DETAILED ACTION
Response to Arguments
Objections to the Specification and Drawings
In view of the amendment to the specification, the objection to the specification and the objection to the drawings has been withdrawn.
Rejections under 35 USC 112(a)
In view of the amendment to claim 1, claim 1 is rejected under 35 USC 112(a) for lack of written description.
Rejections under 35 USC 112(b)
In view of the amendment to claims 3 and 5 and the cancellation of claim 4, the rejections of claims 3 and 5 under 35 USC 112(b) have been withdrawn and the rejection of claim 4 has been rendered moot.
In view of the amendment to claim 1, claim 1 is rejected under 35 USC 112(b) for indefiniteness.
Rejections under 35 USC 112(d)
In view of the cancellation of claim 4, the rejection of claim 4 under 35 USC 112(d) has rendered moot.
Rejections under 35 USC 103
Applicant's arguments have been fully considered but they are not persuasive. The preamble of claim 1 has been amended to “a method of ionizing a liquid for use in ambient-pressure DESI mass spectrometry.” Venter still teaches this limitation of the preamble because Venter’s use of DESI under an enclosure takes place at the ambient-pressure inside of the enclosure. Embodiments of Venter are disclosed that do not involve bringing the enclosure to vacuum. This is additionally evident by the fact that the mass spectrometer of Venter’s system has an atmospheric-pressure-vacuum interface where the atmospheric pressure inside the closure meets the vacuum environment inside of the mass spectrometer. Furthermore, since Venter and Bajic are both concerned with ionizing samples for analysis, particularly with types of electrospray ionization, it would be obvious to experiment with different nebulizing gases, as suggested by Bajic, in order to increase sensitivity and resulting signals.
Regarding the rejection of claim 2 under 35 USC 103, the claim is not written to require a specific or threshold location for the attachment to change the voltage. The claim merely requires that the voltage is applied to the liquid at a location that is sufficiently far upstream from the ion source so as to prevent discharge sufficient to substantially alter the signal intensity. Cooks modifies the combination by suggesting this limitation since Cooks teaches the voltage is applied to the liquid at a location that is sufficiently far upstream from the ion source (Fig. 40C shows voltage source applied to solvent at a distance from probe tip where ions are created) so as to prevent discharge at the ion source sufficient to substantially alter the signal intensity ([0080] teaches appropriate voltage is applied such that there is stable signal with no corona discharge). Consequently, under the broadest reasonable interpretation of the claim, claim 2 is rendered obvious by the combination.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 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 1-3 and 5-11 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.
Claim 1 recites the limitation “adjusting one or more process parameters selected from gas flow rate and/or velocity, solvent flow rate, voltage, and pressure differential at the inlet of a mass spectrometer, to provide increased signal intensity for at least one m/z relative to a signal intensity produced utilizing nitrogen nebulizing gas” is not supported by the original disclosure, at least because the disclosure does not disclose adjusting voltage to provide increased signal intensity for at least on m/z relative to a signal intensity produced utilizing nitrogen nebulizing gas. Paragraphs [0070]-[0074] disclose adjusting the gas flow rate and/or velocity, solvent flow rate, and pressure to provide the claimed result, but there is no mention in the specification of adjusting the voltage to produce the claimed result. Consequently, the claim language is not supported by the disclosure to reasonably convey possession for the claimed subject matter, and therefore the claim is rejected for lacking written description.
Claims 2-3 and 5-11 are rejected by virtue of their dependence on claim 1.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3 and 5-11 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “a method of ionizing a liquid for use in ambient-pressure DESI mass spectrometery, the method comprising: causing a liquid comprising…” is indefinite because it is not clear if the “a liquid” and the “a liquid” are the same or different to each other.
Claim 1 recites “adjusting one or more process parameters selected from gas flow rate and/or velocity, solvent flow rate, voltage, and pressure differential at the inlet of a mass spectrometer, to provide increased signal intensity for at least one m/z relative to a signal intensity produced utilizing nitrogen nebulizing gas” is indefinite because it is not clear and therefore indefinite if adjusting the process parameters as written comprises adjusting the gas flow rate and/or the entire group consisting of velocity, solvent flow rate, voltage, and pressure differential at the inlet of a mass spectrometer; or if adjusting the process parameters comprises adjusting one or more process parameters from the group consisting of gas flow rate, velocity, solvent flow rate, voltage, and pressure differential at the inlet of a mass spectrometer, or if some other combination or selection is intended.
Claim 1 recites “adjusting one or more process parameters selected from gas flow rate and/or velocity, solvent flow rate, voltage, and pressure differential at the inlet of a mass spectrometer, to provide increased signal intensity for at least one m/z relative to a signal intensity produced utilizing nitrogen nebulizing gas” is indefinite because it is not clear what voltage is being adjusted to achieve the claimed result.
Claim 1 recites “adjusting one or more process parameters selected from gas flow rate and/or velocity, solvent flow rate, voltage, and pressure differential at the inlet of a mass spectrometer, to provide increased signal intensity for at least one m/z relative to a signal intensity produced utilizing nitrogen nebulizing gas” is indefinite because it is not clear what the process parameters selected from gas flow rate and/or velocity, solvent flow rate, voltage, and pressure differential at the inlet of a mass spectrometer are being adjusted relative to.
Claim 1 recites “adjusting one or more process parameters selected from gas flow rate and/or velocity, solvent flow rate, voltage, and pressure differential at the inlet of a mass spectrometer, to provide increased signal intensity for at least one m/z relative to a signal intensity produced utilizing nitrogen nebulizing gas” is also indefinite because it is unclear whether the “increased signal intensity” is relative to the same parameters/device/etc. with a difference only in nitrogen nebulizing gas rather than helium nebulizing gas, or if the comparison is made to some other arbitrary arrangement of parameters that also includes nitrogen nebulizing gas.
Claims 2-3 and 5-11 are rejected by virtue of their dependence on claim 1.
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.
Claims 1, 7-9, and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Venter (US 20080156985 A1) in view of Bajic (US 20210210320 A1).
Regarding claim 1, Venter teaches a method of ionizing a liquid for use in ambient-pressure DESI mass spectrometry (Intended use) (Abstract and [0010] teaches ambient-pressure DESI. Note that the DESI takes place at the ambient pressure of the enclosure, and the vacuum is part of the MS system, which has an atmospheric-pressure-vacuum interface, indicating that the DESI takes place near atmospheric pressure), the method comprising:
causing a liquid comprising at least a solvent to flow through a first capillary in a downstream direction ([0034], [0037] internal solvent capillary, Fig. 1A);
causing nebulizing gas to flow in a downstream direction through a space formed between the first capillary and a second capillary that surrounds at least a portion of the first capillary ([0037] outer gas capillary has nebulizing gas, [0039], Fig. 1A), wherein the first and second capillaries have open ends that are adjacent one another to form, in use, an ion source that emits electrospray droplets ([0033], Fig. 1A);
applying voltage to the liquid at a location that is upstream from the ion source ([0034]);
causing sample material to enter an inlet of a mass spectrometer ([0038]-[0040], Fig. 1A) whereby the mass spectrometer is able to provide a signal intensity at a plurality of mass-to-charge ratios (m/z) ([0040], Figs. 3A, 3B).
Venter does not teach helium nebulizing gas or adjusting one or more process parameters selected from gas flow rate and/or velocity solvent flow rate, voltage, and pressure differential at the inlet of a mass spectrometer, to provide increased signal intensity for at least one m/z relative to a signal intensity produced utilizing nitrogen nebulizing gas.
Bajic teaches helium nebulizing gas ([0029], [0104]), and adjusting one or more process parameters selected from gas flow rate and/or velocity solvent flow rate, voltage, and pressure differential at the inlet of a mass spectrometer ([0005] improving ion sampling efficiency at various flow rates, flow rates [0107], voltage, [0110]) to provide increased signal intensity for at least one m/z relative to a signal intensity produced utilizing nitrogen nebulizing gas ([[0104]).
Bajic modifies Venter by suggesting helium as a nebulizing gas and adjusting one or more process parameters to provide increased signal intensity for at least one m/z relative to a signal intensity produced utilizing nitrogen nebulizing gas.
Since both Bajic and Venter are directed to types of electrospray ionization, it would have been obvious to one of ordinary skill in the art to incorporate using helium gas as the nebulizing gas, as suggested by Bajic because “helium as a nebulizer gas can give sensitivity enhancements over nitrogen in some embodiments” and “the nebuliser described above can accordingly be modified for use in an electrospray ionization source in other embodiments,” (Bajic, [0104], [0107]). Furthermore, it would have been obvious to incorporate the teachings of Bajic because process parameters such as the flow rate and voltage are shown to be results-effective variables (i.e. Bajic, Fig. 9 shows signal intensity obtained with an electrospray ionization source biased to different voltages), and it would be obvious within prior art conditions and through routine experimentation to optimize these parameters to achieve increased signal intensity, and in particular increased signal intensity for at least one m/z relative to a signal intensity produced utilizing nitrogen gas, since Bajic teaches the comparison of using hydrogen and nitrogen as nebulizing gas in the context of electrospray ionization (Bajic, [0104], [0107]). See MPEP 2144.05 II, which teaches "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”. Since Bajic teaches adjusting the claimed process parameters, and that some scenarios produce more significant sensitivity when helium is used as the nebulizing gas over nitrogen, it would be obvious that one could optimize the process parameter in order to achieve an increased signal intensity for at least one m/z relative to a signal intensity produced utilizing nitrogen nebulizing gas. Therefore, the claim is obvious in view of Bajic.
Regarding claim 7, Venter teaches wherein adjusting one or more process parameters includes: adjusting a mass flow rate of the gas to increase signal intensity for at least one m/z ([0045]).
Venter fails to teach helium gas.
Bajic teaches helium gas ([0029]).
Bajic modifies Venter by suggesting using helium gas as the nebulizing gas.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Bajic because helium as a nebulizer gas can give sensitivity enhancements over nitrogen in some embodiments ([0104]).
Regarding claim 8, Venter teaches wherein: a syringe pump having an electrically conductive needle is utilized to cause the liquid to flow through the first capillary ([0034], [0037]); and
the voltage is applied to the conductive needle ([0037]).
Regarding claim 9, wherein: the first capillary comprises fused silica ([0037] teaches briefly, the internal solvent capillary was a section of fused silica capillary tubing) having an internal passageway that is fluidly connected to the electrically conductive needle ([0034], [0037] syringe pump connects to capillary such that stainless steel needle of glass syringe must be fluidically connected to capillary); and including:
causing liquid to flow through the electrically conductive needle and the internal passageway of the fused silica (syringe pump delivers solution through stainless steel needle into fused silica capillary to sprayer, [0034], [0037]).
Regarding claim 11, Venter teaches wherein adjusting one or more process parameters includes: adjusting a mass flow rate of the nebulizing gas flowing through the second capillary to determine a mass flow rate of the nebulizing gas at which an optimum signal intensity is generated by the mass spectrometer (Fig. 5B, [0045]).
Venter fails to teach helium gas.
Bajic teaches helium gas ([0029]).
Bajic modifies Venter by suggesting using helium gas as the nebulizing gas.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Bajic because helium as a nebulizer gas can give sensitivity enhancements over nitrogen in some embodiments ([0104]).
Regarding claim 12, including: directing the electrospray droplets at a sample surface to extract ions from the sample surface (DESI, [0004], Fig. 1A).
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Venter (US 20080156985 A1) in view of Bajic (US 20210210320 A1), further in view of Cooks et. al. (US 20140264004 A1), hereinafter Cooks.
Regarding claim 2, Venter does not explicitly teach wherein: the voltage is applied to the liquid at a location that is sufficiently far upstream from the ion source so as to prevent discharge at the ion source sufficient to substantially alter the signal intensity.
Cooks teaches wherein: the voltage is applied to the liquid at a location that is sufficiently far upstream from the ion source (Fig. 40C shows voltage source applied to solvent at a distance from probe tip where ions are created) so as to prevent discharge at the ion source sufficient to substantially alter the signal intensity ([0080] teaches appropriate voltage is applied such that there is stable signal with no corona discharge).
Cooks modifies Venter by suggesting applying the voltage at a location sufficiently far from the ion source such that discharge is prevented that would substantially alter the signal intensity.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Cooks because applying the voltage as suggested by Cooks, a stable electrospray signal is generated without corona discharge ([0080]).
Claims 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Venter (US 20080156985 A1) in view of Bajic (US 20210210320 A1), further in view of Jolliffe, et. al. (US 20150214021 A1), hereinafter Jolliffe.
Regarding claim 3, Venter does not explicitly teach wherein adjusting one or more process parameters includes: adjusting a pressure differential at the inlet of the mass spectrometer to provide increased signal intensity.
Jolliffe teaches adjusting a pressure differential at the inlet of the mass spectrometer to provide increased signal intensity ([0034], [0037], [0034]-[0040], Fig. 1).
Jolliffe modifies Venter by suggesting adjusting a pressure differential at the inlet of the mass spectrometer by utilizing a mass spectrometer interface at the inlet of the mass spectrometer which increases signal intensity.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Jolliffe because the mass spectrometer interface enhances concentration or sensitivity of ions of characteristic m/z and reduces chemical background while providing the appropriate gas flow to a mass spectrometer system (Jolliffe, [0034]).
Regarding claim 5, Venter teaches wherein adjusting a pressure differential at the inlet of the mass spectrometer includes: the inlet of the mass spectrometer comprising a tube (see Fig. 1A where mass inlet capillary has tube structure);
Venter does not teach and including: increasing a length of the tube to reduce a vacuum at the inlet of a mass spectrometer to provide increased signal intensity.
Jolliffe teaches increasing a length of the tube (diameters of flow tubes and channels making up the mass spectrometer interface 10 (the interpreted tube), [0042]-[0043], Fig. 1) to reduce a vacuum ([0043], [0034], [0037]) at the inlet of a mass spectrometer (mass spectrometer interface 10 couples to mass spectrometer 14, [0034], Fig. 1) to provide increased signal intensity ([0034], [0043]).
Jolliffe modifies Venter by suggesting successively increasing a length (diameter) of the tube (mass spectrometer interface) to reduce a vacuum (increased concentration of ions leads to reduced vacuum) at the inlet of a mass spectrometer (in the interface which directly connects to the mass spectrometer) to provide increased signal intensity (resulting in enhanced sensitivity of ions of characteristic m/z).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Jolliffe because the mass spectrometer interface enhances concentration or sensitivity of ions of characteristic m/z and reduces chemical background while providing the appropriate gas flow to a mass spectrometer system (Jolliffe, [0034]).
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Venter (US 20080156985 A1) in view of Bajic (US 20210210320 A1), further in view of Muller, et. al. (EP 3920208 A1), hereinafter Muller.
Regarding claim 6, Venter does not teach including: adjusting at least one of a size and shape of at least one of the first capillary and the second capillary to increase signal intensity for at least one m/z.
Muller teaches adjusting at least one of a size and shape of at least one of the first capillary and the second capillary to increase signal intensity for at least one m/z (Column 6, [0021], lines 2-20, especially lines 16-20).
Muller modifies Venter by suggesting adjusting the diameters of the inner and outer capillaries and their ratios to each other in order to achieve optimum ionization efficiencies in DESI.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Muller because adjusting and choosing the diameters appropriately can achieve optimum ionization efficiencies, (Muller, Column 6, [0021], lines 16-20). Note that MPEP 2144.01 teaches, "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968). It would be understood to one skilled in the art that achieving optimum ionization efficiencies would generally subsequently result in increased signal intensity in mass spectrometry, since more ions would lead to a higher signal. As a result, Venter in view of Bajic, further in view of Muller renders obvious adjusting at least one of a size and shape of at least one of the first capillary and the second capillary to increase signal intensity for at least one m/z since Muller suggests the teachings of this limitation via specific teachings and inferences one of ordinary skill in the art would be expected to draw therefrom.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Venter (US 20080156985 A1) in view of Bajic (US 20210210320 A1), further in view of Fukui (US 20210208113 A1).
Regarding claim 10, Venter does not teach wherein: the second capillary comprises an electrically conductive material; applying a voltage to a liquid includes applying a voltage to the second capillary.
Fukui teaches wherein: the second capillary comprises an electrically conductive material ([0017]);
applying a voltage to a liquid includes applying a voltage to the second capillary ([0017]).
Fukui modifies Venter by suggesting the second capillary is made of a conductive material and applying a voltage to a liquid includes applying a voltage to the second capillary.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Fukui because doing so “further ensures the electrification of the sample liquid flowing through the first tube,” (Fukui, [0017]).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ibrahim YM, Garimella SV, Tolmachev AV, Baker ES, Smith RD. Improving ion mobility measurement sensitivity by utilizing helium in an ion funnel trap. Anal Chem. 2014 Jun 3;86(11):5295-9. doi: 10.1021/ac404250z. Epub 2014 May 13. PMID: 24786390; PMCID: PMC4051256.
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 LAURA E TANDY whose telephone number is (703)756-1720. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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LAURA E TANDY
Examiner
Art Unit 2881
/WYATT A STOFFA/Primary Examiner, Art Unit 2881