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 .
Examiner’s note
The Office identified the following March Meeting Abstract during search for relevant art:
Drachman, et. al. Towards Single Molecule Protein Sequencing by Nanopore Mass Spectrometry. APS March Meetings Abstracts, March 2019. https://ui.adsabs.harvard.edu/abs/2019APS..MARS55013D
Please provide any posters, presentation slides, or other documents presented at the 2019 March meeting in the next IDS.
Response to Arguments
Rejections under 35 USC §103
Applicant’s arguments filed 10/20/2025, with respect to the rejection(s) under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Yuill, et. al. (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g).
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 37, 41, and 90 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 37 recites “wherein the electrode and the capillary has an interior connected to a voltage source” is indefinite because it is unclear if both the electrode and the capillary have an interior that is connected to a voltage source, or if only the capillary has an interior connected to a voltage source.
Claim 41 is rejected by virtue of its dependence on claim 37.
Claim 90 recites “further comprising sequencing the ions or ion clusters to determine the molecule,” is indefinite because it is not clear if ‘the molecule’ of claim 90 is the same or different to the ‘molecules’ of claim 75 from which claim 90 depends.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 75, 76, 81, and 85 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yuill, et. al. (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g), hereinafter Yuill, as evidenced by the instant application, hereinafter Stein.
Regarding claim 75, Yuill teaches a method, comprising:
passing a fluid comprising water (all solutions were prepared with 18 MΩ·cm H2O. The solvent spray is disclosed to be 70% methanol and 0.1% glacial acetic acid, indicating that the remaining percentage comprises the 18 MΩ·cm H2O. See ‘Experimental Section’ on page 8499) and molecules, dissolved in the fluid and comprising biomolecules, polymers, peptides or proteins and/or nucleic acids (bovine insulin, leucine enkephalin, equine cytochrome c, and ubiquitin, See ‘Experimental Section’ on page 8499), into a capillary defining an opening (nanopipette with orifice, pg. 8498, right column, last paragraph)); and
applying an electric field at least sufficient to cause molecules within the fluid to exit the fluid (pg. 8500, right column, paragraph below eq. (2)), wherein the opening is sized to cause at least 50% of the molecules to exit as ions or ion clusters (Yuill teaches an opening size less than 100 nm. The instant application, Stein, teaches that this result (at least 50% of the molecules exiting as ions or ion clusters) is the consequence of the opening size being less than 125 or 100 nm (see [0028], [0054]-[0055] of the US publication of the patent application). Since Yuill teaches an opening size of less than 100 nm, the opening of Yuill is sized to cause at least 50% of the molecules to exit as ions or ion clusters, as evidenced by Stein. See MPEP 2112 (II), "[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention.”).
Regarding claim 76, Yuill teaches further comprising determining an identity of the ions or ion clusters (mass spectrometric analysis, Abstract, which fundamentally involves the identification of ions).
Regarding claim 81, Yuill teaches wherein the ion clusters contain an average of no more than 7 molecules of solvent (Yuill teaches an opening size less than 100 nm. The instant application, Stein, teaches that this result (ion clusters containing an average of no more than 7 molecules of solvent) is the consequence of the opening size being less than 125 or 100 nm (see [0026], [0055] of the US publication of the patent application). Since Yuill teaches an opening size of less than 100 nm, the opening of Yuill is such that it would produce ion clusters containing an average of no more than 7 molecules of solvent, as evidenced by Stein. See MPEP 2112 (II), "[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention.”).
Regarding claim 85, Yuill teaches wherein the opening of the capillary is sized such that, when the electric field is applied, at least 50% of the exiting species exit the charged meniscus via ion evaporation (Yuill teaches an opening size less than 100 nm. The instant application, Stein, teaches that this result (at least 50% of the exiting species exit the charged meniscus via ion evaporation) is the consequence of the opening size being less than 125 or 100 nm (see [0028], [0054]-[0055] of the US publication of the patent application). Since Yuill teaches an opening size of less than 100 nm, the opening of Yuill is sized to cause at least 50% of the exiting species exit the charged meniscus via ion evaporation, as evidenced by Stein. See MPEP 2112 (II), "[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention.”).
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 2, 6, 17, 20, 25, 29, 31, 35, 37, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Yuill, et. al. (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g), hereinafter Yuill in view of Bush, et. al. (The nanopore mass spectrometer, Review of Scientific Instruments, American Institute of Physics, Vol. 8, no. 11, 29 November 2017), hereinafter Bush.
Regarding claim 1, Yuill teaches an ion source (nanopipette emitter for nanoelectrospray ionization (nano-ESI), first paragraph in left column of page 8498), comprising:
a capillary defining an opening having a cross-sectional dimension of less than 100 nm (nanopipette with orifice diameter < 100 nm (typically ~50 nm), pg. 8498, right column, last paragraph));
a fluid inside the capillary (solution, see ‘Experimental Section’ on page 8499), the fluid comprising:
a solvent comprising water (all solutions were prepared with 18 MΩ·cm H2O. The solvent spray is disclosed to be 70% methanol and 0.1% glacial acetic acid, indicating that the remaining percentage comprises the 18 MΩ·cm H2O. See ‘Experimental Section’ on page 8499); and
molecules dissolved in the solvent, the molecules comprising biomolecules, polymers, peptides or proteins and/or nucleic acids (bovine insulin, leucine enkephalin, equine cytochrome c, and ubiquitin, See ‘Experimental Section’ on page 8499); and
Yuill does not teach an electrode positioned proximate the opening of the capillary in a downstream direction.
Bush teaches an electrode positioned proximate the opening of the capillary in a downstream direction (Fig. 3, extractor, pg. 113307-2).
Since Bush and Yuill are both directed to nanoscale electrospray ionization, 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 Bush because the electric fields draw ions from liquid into vacuum at the nano-scale aperture in the ion source. The extactor electrode allows for ion emission to be achieved and the extractor works with einzel lenses to efficiently collect ions forma wide range of initial directions and kinetic energies to direct the ions through the mass spectrometry system (Bush, Fig. 2 and caption on page 11307-2, Fig. 3, right column 1st and 2nd full paragraphs of pg. 113307-3).
Regarding claim 2, Yuill teaches wherein the opening of the capillary has a cross- sectional dimension of less than 65 nm (~50 nm nanopipette orifice diameter, pg. 8498, right column, last paragraph.
Regarding claim 6, Yuill teaches wherein the capillary is tapered at the opening (Fig. 1 shows nanopipette is tapered at the opening).
Regarding claim 17, Yuill does not explicitly teach wherein the capillary has an aspect ratio of length to cross-sectional dimension of greater than or equal to 100.
Bush teaches wherein the capillary has an aspect ratio of length to cross-sectional dimension of greater than or equal to 100 (pg. 4, Fig. 5c and 5d show dimensions; using these dimension, aspect ratio of length to outer diameter: 644um/170nm ≈ 3,788 ≥ 100, aspect ratio of length to inner diameter: 644um/61nm ≈ 10,557 ≥ 100).
Bush modifies Yuill by suggesting an aspect ratio of length to cross-sectional dimension greater than 100.
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 Bush because “the high aspect ratio of the structure enhances the electric fields at the tip, thereby lowering the voltage required to generate an electrospray,” (Bush, pg. 113307-4, left column).
Regarding claim 20, Yuill teaches wherein the capillary has a cross-sectional dimension of less than 100 nm (nanopipette with orifice diameter < 100 nm (typically ~50 nm), pg. 8498, right column, last paragraph)).
Regarding claim 25, Yuill does not teach wherein the center opening of the electrode is larger than the opening of the capillary.
Bush teaches wherein the center opening of the electrode is larger than the opening of the capillary (Fig. 2 on pg. 113307-2, Fig. 3 on pg. 113307-3 shows extractor having opening greater than the opening of the nanopore ion source).
Bush modifies Yuill by suggesting an extractor electrode where the center opening of the electrode is larger than the opening of the 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 Bush because having the center opening of the electrode larger than the opening of the capillary allows the ions to travel through the circular hole in the center of the extractor to be focused into the mass spectrometer, (Bush, pg. 113307-2, right column).
Regarding claim 29, Yuill does not teach wherein the electrode is annular.
Bush teaches wherein the electrode is annular (Fig. 3 shows the extractor electrode has annular shape. Further, pg. 2, right column teaches the extractor has a circular hole in its center).
Bush modifies Yuill by suggesting an annular extractor electrode.
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 Bush because the annular shape allows the ions to travel through the circular hole in the center of the extractor to be focused into the mass spectrometer, (Bush, pg. 113307-2, right column).
Regarding claim 31, Yuill does not teach wherein the electrode is positioned within 10 mm of the opening of the capillary.
Bush teaches wherein the electrode is positioned within 10 mm of the opening of the capillary (pg. 2, right column, first paragraph of II. teaches the extraction electrode is 0.5 cm = 5 mm < 10mm away from the capillary tip).
Bush modifies Yuill by suggesting an extractor electrode positioned within 10 mm of the capillary opening.
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 Bush because the proximity allows the ions to be extracted by the extractor electrode to be drawn and focused toward the mass spectrometer, (Bush, pg. 113307-2, right column).
Regarding claim 35, Yuill does not teach wherein the electrode is positioned in front of the opening of the capillary.
Bush teaches wherein the electrode is positioned in front of the opening of the capillary (pg. 2, right column, first paragraph of II., Fig. 3).
Bush modifies Yuill by suggesting an extractor electrode positioned in front of the opening of the 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 Bush because an extractor electrode in front of the capillary opening allows ions to be extracted by the extractor electrode to be drawn and focused toward the mass spectrometer, (Bush, pg. 113307-2, right column).
Regarding claim 37, Yuill does not teach wherein the electrode and the capillary has an interior connected to a voltage source.
Bush teaches wherein the electrode and the capillary has an interior connected to a voltage source (pg. 3, right column, 2nd paragraph of section III teaches a voltage supply connecting to the interior of the nanopore such that the liquid is biased to a potential of 201 V. The extractor electrode is adjusted between -300 V and + 300 V and so must also be connected to a voltage supply).
Bush modifies Yuill by suggesting the electrode and capillary has an interior connected to a voltage source.
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 Bush because the applied voltages create an electric field to create ionization at the end of the capillary, (Bush, pg. 113307-3, right column).
Regarding claim 46, Yuill teaches a mass spectrometer (mass spectrometer, ‘Experimental Section’ on pg. 8499), comprising: the ion source of claim 1 (Yuill in view of Bush, see 103 rejection of claim 1 above);
Although Yuill does not explicitly mention ion optics downstream of the ion source; a mass filter downstream of the ion optics; and a detector downstream of the mass filter, these are common components of a mass spectrometer system and are taught by Bush.
Bush teaches ion optics downstream of the ion source (ion optics, Fig. 2 and caption on pg. 113307-2); a mass filter downstream of the ion optics (quadrupole mass filter, Fig. 2 and caption on pg. 113307-2); and a detector downstream of the mass filter (detector, Fig. 2 and caption on pg. 113307-2).
Bush modifies Yuill by suggesting ion optics, a mass filter, and a detector in order downstream from the ion source.
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 Bush because these elements work together to create a mass spectrometry system in which the ion optics gather and transmit the ions and the mass filter transmits the ions selectively on the basis of their m/z, and the detector registers the transmitted ions, (Bush, caption of Fig. 2).
Claims 30 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Yuill (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g) in view of Bush, et. al. (The nanopore mass spectrometer, Review of Scientific Instruments, American Institute of Physics, Vol. 8, no. 11, 29 November 2017), further in view of Luedtke, et al (Nanojets, Electrospray, and Ion Field Evaporation: Molecular Dynamics Simulations and Laboratory Experiments, J. Phys. Chem. A, 112, 9628-9649, (2008)), hereinafter Luedtke.
Regarding claim 30, Although Bush teaches the electrode (extraction electrode, pg. 3, first paragraph of section III., Fig. 3), Yuill in view of Bush does not explicitly teach wherein the electrode has a cross- sectional dimension of less than 5 cm.
Luedtke teaches wherein the electrode has a cross- sectional dimension of less than 5 cm (6mm diameter of the orifice of the extractor electrode is a cross-sectional dimension of the electrode, pg. 9632, first paragraph of section 2).
Luedtke modifies the combination by suggesting the extractor electrode suggested by Bush has a cross-sectional dimension of 6 mm, which is less than 5 cm.
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 Luedtke because a device having the claimed relative dimensions would not perform differently than the prior art device and is therefore not patentably distinct, (MPEP 2144.04, IV. A., “In Gardner v. TEC Syst., Inc., 725 F.2d 1338, 220 USPQ 777 (Fed. Cir. 1984), cert. denied, 469 U.S. 830, 225 USPQ 232 (1984), the Federal Circuit held that, where the only difference between the prior art and the claims was a recitation of relative dimensions of the claimed device and a device having the claimed relative dimensions would not perform differently than the prior art device, the claimed device was not patentably distinct from the prior art device.”).
Regarding claim 41, Yuill does not teach wherein the voltage source is capable of producing an electric field between the electrode and the capillary having a maximum of less than or equal to 4 V/nm.
Although Bush teaches wherein the voltage source is capable of producing an electric field between the electrode and the capillary (pg. 3, right column, 2nd paragraph of section III, also caption of Fig. 2), Bush fails to explicitly teach an electric field having a maximum of less than or equal to 4 V/nm
Luedtke teaches having a maximum of less than or equal to 4 V/nm (Abstract).
Luedtke modifies the combination by suggesting an electric field between the electrode and the capillary having a maximum of less than 4 V/nm.
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 Luedtke because electric fields around 1 V/nm or 0.7-1.9 V/nm have been found to be critical electric fields to expect field evaporation for nm sized droplets, (Luedtke, pg. 9630, left column, second full paragraph).
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Yuill (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g) in view of Bush, et. al. (The nanopore mass spectrometer, Review of Scientific Instruments, American Institute of Physics, Vol. 8, no. 11, 29 November 2017), further in view of Li, et al (US 6462337 B1), hereinafter Li.
Regarding claim 34, Yuill in view of Bush does not teach wherein the electrode is positioned around the capillary.
Li teaches wherein the electrode is positioned around the capillary (auxiliary electrode 30a, Fig. 5, Fig. 8).
Li modifies the combination by suggesting the electrode is positioned around the 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 Li because positioning the electrode around the capillary increases the electric field gradient from the capillary tip, (Li, Col 2, lines 59-66).
Claim 90 is rejected under 35 U.S.C. 103 as being unpatentable over Yuill, et. al. (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g) in view of Drachman, et. al. (Towards Single Molecule Protein Sequencing by Nanopore Mass Spectrometry, APS March Meetings Abstracts, March 2019. https://ui.adsabs.harvard.edu/abs/2019APS..MARS55013D).
Regarding claim 90, although Yuill teaches mass spectrometric analysis of a series of peptides and proteins electrosprayed from pulled-quartz capillary nanopipette emitters with internal diameters ranging from 37 to 70 nm (see Abstract of Yuill), Yuill does not explicitly teach further comprising sequencing the ions or ion clusters to determine the molecule.
Drachman teaches further comprising sequencing the ions or ion clusters to determine the molecule (an approach to sequencing protein molecules using nanopore mass spectrometry using mass and time of detection of the resulting fragments).
Drachman modifies Yuill by suggesting sequencing the ions or ion clusters to determine the molecule.
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 Drachman because Drachman allows an approach to sequencing single protein molecules for their identification, (Drachman, Abstract).
Claim 97 is rejected under 35 U.S.C. 103 as being unpatentable over Yuill (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g).
Regarding claim 97, Yuill does not explicitly teach wherein the molecules exiting as ions or ion clusters exit at an overall ion transmission efficiency of greater than 0.1; however, the claimed invention is obvious because one of ordinary skill in the art could achieve the claimed range through routine experimentation. Yuill teaches that Nano-ESI, reducing the orifice diameter of the emitter, provides increased ionization efficiency relative to conventional ESI as a consequence of the smaller droplets initially produced, which yields an increased surface charge-to-volume ratio that promotes more efficient ion formation, (Yuill, pg. 8498, left column). Consequently, Yuill demonstrates that the opening size of the capillary is a results-effective variable related to ionization efficiency. 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 Yuill suggests that adjusting the opening size effects the ionization efficiency, it would be obvious that one could optimize the capillary opening size in order to achieve the claimed result of an overall ion transmission efficiency of greater than 0.1. Therefore, the claim is obvious in view of Yuill.
Claims 108, 109, 111, are rejected under 35 U.S.C. 103 as being unpatentable over Yuill (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g) in view of Pan, et. al. (Nanoelectrospray Ionization of Protein Mixtures: Solution pH and Protein pI, Analytical Chemistry, Vol 76, Issue 4, (2004)), hereinafter Pan.
Regarding claim 108, Yuill teaches a method, comprising: passing a fluid (solution, see ‘Experimental Section’ on page 8499) comprising water (all solutions were prepared with 18 MΩ·cm H2O. The solvent spray is disclosed to be 70% methanol and 0.1% glacial acetic acid, indicating that the remaining percentage comprises the 18 MΩ·cm H2O. See ‘Experimental Section’ on page 8499) and a biopolymer comprising amino acids, the biopolymer dissolved in the fluid (bovine insulin, leucine enkephalin, equine cytochrome c, and ubiquitin, See ‘Experimental Section’ on page 8499), into a capillary defining an opening having a cross- sectional dimension of less than 100 nm (nanopipette with orifice diameter < 100 nm (typically ~50 nm), pg. 8498, right column, last paragraph)); applying an electric field to ionize the biopolymer proximate the opening to produce ions or ion clusters (electric field at the nanopipette tip, pg. 8500); and directing the ions or ion clusters to a detector (mass spectrometer, see ‘Experimental Section’ on pg. 8499.
Yuill does not explicitly teach wherein the fluid has a pH lower than an isoelectric point of the amino acids of interest of the biopolymer
Pan teaches wherein the fluid has a pH lower than an isoelectric point of the amino acids of interest of the biopolymer (Abstract teaches “maximum signals in positive ion mode were noted when the pH value of the solution was 4-5 units lower than the protein pI”).
Pan modifies Yuill by suggesting that the fluid has a pH lower than the isoelectric point of the amino acids of interest of the biopolymer.
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 Pan because having a pH lower than the protein pI results in maximum signals, (Pan, Abstract).
Regarding claim 109, Yuill teaches comprising applying an electric field to ionize the biopolymer proximate the opening (pg. 8500, right column, paragraph below eq. (2)) to produce amino acid ions, (Yuill teaches an opening size less than 100 nm. The instant application, Stein, teaches that this result (producing amino acid ions) is the consequence of the opening size being less than 300 nm (see [0092], [0093] of the US publication of the patent application). Since Yuill teaches an opening size of less than 100 nm, the opening of Yuill would produce amino acid ions, as evidenced by Stein. See MPEP 2112 (II), "[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention.”).
Regarding claim 111, Yuill does not explicitly teach wherein the pH is less than 6.22
Pan teaches the pH is less than 6.22 (pH = 2.3, see Fig. 1 caption).
Pan modifies Yuill by suggesting a pH less than 6.22.
The combination renders the claimed invention obvious because Pan teaches that “maximum signals in positive ion mode were noted when the pH value of the solution was 4-5 units lower than than the protein pI” (Pan, Abstract) and because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Claim 110 is rejected under 35 U.S.C. 103 as being unpatentable over Yuill, et. al. (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g), hereinafter Yuill in view of Pan (Nanoelectrospray Ionization of Protein Mixtures: Solution pH and Protein pI, Analytical Chemistry, Vol 76, Issue 4, (2004)), further in view of Drachman, et. al. (Towards Single Molecule Protein Sequencing by Nanopore Mass Spectrometry, APS March Meetings Abstracts, March 2019. https://ui.adsabs.harvard.edu/abs/2019APS..MARS55013D).
Regarding claim 110, although Yuill teaches mass spectrometric analysis of a series of peptides and proteins electrosprayed from pulled-quartz capillary nanopipette emitters with internal diameters ranging from 37 to 70 nm (see Abstract of Yuill), Yuill does not explicitly teach further comprising sequencing the ions or ion clusters to determine the biopolymer.
Drachman teaches further comprising sequencing the ions or ion clusters to determine the biopolymer (an approach to sequencing protein molecules using nanopore mass spectrometry using mass and time of detection of the resulting fragments).
Drachman modifies the combination by suggesting sequencing the ions or ion clusters to determine the biopolymer comprising amino acids.
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 Drachman because Drachman allows an approach to sequencing single protein molecules for their identification, (Drachman, Abstract).
Claim 112 is rejected under 35 U.S.C. 103 as being unpatentable over Yuill (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g), hereinafter Yuill in view of Pan, et. al. (Nanoelectrospray Ionization of Protein Mixtures: Solution pH and Protein pI, Analytical Chemistry, Vol 76, Issue 4, (2004)), as evidenced by Sigma (Product Information Cytochrome c from equine heart (C7752), Datasheet).
Regarding claim 112, Yuill does not explicitly teach wherein the pH is between 3.8 and 8.6.
Pan teaches “maximum signals in positive ion mode were noted when the pH value of the solution was 4-5 units lower than the protein pI”. Yuill teaches a fluid comprising a biopolymer comprising amino acids (equine cytochrome c is taught in the ‘Experimental Section’ on page 8499). Sigma teaches that equine cytochrome c has a pI of 10.0-10.5. A pH 4-5 units lower than this pI range is a pH of 6-6.5 or 5-5.5.
The combination of Yuill in view of Pan as evidenced by Sigma suggests a pH within the claimed range.
The combination renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Maulbetsch, et. al. “Preserving the Sequence of a Biopolymer’s Monomers as They Enter an Electrospray Mass Spectrometer” Phys. Rev. Applied 6, 054006 (2016). https://doi.org/10.1103/PhysRevApplied.6.054006
Karas, et. al. “Nano-electrospray ionization mass spectrometry: addressing analytical problems beyond routine” Anal Chem (2000) 366:669-676
Teaches Nano-ESI of aqueous solution of myoglobin (Fig. 10)
Teaches nano ESI facilitates stable spraying of solvents such as water and aqueous salt solutions which causes problems in conventional ESI due to low spray stability.
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LAURA E TANDY
Examiner
Art Unit 2881
/DAVID E SMITH/Examiner, Art Unit 2881