col. 2, Lns. 65–67). The stationary phase comprises a rigid supporting material such as silica gel with an ion-bearing functional group and a hydrophobic functional group chemically attached to the surface, and ligands extending from the surface carry negative ions (Col. 4, Lns. 26–34).
The first-dimension cleaning column disclosed by ZELECHONOK, positioned upstream of the second-dimension analytical column, avoids interference from contaminants, which mitigates the problems that interferences and sample-to-sample variability shorten column life due to irreversibly retained contamination and drive the use of long cleaning procedures and guard columns (Col. 1, Ln. 47–Col. 2, Ln. 3). In view of EPA’s fluorinated compound analysis method, a person skilled in the art would incorporate the mixed-mode anion-exchange stationary phase for at least one column to predictably avoid interference from contaminants.
Therefore, it would have been obvious to a person having ordinary skill in the art, prior to the effective filing date of the claimed invention, to incorporate the mixed-mode anion-exchange stationary phase, as disclosed by ZELECHONOK, into at least one column in the fluorinated compound analysis method by EPA.
Regarding Claim 2, modified EPA makes obvious the fluorinated compound analysis method of Claim 1. EPA discloses that at least one type of fluorinated compound is a polyfluoroalkyl or perfluoroalkyl substance (§1.0).
Regarding Claim 3, modified EPA makes obvious the fluorinated compound analysis method of Claim 2. EPA discloses polyfluoroalkyl substances having 3 to 5 carbon atoms, such as PFBA (C4) and PFPeA (C5) (§6.1, Table 1).
Regarding Claim 4, modified EPA makes obvious the fluorinated compound analysis method of Claim 2. EPA discloses polyfluoroalkyl substances having more than 5 carbon atoms, such as PFHxA (C6) through PFDA (C10) and longer (§6.1, Table 1).
Regarding Claim 6, modified EPA makes obvious the fluorinated compound analysis method of Claim 1. ZELECHONOK discloses that the analytical Primesep SB column retains negatively charged compounds and that the Primesep SB used as the main second-dimension column has strong basic functional groups attached to hydrophobic ligands (Col. 6, Lns. 40–52). The strong basic functional groups provide anion-exchange surface chemistry, while the hydrophobic ligands provide reversed-phase surface chemistry, such that the stationary phase is mixed mode.
Regarding Claims 7 and 8, modified EPA makes obvious the fluorinated compound analysis method of Claim 1. EPA discloses that the analytical column comprises a stationary phase material comprising a reversed phase surface chemistry, such as C18 alkyl-bonded surface chemistry (§6.1.2).
Regarding Claims 9 and 10, modified EPA makes obvious the fluorinated compound analysis method of Claim 1. EPA discloses that the mass spectrometer is capable of tandem mass spectrometry (MS/MS) analysis and is specifically a triple quadrupole mass spectrometer (§6.1.4).
Regarding Claim 12, modified EPA makes obvious the fluorinated compound analysis method of Claim 1. EPA discloses identifying target analytes based on mass spectrometry ion responses and retention time, and quantifying an identified target compound based on the integrated abundance of the primary product ion (§11.6; §11.7).
Regarding Claim 13, modified EPA makes obvious the fluorinated compound analysis method of Claim 1. EPA discloses that LLOQs are established to meet project-specific decision levels and regulatory action levels, and that concentrations below the established LLOQ may still be detected and reported (§9.9; §9.9.4).
Regarding the limitation “the concentration of at least one type of fluorinated compound in the liquid sample is less than 0.1 ng/L,” this describes a property of the starting liquid sample rather than a step of the method. The limitation does not require the method to detect, quantify, recover, or separate the fluorinated compound at a concentration less than 0.1 ng/L and does not require any different operating step. Therefore, the limitation adds no patentable weight to the claimed method. See MPEP § 2111.04.
Regarding Claim 17, EPA discloses a method for analyzing per- and polyfluoroalkyl substances (PFAS) using a liquid chromatography/tandem mass spectrometry (LC/MS/MS) system (Title, §1.1).
In particular, precautionary measures are employed to minimize problems with measurement precision and bias, including verifying supplies and LC-system materials to reduce PFAS contamination (§4.3) and placing an isolator column upstream of the sample injection valve to delay contaminants to the analytical column (§4.3.5).
Consistent with these contamination-control measures, the equipment includes a liquid chromatograph (LC) system described as a UPLC, analytical LC columns including phenyl-hexyl and C18 reversed-phase columns, isolator columns specified as C18 columns, and a tandem mass spectrometry (MS/MS) detector (§6.0–§6.1). Samples are analyzed using the same LC/MS/MS conditions as used to generate the initial calibration (§11.5.1).
However, EPA does not explicitly disclose that “at least one column comprises a stationary phase material possessing a mixed mode with anion exchange surface chemistry.”
ZELECHONOK discloses a high-pressure liquid chromatography system using multiple mixed-mode columns connected to a switching valve (Col. 1, Lns. 30–33).
The high-pressure liquid chromatography system avoids interference from contaminants by initially passing mobile phase containing unwanted material through the first-dimension column as a cleaning column before the second-dimension analytical column. The mixed-mode columns have reverse phase and ion-exchange characteristics to combine sample cleaning and analyte separation in one automated process (Col. 2, Lns. 7–43).
FIG. 1 is a schematic representation of a stationary phase with a ligand structure that performs as mixed-mode chromatography material with anion exchange properties (Col. 2, Lns. 65–67). The stationary phase comprises a rigid supporting material such as silica gel with an ion-bearing functional group and a hydrophobic functional group chemically attached to the surface, and ligands extending from the surface carry negative ions (Col. 4, Lns. 26–34).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over EPA in view of ZELCHONOK as applied to claim 1 above, and further in view of DING et al. (Simultaneous determination of mono- and disubstituted polyfluoroalkyl phosphates in drinking water by liquid chromatography–electrospray tandem mass spectrometry, 2012, hereinafter DING).
Regarding Claim 5, modified EPA makes obvious the fluorinated compound analysis method of Claim 1. However, modified EPA does not explicitly disclose “at least one type of fluorinated compound comprises one or more phosphate group(s).”
DING discloses that polyfluoroalkyl phosphates (PAPs) include mono- and disubstituted polyfluoroalkyl phosphates having various fluoroalkyl chain lengths, and that a method was developed to simultaneously concentrate five monoPAPs and eight diPAPs and analyze the 13 target PAPs by LC–MS/MS with high sensitivity and separation efficiency (Introduction, p. 245).
In Liquid chromatography and mass spectrometry, the PAPs were analyzed using a UPLC system and separated using a UPLC BEH C8 column with methanol and water containing 0.1% NH₄OH as the mobile phases. The separated PAPs were detected by electrospray tandem mass spectrometry in negative-ion multiple-reaction-monitoring mode (§2.4, p. 247).
In view of EPA’s fluorinated compound analysis method, a person skilled in the art would predictably separate and analyze the phosphate-containing fluorinated compounds using the modified liquid chromatography system.
Therefore, it would have been obvious to a person having ordinary skill in the art, prior to the effective filing date of the claimed invention, to include the phosphate-containing fluorinated compounds, as disclosed by DING, as analytes in the fluorinated compound analysis method by modified EPA.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over EPA in view of ZELCHONOK as applied to claim 1 above, and further in view of LAUBER et al. (US20190086371A1, hereinafter LAUBER).
Regarding Claim 11, modified EPA makes obvious the fluorinated compound analysis method of Claim 1. However, modified EPA does not explicitly disclose "an interior surface of the isolator column is coated with an alkylsilyl coating."
LAUBER discloses the use of vapor deposition coated flow paths for improved chromatography (¶[0002]). The chromatographic device includes a chromatography column downstream of a sample injector, wherein interior surfaces of the chromatography column form part of a fluidic flow path having wetted surfaces, and at least a portion of the wetted surfaces of the fluidic flow path are coated with an alkylsilyl coating (¶[0015]).
The alkylsilyl coating disclosed by LAUBER reduces unfavorable chromatographic secondary interactions between analytes and metallic flow path surfaces while maintaining high-pressure capability for chromatographic separation (¶[0003]; ¶[0008]). In view of modified EPA’s fluorinated compound analysis method, a person skilled in the art would incorporate the alkylsilyl coating for the interior surface of the isolator column to predictably reduce unfavorable chromatographic secondary interactions while maintaining high-pressure capability for chromatographic separation.
Therefore, it would have been obvious to a person having ordinary skill in the art, prior to the effective filing date of the claimed invention, to incorporate the alkylsilyl coating, as disclosed by LAUBER, into the interior surface of the isolator column in the fluorinated compound analysis method by modified EPA.
Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over EPA in view of ZELECHONOK and STRAMENGA et al. (Perfluoroalkyl and polyfluoroalkyl substances (PFASs): An optimized LC-MS/MS procedure for feed analysis, 2021, hereinafter STRAMENGA).
Regarding Claim 14, EPA discloses a method for analyzing per- and polyfluoroalkyl substances (PFAS) using a liquid chromatography/tandem mass spectrometry (LC/MS/MS) system (Title, §1.1).
In particular, precautionary measures are employed to minimize problems with measurement precision and bias, including verifying supplies and LC-system materials to reduce PFAS contamination (§4.3) and placing an isolator column upstream of the sample injection valve to delay contaminants to the analytical column (§4.3.5).
Consistent with these contamination-control measures, the equipment includes a liquid chromatograph (LC) system described as a UPLC, analytical LC columns including phenyl-hexyl and C18 reversed-phase columns, isolator columns specified as C18 columns, and a tandem mass spectrometry (MS/MS) detector (§6.0–§6.1). Samples are analyzed using the same LC/MS/MS conditions as used to generate the initial calibration (§11.5.1).
However, EPA does not explicitly disclose “wherein at least one column comprises a stationary phase material comprising a mixed mode with anion exchange surface chemistry.”
ZELECHONOK discloses a high-pressure liquid chromatography system using multiple mixed-mode columns connected to a switching valve (Col. 1, Lns. 30–33).
The high-pressure liquid chromatography system avoids interference from contaminants by initially passing mobile phase containing unwanted material through the first-dimension column as a cleaning column before the second-dimension analytical column. The mixed-mode columns have reverse phase and ion-exchange characteristics to combine sample cleaning and analyte separation in one automated process (Col. 2, Lns. 7–43).
FIG. 1 is a schematic representation of a stationary phase with a ligand structure that performs as mixed-mode chromatography material with anion exchange properties (Col. 2, Lns. 65–67). The stationary phase comprises a rigid supporting material such as silica gel with an ion-bearing functional group and a hydrophobic functional group chemically attached to the surface, and ligands extending from the surface carry negative ions (Col. 4, Lns. 26–34).
The first-dimension cleaning column disclosed by ZELECHONOK, positioned upstream of the second-dimension analytical column, avoids interference from contaminants, which mitigates the problems that interferences and sample-to-sample variability shorten column life due to irreversibly retained contamination and drive the use of long cleaning procedures and guard columns (Col. 1, Ln. 47–Col. 2, Ln. 3). In view of EPA’s method of delaying retention time of a contamination in a liquid chromatography system, a person skilled in the art would incorporate the mixed-mode anion-exchange stationary phase for at least one column to predictably avoid interference from contaminants.
Therefore, it would have been obvious to a person having ordinary skill in the art, prior to the effective filing date of the claimed invention, to incorporate the mixed-mode anion-exchange stationary phase, as disclosed by ZELECHONOK, into at least one column in the method of delaying retention time of a contamination in a liquid chromatography system by EPA.
However, modified EPA does not explicitly disclose that the second fluorinated compound reaches the detector prior to the first fluorinated compound and that the contamination is delayed by at least 1 minute in step (d).
STRAMENGA discloses development, optimization, and validation of an LC-MS/MS analytical protocol enabling quantification of PFAS in animal feeds, including assessing matrix interferences and validating using spiked feed samples (Abstract, Pg. 1).
Similar to the modified EPA method, the experimentation was performed on a UPLC LC-MS/MS system, and an isolator column was installed between the pump and the injector (§2.4, Pg. 3). The short C18 isolator column was installed between the mixer and the sample loop with the aim of trapping and delaying PFAS originating from the LC system, such that injected analytes are eluted earlier than those originating from tubing contamination (§3.1, Pg. 4–5).
The trapping and delaying of PFAS originating from the LC system disclosed by STRAMENGA enables injected analytes to be eluted earlier than tubing contamination, which mitigates laboratory contamination that limits achieving low detection limits in PFAS analysis (§3.1, Pg. 4–5). In view of modified EPA’s method of delaying retention time of a contamination in a liquid chromatography system, a person skilled in the art would incorporate the method for trapping and delaying PFAS originating from the LC system to predictably cause the second fluorinated compound to reach the detector prior to the first fluorinated compound.
Regarding the limitation “delayed at least 1 minute,” the amount of delay is a result-effective variable. In view of STRAMENGA’s trapping and delaying method, a delay of at least 1 minute would have been a routine optimization to provide sufficient temporal separation between the injected analytes and the delayed contamination.
Therefore, it would have been obvious to a person having ordinary skill in the art, prior to the effective filing date of the claimed invention, to incorporate the method for trapping and delaying PFAS originating from the LC system, as disclosed by STRAMENGA, into the method of delaying retention time of a contamination in a liquid chromatography system by modified EPA.
Regarding Claim 15, modified EPA makes obvious the method of delaying retention time of a contamination in a liquid chromatography system of Claim 14. ZELECHONOK discloses that the first-dimension cleaning column comprises a mixed-mode stationary phase having anion-exchange characteristics (Col. 2, Lns. 7–43).
Regarding Claim 16, modified EPA makes obvious the method of delaying retention time of a contamination in a liquid chromatography system of Claim 14. STRAMENGA discloses a method for trapping and delaying PFAS originating from the LC system (§3.1, Pg. 4–5).
Regarding the limitation “delayed at least 5 minutes,” the amount of delay is a result-effective variable. In view of STRAMENGA’s trapping and delaying method, a delay of at least 5 minutes would have been a routine optimization to provide sufficient temporal separation between the injected analytes and the contamination (In re Aller, 220 F.2d 454, 456–57; 1955).
Response to Arguments
Applicant’s arguments, see Remarks filed May 28, 2026, with respect to the rejections under 35 U.S.C. § 103 dated March 4, 2026, have been fully considered but are not persuasive. The rejections under 35 U.S.C. § 103 are maintained and updated as set forth above in view of EPA, ZELECHONOK, DING, LAUBER, and STRAMENGA.
In response to Applicant’s argument that ZELECHONOK’s first-dimension column is positioned downstream of the sample injector, performs sample cleanup rather than delaying LC-system contamination, and is demonstrated using nitrate and peptide analytes, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference. Rather, the test is what the combined teachings of the references would have suggested to a person having ordinary skill in the art. EPA supplies the claimed upstream placement and contaminant-delay function of the isolator column, while ZELECHONOK supplies the mixed-mode anion-exchange stationary-phase material. The rejection does not rely on ZELECHONOK’s switching-valve configuration, downstream placement of its exemplary first-dimension column, or exemplary nitrate and peptide analytes. A person skilled in the art would have selected the mixed-mode anion-exchange stationary-phase material for EPA’s already-positioned isolator column to predictably delay contaminant fluorinated compounds. Accordingly, Applicant’s argument does not overcome the rejection.
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 TAK L. CHIU whose telephone number is (703)756-1059. The examiner can normally be reached M-F: 9:00am - 6:00pm (CST).
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/TAK L. CHIU/Examiner, Art Unit 1771
/KRISHNAN S MENON/Primary Examiner, Art Unit 1771
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