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 amendments and arguments, filed 8/4/2026, with respect to the rejection(s) of claim(s) 1 – 6 and 10 – 20 under 35 U.S.C. 102(a)(1) as being anticipated by Wen et al. (Cite No. 5 on page 2 of the IDS filed 12/8/2023 by Applicant; published: April 5, 2021), have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. The 103 rejection of claims 7 – 9 of Wen et al. in view of Liu et al. has been withdrawn as well. However, upon further consideration, a new ground(s) of rejection is made in view of Hughes (2011/0201126 A1), Kertesz et al. (US 2022/0102127 A1), McEwen et al. (US 2011/0031392 A1) and Karger et al. (US 6,175,112 B1).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 – 20 are rejected under 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 1, in line 9, the newly recited step of introducing one or more samples from at least one of the phases of the multi-phase liquid directly into the mass spectrometer” is not supported in the specification.
Regarding claim 13, in line 12, the newly recited “mechanism operably coupled to said first reservoir for ejecting a plurality of droplets from any said first phase and second phase for direct introduction into said mass spectrometer” is not supported by the specification.
Drawings
The drawings are objected to under 37 CFR 1.83(a). The drawings must show every feature of the invention specified in the claims. Therefore, in line 12, the recited “mechanism operably coupled to said first reservoir for ejecting a plurality of droplets from any said first phase and second phase for direct introduction into said mass spectrometer (emphasis added)” must be shown and labeled or the feature(s) canceled from the claim(s). No new matter should be entered.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Note Regarding Prior Art
Examiner cites particular sections, columns, line numbers, paragraphs and figures, in the references as applied to the claims below for the convenience of the Applicant. Although the specified citations are representative of the teachings in the art and are applied to the specific limitations within the individual claim, other passages and figures may apply as well. It is respectfully requested that, in preparing responses, the Applicant fully consider the references in their entirety as potentially teaching all or part of the claimed invention, as well as the context of the passage as taught by the prior art or disclosed by the Examiner.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(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.
Claim(s) 1 – 6 and 10 – 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (Cite No. 5 on page 2 of the IDS filed 12/8/2023 by Applicant; published: April 5, 2021; hereinafter “Wen”) in view of either Hughes (2011/0201126 A1; hereinafter “Hughes”), Kertesz et al. (US 2022/0102127 A1; hereinafter “Kertesz”), McEwen et al. (US 2011/0031392 A1; hereinafter “ McEwen”) or Karger et al. (US 6,175,112 B1; hereinafter “Karger”).
Regarding claim 1, Wen teaches a method of introducing a biological sample (e.g., various assay mixtures containing biological components and compounds; Experimental Section; page 6072) into a mass spectrometer (Abstract; pages 6072-6073; DGAT2 Cell-Free Activity Assay section, pages 6072 and 6073; Results and Discussion section and figure 1), comprising:
mixing the biological sample (aquatic solvent with DGAT2 and triolein) with at least one solvent (pentanol; page 6073) in which an aqueous matrix of an aqueous phase of said sample (salts in the aqueous layer) is immiscible and in which at least a target analyte (peptides formed by DGAT2 and triolein), when present in said sample, is miscible so as to extract at least a portion of said at least one target analyte into said at least one solvent, thereby generating a multi-phase liquid having said aqueous phase and one or more organic phases, wherein at least one of said organic phases contains said at least one target analyte (figure 1A), and
introducing one or more samples from at least one of the phases of the multi-phase liquid into the mass spectrometer (via ADE-OPI-MS/MS Analysis; page 6073).
Wen does not explicitly teach the step of introducing one or more samples from at least one of the phases of the multi-phase liquid directly into the mass spectrometer.
However, the concept of introducing biological samples directly into a mass spectrometer for analysis is well known in the art, as evidenced by Hughes, Kertesz, McEwen and Karger: Hughes teaches an interface that introduces samples directly into a mass spectrometer without the need for injection loops of GC columns (paragraph 15); Kertesz teaches the liquid introduction of a sample to be analyzed that is pumped directly into a mass spectrometer (paragraphs 3 and 5); McEwen teaches the introduction of liquid effluent sample directly into the ionization region of a mass spectrometer (paragraph 52); and Karger teaches the direct introduction of liquid samples directly to the evacuated source of a mass spectrometer (col. 2, lines 33 – 41). Consequently, as shown by the aforementioned cited prior art above, it would have been considered suitable and predictable to a person of ordinary skill in the art to consider adding the step of introducing one or more samples from at least one of the phases of the multi-phase liquid directly into the mass spectrometer. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results (see MPEP § 2143, A.). Furthermore, the Supreme Court decided that a claim can be proved obvious merely by showing that the combination of known elements was obvious to try. In this regard, the Supreme Court explained that, “[w]hen there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill in the art has a good reason to pursue the known options within his or her technical grasp.” An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of the case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. Therefore, choosing from a finite number of identified, predictable solutions, with a reasonable expectation for success, is likely to be obvious to a person if ordinary skill in the art (see MPEP § 2143, E.). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to provide the step of introducing one or more samples from at least one of the phases of the multi-phase liquid directly into the mass spectrometer. The Applicant has not shown objective factual evidence that introducing a sample from at least one of the phases of the multi-phase liquid directly into the mass spectrometer would have yielded an unexpected result or was beyond the skill of, or uniquely challenging to, a person of ordinary skill in the art. An argument does not replace evidence, where evidence is necessary (see MPEP § 2145). The Courts have held that the arguments of counsel cannot take the place of evidence in the record. See In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); & In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). Moreover, this position is merely attorney argument lacking evidentiary support. See Gemtron Corp. v. Saint-Gobain., 572 F.3d 1371, 1380 (Fed. Cir. 2009) (noting that “unsworn attorney argument … is not evidence”).
Regarding claim 2, Wen teaches the method of claim 1, wherein said step of introducing one or more samples comprises introducing one or more samples of said organic phase containing said at least one target analyte into the mass spectrometer (assay plates containing multiple samples from the individual wells were used; Abstract; pages 6072-6073; DGAT2 Cell-Free Activity Assay section, pages 6072 and 6073; Results and Discussion section and figure 1; ADE-OPI-MS/MS Analysis section; page 6073).
Regarding claim 3, Wen teaches the method of claim 1, wherein said step of introducing said at least one of the phases comprises ejecting a plurality of droplets from said at least one phase containing said target analyte into the mass spectrometer (ADE-OPI-MS/MS Analysis section; page 6073).
Regarding claim 4, Wen teaches the method of claim 3, further comprising using an acoustic actuator for ejecting said plurality of droplets (acoustic transducer; ADE-OPI-MS/MS Analysis section; page 6073).
Regarding claim 5, Wen teaches the method of claim 1, wherein said at least one solvent comprises a first and a second solvent and said at least one target analyte comprises a first and a second analyte, wherein said first analyte is miscible in said first solvent and said second analyte is miscible in said second solvent (see the discussion of the 2-phase system in Results and Discussion section; Abstract; pages 6072-6073; DGAT2 Cell-Free Activity Assay section, pages 6072 and 6073; Results and Discussion section and figure 1; ADE-OPI-MS/MS Analysis section; page 6073).
Regarding claim 6, Wen teaches the method of claim 1, wherein said one or more organic phases comprise two organic phases (see the discussion of the 2-phase system in Results and Discussion section; Abstract; pages 6072-6073; DGAT2 Cell-Free Activity Assay section, pages 6072 and 6073; Results and Discussion section and figure 1; ADE-OPI-MS/MS Analysis section; page 6073).
Regarding claim 10, Wen teaches the method of claim 1, wherein said aqueous phase is more dense than at least one of said organic phases (see the discussion of the 2-phase system in Results and Discussion section; Abstract; pages 6072-6073; DGAT2 Cell-Free Activity Assay section, pages 6072 and 6073; Results and Discussion section and figure 1; ADE-OPI-MS/MS Analysis section; page 6073).
Regarding claim 11, Wen teaches the method of claim 10, wherein said at least one of said organic phases comprises an alcohol (1-pentanol; page 6073).
Regarding claim 12, Wen teaches the method of claim 11, wherein said alcohol comprises pentanol (1-pentanol; page 6073).
Regarding claim 13, Wen teaches a system for introducing a biological sample (e.g., various assay mixtures containing biological components and compounds; Experimental Section; page 6072) into a mass spectrometer (Abstract; pages 6072-6073; DGAT2 Cell-Free Activity Assay section, pages 6072 and 6073; Results and Discussion section and figure 1), comprising:
a first reservoir for storing the biological sample containing or suspected of containing one or more analytes (a reservoir comprising one of the 384 wells of the assay microplate),
a second reservoir for storing a solvent in which an aqueous matrix of said sample is immiscible and said one or more analytes are miscible (a reservoir is necessarily present is implicit for the 1-pentanol used),
a mechanism (Matrix Wellmate dispenser) for generating a flow of said solvent from said second reservoir into said first reservoir so as to mix said solvent with said sample so as to extract at least a portion of said one or more analytes into said solvent, thereby generating a two- phase solution having a first phase comprising said aqueous matrix and a second phase comprising a mixture of said solvent and at least a portion of said one or more analytes, and
a mechanism (ADE-OPI-MS system) operably coupled to said first reservoir for ejecting a plurality of droplets from any of said first phase and second phase for introduction into said mass spectrometer.
Wen does not explicitly teach a mechanism operably coupled to said first reservoir for ejecting a plurality of droplets from any of said first phase and second phase for direct introduction into said mass spectrometer.
However, the concept of introducing biological samples directly into a mass spectrometer for analysis is well known in the art, as evidenced by Hughes, Kertesz, McEwen and Karger: Hughes teaches an interface that introduces samples directly into a mass spectrometer without the need for injection loops of GC columns (paragraph 15); Kertesz teaches the liquid introduction of a sample to be analyzed that is pumped directly into a mass spectrometer (paragraphs 3 and 5); McEwen teaches the introduction of liquid effluent sample directly into the ionization region of a mass spectrometer (paragraph 52); and Karger teaches the direct introduction of liquid samples directly to the evacuated source of a mass spectrometer (col. 2, lines 33 – 41). Consequently, as shown by the aforementioned cited prior art above, it would have been considered suitable and predictable to a person of ordinary skill in the art to consider adding a mechanism operably coupled to said first reservoir for ejecting a plurality of droplets from any of said first phase and second phase for direct introduction into said mass spectrometer. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results (see MPEP § 2143, A.). Furthermore, the Supreme Court decided that a claim can be proved obvious merely by showing that the combination of known elements was obvious to try. In this regard, the Supreme Court explained that, “[w]hen there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill in the art has a good reason to pursue the known options within his or her technical grasp.” An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of the case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. Therefore, choosing from a finite number of identified, predictable solutions, with a reasonable expectation for success, is likely to be obvious to a person if ordinary skill in the art (see MPEP § 2143, E.). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to provide a mechanism operably coupled to said first reservoir for ejecting a plurality of droplets from any of said first phase and second phase for direct introduction into said mass spectrometer. The Applicant has not shown objective factual evidence that introducing a sample from at least one of the phases of the multi-phase liquid directly into the mass spectrometer would have yielded an unexpected result or was beyond the skill of, or uniquely challenging to, a person of ordinary skill in the art. An argument does not replace evidence, where evidence is necessary (see MPEP § 2145). The Courts have held that the arguments of counsel cannot take the place of evidence in the record. See In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); & In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). Moreover, this position is merely attorney argument lacking evidentiary support. See Gemtron Corp. v. Saint-Gobain., 572 F.3d 1371, 1380 (Fed. Cir. 2009) (noting that “unsworn attorney argument … is not evidence”).
Regarding claim 14, Wen teaches the system of claim 13, wherein said mechanism is configured to apply one or more acoustic pulses to any of said first and said second phase for generating said droplets (via acoustic transducer; ADE-OPI-MS/MS Analysis section; page 6073).
Regarding claim 15, Wen teaches the system of claim 13, wherein said solvent comprises an alcohol (1-pentanol; page 6073).
Regarding claim 16, Wen teaches the system of claim 13, wherein said mechanism for generating the flow of the solvent comprises a pump (e.g., a Matrix Wellmate dispenser and Waters Acquity binary UPLC pump; page 6073) fluidly coupled to said first and second reservoir.
Regarding claim 17, Wen teaches the system of claim 16, further comprising a controller (e.g., a controller is implicit since software (v.2.5.MS Labcyte, Inc) is used to operate the system; page 6073) operably coupled to said pump for controlling thereof.
Regarding claim 18, Wen teaches the system of claim 17, wherein said controller controls the pump so as to cause transfer of a predefined volume of said solvent from said second reservoir to said first reservoir (e.g., a controller is implicit since software (v.2.5.MS Labcyte, Inc) is used to operate the system; page 6073).
Regarding claim 19, Wen teaches the system of claim 13, wherein said mechanism for ejecting the plurality of droplets comprises an acoustic actuator (acoustic transducer; ADE-OPI-MS/MS Analysis section; page 6073).
Regarding claim 20, Wen teaches the system of claim 13, wherein said mass spectrometer comprises an open port interface (OPI) for receiving said plurality of droplets (an open-port interface is connected to both the carrier solvent pump and a transfer capillary; page 6073).
Claim(s) 7 – 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (Cite No. 5 on page 2 of the IDS filed 12/8/2023 by Applicant; published: April 5, 2021; hereinafter “Wen”), in view of either Hughes (2011/0201126 A1; hereinafter “Hughes”), Kertesz et al. (US 2022/0102127 A1; hereinafter “Kertesz”), McEwen et al. (US 2011/0031392 A1; hereinafter “ McEwen”) or Karger et al. (US 6,175,112 B1; hereinafter “Karger”), and further in view of Liu et al. (Cite No. 3 on page 2 of the IDS filed 12/8/2023 by Applicant; published online: 1 May 2021; hereinafter “Liu”).
Regarding claim 7, modified Wen does not specifically teach the method of claim 6, wherein said two organic phases comprise hexane and methyl acetate and said aqueous phase comprises acetonitrile and water.
Liu teaches multi-phase liquid extraction using two organic phases comprising hexane and methyl acetate and an aqueous phase comprising acetonitrile and water, and subsequent UHPLC-MS/MS analysis (Abstract; Sample collection and lipid extraction section; and Data acquisition by UHPLC-Q-TOF MS section; page 3977; and 3PLE for lipid extraction section; page 3979). The use of these recited chemical components for their intended use would have been considered to be suitable and predictable to a person of ordinary skill in the art. The selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art (see MPEP § 2144.07). The combination of familiar elements is likely to be obvious when it does no more than yield predictable results (see MPEP § 2143, A.). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to provide wherein said two organic phases comprise hexane and methyl acetate and said aqueous phase comprises acetonitrile and water.
Regarding claim 8, Liu further teaches wherein a relative concentration ratios of said hexane, said methyl acetate, said acetonitrile and said water is 4:4:3:4 (see 3PLE for lipid extraction section; page 3979).
Regarding claim 9, modified Wen does not specifically teach the method of claim 1, wherein at least one of said organic phases is more dense than said aqueous phase. Liu does further teach wherein a relative concentration ratios of said hexane, said methyl acetate, said acetonitrile and said water is 4:4:3:4 (see 3PLE for lipid extraction section; page 3979). Optimizing an extraction and separation technique via the selection of appropriate solvents and organic phases would have been within the ambit of a person of ordinary skill in the art. The use of different organic phases would logically include organic and liquid phases of differing densities in order to provide for an effective sample extraction. The rationale to support an obviousness rejection under 35 U.S.C. 103 may rely on logic and sound scientific principle (see MPEP § 2144.02). The selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art (see MPEP § 2144.07). The combination of familiar elements is likely to be obvious when it does no more than yield predictable results (see MPEP § 2143, A.). The prior art can be modified or combined to reject claims as prima facie obvious as long as there is a reasonable expectation of success (see MPEP § 2143.02). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to provide wherein at least one of said organic phases is more dense than said aqueous phase.
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 BRIAN J. SINES whose telephone number is (571)272-1263. The examiner can normally be reached 9 AM-5 PM EST M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lyle Alexander can be reached at (571) 272-1254. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
BRIAN J. SINES
Primary Patent Examiner
Art Unit 1796
/BRIAN J. SINES/Primary Examiner, Art Unit 1796
Prosecution Insights