DETAILED ACTION
Response to Arguments
Rejections under 35 USC 112(a)
Applicant's arguments filed 05/28/2026 have been fully considered but they are not persuasive. The amendment to claim 1 does not have support sufficient to overcome the rejection under 35 USC 112(a) for lack of written description because the amended limitation is similarly devoid of written description support in the disclosure as the original limitation. Specifically, the disclosure does not provide for the way in which “adjusting… [a] voltage applied to the liquid…provide[s] increased signal intensity for the sample material for at least one m/z relative to a baseline signal intensity produced utilizing nitrogen nebulizing gas.” The specification does not teach this limitation. The remarks point to [0033] of the instant specification, which teaches a voltage applied to a solvent syringe or nebulizing capillary. This disclosure fails to provide written description of the claim limitation because it does not teach that the voltage applied to the liquid is adjusted in order to provide increased signal intensity for the sample material for at least one m/z relative to a baseline signal intensity produced utilizing nitrogen nebulizing gas. Additionally, the disclosure fails to explain how the adjustment is performed in order to accomplish this result. Consequently, the claim limitation is not sufficiently supported by the disclosure to reasonably convey possession of the claimed subject matter, and therefore the claim is rejected for lacking written description.
Rejections under 35 USC 112(b)
In view of the amendments to claim 1, the rejection of claim 1-3 and 5-11 under 35 USC 112 (b) has been withdrawn.
Rejections under 35 USC 103
Applicant’s arguments filed 05/28/2026, with respect to the rejections under 35 USC 103 have been fully considered and are partially persuasive. Upon further consideration, a new ground(s) of rejection is made in view of Knapp (US 20080087811 A1), which teaches helium as a nebulizing gas in a specifically DESI application. Note that Bajic is still relevant to the claimed invention as analogous art (See MPEP 2141.01 (a)). Although directed to ESI, and not specifically DESI, Bajic is similarly concerned with ionizing samples for analysis, particularly through a form of electrospray ionization that utilizes a nebulization gas. Consequently, Bajic remains as pertinent prior art of record.
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 Objections
Claim 5 is objected to because of the following informalities:
Improper capitalization of “The” in the 3rd line of the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claims 3 and 5 are 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 3 recites the limitation "wherein adjusting one or more process parameters includes: adjusting a pressure differential at the inlet of the mass spectrometer to provide increased signal intensity". It is unclear if the “a pressure differential” of claim 3 is the same or different to the “pressure differential” of claim 1 upon which claim 3 depends. For purposes of examination, the claim will be interpreted as teaching “the pressure differential”, as referring to the pressure differential of claim 1.
Claim 5 recites the limitation "wherein adjusting a pressure differential at the inlet of the mass spectrometer includes…". It is unclear if the “a pressure differential” of claim 5 is the same or different to the “pressure differential” of claim 3 and/or claim 1 upon which claim 5 depends. For purposes of examination, the claim will be interpreted as teaching “the pressure differential”, as referring to the pressure differential of claim 1 and claim 3.
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, gas flow velocity, solvent flow rate, voltage applied to the liquid, and pressure differential at the inlet of a mass spectrometer, to provide increased signal intensity for the sample material 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 applied to the liquid, and pressure differential at the inlet of a mass spectrometer, 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, such as the linear gas velocity, and solvent flow rate to provide the claimed result, but there is no mention in the specification of adjusting the voltage applied to the liquid or adjusting the pressure differential at the inlet of a mass spectrometer, or how either of these parameters would be adjusted, in order to produce the result of providing an increased signal intensity as claimed. 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 3 recites “wherein adjusting one or more process parameters includes” adjusting a pressure differential at the inlet of the mass spectrometer to provide increased signal intensity” is not supported by the disclosure, at least because the disclosure does not disclose adjusting a pressure differential at the inlet of a mass spectrometer to provide increased signal intensity. Paragraphs [0070]-[0074] disclose adjusting the gas flow rate, such as the linear gas velocity, and solvent flow rate to provide the claimed result, but there is no mention in the specification of adjusting the pressure differential at the inlet of a mass spectrometer to increase signal intensity, or how either of this parameter would be adjusted in order to produce the result of providing an increased signal intensity as claimed. 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.
Claim 5 is rejected by virtue of claim 3.
Claim 5 recites “wherein adjusting a pressure differential at the inlet of the mass spectrometer includes: The inlet of the mass spectrometer comprising a tube; and including increasing a length of the tube to reduce a vacuum at the inlet of a mass spectrometer to provide increased signal intensity” is not supported by the disclosure, at least because the disclosure does not disclose adjusting a pressure differential at the inlet of a mass spectrometer includes increasing a length of the tube of the mass spectrometer to reduce a vacuum at the inlet of a mass spectrometer to provide increased signal intensity. Paragraphs [0070]-[0074] disclose adjusting the gas flow rate, such as the linear gas velocity, and solvent flow rate to provide the claimed result, but there is no mention in the specification of adjusting the pressure differential at the inlet of a mass spectrometer in the claimed manner in order to increase signal intensity. Further, [0031] dsicusses the mass spectrometer having a tubular extension with a length that may reduce the volume and/or velocity of air drawn into inlet; however, this disclosure fails to discuss adjusting a pressure differential to reduce a vacuum at the inlet to provide increased signal intensity. 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.
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 are rejected under 35 U.S.C. 103 as being unpatentable over Venter (US 20080156985 A1) in view of Knapp (US 20080087811 A1) and Bajic (US 20210210320 A1).
Regarding claim 1, Venter teaches a method of ionizing a liquid for use in DESI mass spectrometry (Intended use) (Abstract and [0010] teaches ambient-pressure DESI.), the method comprising:
causing the 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); and
adjusting one or more process parameters selected from gas flow rate, gas flow velocity, solvent flow rate, voltage applied to the liquid, and pressure differential at the inlet of a mass spectrometer, to provide increased signal intensity for the sample material ([0004] teaches that signal intensity depends strongly on geometric factors and the optimization of various parameters. [0023] teaches nebulizing gas flow rates as a process parameter that is adjusted between different values, [0024] teaches spray solvent flow rate as a process parameter that is adjusted (increased), see Figs. 5A-5C).
Venter does not teach helium nebulizing gas and Venter does not explicitly teach a comparison of the signal intensity relative to a baseline signal intensity produced utilizing nitrogen nebulizing gas.
Knapp teaches helium nebulizing gas (helium nebulization gas in the application of desorption electrospray ionization (DESI) mass spectrometry, [0060]-[0061]).
Bajic also teaches helium nebulizing gas ([0029], [0104]), and adjusting one or more process parameters selected from gas flow rate, gas flow velocity, solvent flow rate, voltage applied to the liquid, 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]-[0107]).
Knapp modifies Venter by suggesting helium as the nebulizing gas.
Bajic modifies the combination by suggesting a comparison of signal intensity relative to a signal intensity produced utilizing nitrogen nebulizing gas.
In particular, since Venter utilizes nitrogen as the nebulizing gas in DESI, and Knapp utilizes helium in DESI, Bajic, directed to ESI, suggests comparing signal intensities between configurations utilizing helium and nitrogen as the respective nebulizing gas, and, through routine experimentation, one can achieve embodiments utilizing helium as the nebulizing gas that have an increased signal intensity for the sample material for at least one m/z relative to a baseline signal intensity produced utilizing nitrogen nebulizing gas.
Since Knapp, Bajic and Venter are all directed to types of electrospray ionization utilizing a nebulizing gas, 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 Knapp, since Knapp demonstrates that helium is a known effective nebulizing gas in DESI ([0060]-[0061], [0065], Figs. 1d, 2-5), and since Bajic teaches that within electrospray ionization embodiments, “helium as a nebulizer gas can give sensitivity enhancements over nitrogen,” (Bajic, [0104]-[0107]). Furthermore, it would be obvious to one of ordinary skill in the art in view of the combination of Knapp, Bajic, and Venter that the invention of claim 1 could be achieved via routine experimentation because the process parameters are shown to be results-effective variables (see Venter: ([0004] teaches that signal intensity depends strongly on geometric factors and the optimization of various parameters. [0023] teaches nebulizing gas flow rates as a process parameter that is adjusted between different values, [0024] teaches spray solvent flow rate as a process parameter that is adjusted (increased), see Figs. 5A-5C) 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]). MPEP 2144.05 II 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)”. Therefore the claim is obvious in view of the combination.
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.
Knapp teaches helium nebulizing gas (helium nebulization gas, [0060]-[0061]).
Knapp 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 Knapp because helium is a known effective nebulizing gas in DESI ([0060]-[0061], [0065], Figs. 1d, 2-5).
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 Venter teaches 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.
Knapp teaches helium nebulizing gas (helium nebulization gas, [0060]-[0061]).
Knapp 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 Knapp because helium is a known effective nebulizing gas in DESI ([0060]-[0061], [0065], Figs. 1d, 2-5).
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Venter (US 20080156985 A1) in view of Knapp (US 20080087811 A1) and Bajic (US 20210210320 A1), further in view of Cooks et. al. (US 20140264004 A1), hereinafter Cooks.
Regarding claim 2, the combination 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 the combination 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 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Venter (US 20080156985 A1) in view of Knapp (US 20080087811 A1) and Bajic (US 20210210320 A1), further in view of Jolliffe, et. al. (US 20150214021 A1), hereinafter Jolliffe.
Regarding claim 3, the combination 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 combination 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);
The combination 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 the combination 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 Knapp (US 20080087811 A1) and Bajic (US 20210210320 A1), further in view of Muller, et. al. (EP 3920208 A1), hereinafter Muller.
Regarding claim 6, the combination does not explicitly 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 the combination 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 Knapp (US 20080087811 A1) and Bajic (US 20210210320 A1), further in view of Fukui (US 20210208113 A1).
Regarding claim 10, the combination 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 the combination 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.
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LAURA E TANDY
Examiner
Art Unit 2881
/DAVID E SMITH/Examiner, Art Unit 2881
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