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
Rejections under 35 USC 112(b)
In view of the amendments to claims 37 and 90, the rejection of claims 37, 41, and 90 has been withdrawn.
Rejections under 35 USC §103
Applicant’s arguments filed 04/27/2026, 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 Therefore, the rejection has been withdrawn.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 Drachman, et. al. (“Towards Single Molecule Protein Sequencing by Nanopore Mass Spectrometry”. *APS March Metting*, March 2019. Abstract and presentation. https://meetings.aps.org/Meeting/MAR19/Session/S55.13 See IDS filed 04/27/2026) and Bush, et. al. (The nanopore mass spectrometer, Review of Scientific Instruments, American Institute of Physics, Vol. 8, no. 11, 29 November 2017).
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, 2, 6, 17, 20, 25, 29, 31, 35, 37, 46, 75, 76, 81, 85, and 90 are rejected under 35 U.S.C. 103 as being unpatentable over Drachman, et. al. (“Towards Single Molecule Protein Sequencing by Nanopore Mass Spectrometry”. *APS March Metting*, March 2019. Abstract and presentation. https://meetings.aps.org/Meeting/MAR19/Session/S55.13 See IDS filed 04/27/2026) 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, Drachman teaches an ion source (electrospray source, pg. 4), comprising:
a capillary defining an opening having a cross-sectional dimension of less than 100nm (pg. 6, figure on left hand side shows opening having cross-sectional dimension of less than 100 nm);
a fluid inside the capillary, the fluid comprising:
a solvent comprising water (pg. 6, amino acids in water); and
molecules dissolved in the solvent, the molecules comprising biomolecules, polymers, peptides or proteins and/or nucleic acids (pg. 6, amino acids); and
an electrode positioned proximate the opening of the capillary in a downstream direction (pg. 4),
wherein the opening is exposed to a vacuum environment with no background gas (pg. 4 shows the opening of the capillary in a vacuum chamber, and pg. 6 states there is no background gas).
Drachman does not explicitly specify a pressure of no more than 100 mPa.
Bush teaches a pressure of no more than 100 mPa (see pg. 113307-6, section “V. Vacuum System”, third paragraph, second to last sentence, which teaches a pressure of 10-6 mbar, which is equivalent to 0.1 mPa. See also pg. 113307-1, 2nd paragraph, which teaches delivery of ions directly from liquid into high vacuum, and absence of a background gas).
Bush modifies Drachman by suggesting that the vacuum chamber into which the ionization capillary of Drachman opens into has a pressure less than 100 mPa.
Since both inventions are directed to protein sequencing via nanopore mass spectrometry, 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 collisions with a background gas disperses the ions widely and scrambles their order, which needs to be preserved for sequencing, and therefore a background gas must be abandoned for sequencing to be workable (pg. 113307-1, second paragraph of “I. Introduction”, especially last two sentences.).
Regarding claim 2, Drachman teaches wherein the opening of the capillary has a cross- sectional dimension of less than 65 nm (pg. 6, figure on left side).
Regarding claim 6, Drachman teaches wherein the capillary is tapered at the opening (pg. 4 and pg. 6 show tapered opening of capillary).
Regarding claim 17, Drachman 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 Drachman 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, Drachman teaches wherein the capillary has a cross-sectional dimension of less than 100 nm (pg. 4, figure on left side).
Regarding claim 25, Drachman teaches wherein the center opening of the electrode is larger than the opening of the capillary (pg. 4, pg. 6).
Regarding claim 29, Drachman teaches wherein the electrode is annular (pg. 4, pg. 6).
Regarding claim 31, Drachman does not explicitly 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 Drachman 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). Additionally, Bush 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.
Regarding claim 35, Drachman teaches wherein the electrode is positioned in front of the opening of the capillary (pg. 4, pg. 6).
Regarding claim 37, Drachman teaches wherein the electrode is connected to a voltage source and the capillary has an interior connected to the voltage source (pg. 6).
Regarding claim 46, Drachman teaches a mass spectrometer (pg. 4), comprising:
the ion source of claim 1 (electrospray source, pg. 4);
ion optics downstream of the ion source (ion optics, pg. 4));
a mass filter downstream of the ion optics (magnetic sector, pg. 4); and
a detector downstream of the mass filter (detector array, pg. 4).
Regarding claim 75, Drachman teaches a method, comprising:
passing a fluid comprising water and molecules, dissolved in the fluid and comprising biomolecules, polymers, peptides or proteins and/or nucleic acids (amino acids in water, pg. 6), into a capillary defining an opening (nanoscale capillary tip, pg. 4, pg. 6); and
applying an electric field at least sufficient to cause molecules within the fluid to exit the fluid into a vacuum environment with no background gas (pg. 4 shows opening in vacuum chamber/environment, pg. 6 states there is no background gas), wherein the opening is sized to cause at least 50% of the molecules to exit as ions or ion clusters (pg. 10, pg. 9, pg. 12).
Drachman does not explicitly specify a pressure of no more than 100 mPa.
Bush teaches a pressure of no more than 100 mPa (see pg. 113307-6, section “V. Vacuum System”, third paragraph, second to last sentence, which teaches a pressure of 10-6 mbar, which is equivalent to 0.1 mPa. See also pg. 113307-1, 2nd paragraph, which teaches delivery of ions directly from liquid into high vacuum, and absence of a background gas).
Bush modifies Drachman by suggesting that the vacuum chamber into which the ionization capillary of Drachman opens into has a pressure less than 100 mPa.
Since both inventions are directed to protein sequencing via nanopore mass spectrometry, 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 collisions with a background gas disperses the ions widely and scrambles their order, which needs to be preserved for sequencing, and therefore a background gas must be abandoned for sequencing to be workable (pg. 113307-1, second paragraph of “I. Introduction”, especially last two sentences.).
Regarding claim 76, Drachman teaches further comprising determining an identity of the ions or ion clusters (pg. 12, sequencing).
Regarding claim 81, Drachman teaches wherein the ion clusters contain an average of no more than 7 molecules of solvent (pgs. 10-12 teaches unsolvated ions, and pure ion evaporation regime. Additionally, Drachman 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 Drachman teaches an opening size of less than 100 nm, the opening of Drachman 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, Drachman 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 (Drachman 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 Drachman teaches an opening size of less than 100 nm, the opening of Drachman 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.” See also pgs. 10-12 of Drachman which teaches unsolvated ions and pure ion evaporation regime, indicating that at least 50% of the exiting species exit via ion evaporation.).
Regarding claim 90, Drachman teaches further comprising sequencing the ions or ion clusters to determine the molecules (pg. 12 and title).
Claims 30, 34, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Drachman (“Towards Single Molecule Protein Sequencing by Nanopore Mass Spectrometry”. *APS March Metting*, March 2019. Abstract and presentation. https://meetings.aps.org/Meeting/MAR19/Session/S55.13 See IDS filed 04/27/2026) and Bush (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 Drachman teaches an electrode, Drachman 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.
Luedtke 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.
Regarding claim 34, Drachman 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 positioning the electrode around the capillary instead of in front 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 Li because positioning the electrode around the capillary increases the electric field gradient from the capillary tip, (Li, Col 2, lines 59-66).
Regarding claim 41, Drachman does not explicitly 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.
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). Additionally, Luedtke 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.
Claim 97 is rejected under 35 U.S.C. 103 as being unpatentable over Drachman (“Towards Single Molecule Protein Sequencing by Nanopore Mass Spectrometry”. *APS March Metting*, March 2019. Abstract and presentation. https://meetings.aps.org/Meeting/MAR19/Session/S55.13 See IDS filed 04/27/2026) and Bush (The nanopore mass spectrometer, Review of Scientific Instruments, American Institute of Physics, Vol. 8, no. 11, 29 November 2017), further in view of Yuill (Analytical Chemistry 2013 85 (18), 8498-8502. DOI: 10.1021/ac402214g).
Regarding claim 97, Drachman 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.
Claims 108-112 are rejected under 35 U.S.C. 103 as being unpatentable over Drachman (“Towards Single Molecule Protein Sequencing by Nanopore Mass Spectrometry”. *APS March Metting*, March 2019. Abstract and presentation. https://meetings.aps.org/Meeting/MAR19/Session/S55.13 See IDS filed 04/27/2026) 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, Drachman teaches a method, comprising: passing a fluid comprising water and a biopolymer comprising amino acids, the biopolymer dissolved in the fluid (pg. 6, amino acids in water), into a capillary defining an opening having a cross- sectional dimension of less than 100 nm (nanoscale capillary tip is less than 100 nm as seen on pg. 6); applying an electric field to ionize the biopolymer proximate the opening to produce ions or ion clusters (pg. 4, pg. 6); and directing the ions or ion clusters to a detector (pg. 4, pg. 6, abstract).
Drachman 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 Drachman 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 solution pH lower than the protein pI results in maximum signals, (Pan, Abstract).
Regarding claim 109, Drachman teaches comprising applying an electric field to ionize the biopolymer proximate the opening to produce amino acid ions (pg. 4, pg. 6).
Regarding claim 110, Drachman teaches further comprising sequencing the ions or ion clusters to determine the biopolymer (title, abstract, pgs. 1-2, and 12).
Regarding claim 111, Drachman 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 Drachman 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.
Regarding claim 112, Drachman 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”. Drachman teaches a fluid containing protein/amino acids (title, pg. 4, pg. 6, abstract.) One of oridinary skill would be motivated by the teachings of Pan to achieve the claimed range through routine experimentation. See MPEP 2144.05 II, which teaches “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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 Pan teaches the pH of the solution as a results-effective variable, where the pH has an effect on the resulting signals, one could achieve the claimed range by experimenting with the pH of the solution depending on the amino acids present in order to achieve maximum signals and a pH between 3.8 and 8.6, as claimed. Therefore, the claim is obvious in view of Pan.
Claim 113 is rejected under 35 U.S.C. 103 as being unpatentable over Drachman (“Towards Single Molecule Protein Sequencing by Nanopore Mass Spectrometry”. *APS March Metting*, March 2019. Abstract and presentation. https://meetings.aps.org/Meeting/MAR19/Session/S55.13 See IDS filed 04/27/2026) and Pan (Nanoelectrospray Ionization of Protein Mixtures: Solution pH and Protein pI, Analytical Chemistry, Vol 76, Issue 4, (2004)), further in view of Bush (The nanopore mass spectrometer, Review of Scientific Instruments, American Institute of Physics, Vol. 8, no. 11, 29 November 2017).
Regarding claim 113, Drachman teaches wherein the biopolymer is ionized proximate the opening in an vacuum environment with no background gas (pg. 4 shows ionization in vacuum chamber, and pg. 6 states no background gas is present).
Drachman does not explicitly specify a pressure of no more than 100 mPa.
Bush teaches a pressure of no more than 100 mPa (see pg. 113307-6, section “V. Vacuum System”, third paragraph, second to last sentence, which teaches a pressure of 10-6 mbar, which is equivalent to 0.1 mPa. See also pg. 113307-1, 2nd paragraph, which teaches delivery of ions directly from liquid into high vacuum, and absence of a background gas).
Bush modifies Drachman by suggesting that the vacuum chamber into which the ionization capillary of Drachman opens into has a pressure less than 100 mPa.
Since both inventions are directed to protein sequencing via nanopore mass spectrometry, 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 collisions with a background gas disperses the ions widely and scrambles their order, which needs to be preserved for sequencing, and therefore a background gas must be abandoned for sequencing to be workable (pg. 113307-1, second paragraph of “I. Introduction”, especially last two sentences.).
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.
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LAURA E TANDY
Examiner
Art Unit 2881
/DAVID E SMITH/Examiner, Art Unit 2881
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