IP Library › Granted Patent US 12,293,908
Granted Patent B2
US 12,293,908 · App. 17/781,483 · Granted May 6, 2025

Mass spectrometer with charge measurement arrangement

Inventors: Martin F. Jarrold (Bloomington, IN); David E. Clemmer (Bloomington, IN)
Assignee: THE TRUSTEES OF INDIANA UNIVERSITY
H01J49/025H01J49/027H01J49/165H01J49/40H01J49/421H01J49/422
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Quick Facts
Patent No.
US 12,293,908
App. No.
17/781,483
Granted
May 6, 2025
Kind
B2
Abstract

A mass spectrometer may have an ion source region including an ion generator configured to generate ions from a sample, an ion detector configured to detect ions and produce corresponding ion detection signals, an electric field-free drift region disposed between the ion source region and the ion detector through which the generated ions drift axially toward the ion detector, a plurality of spaced-apart charge detection cylinders disposed in the drift region and through which the ions drifting axially through the drift region pass, and a plurality of charge amplifiers each coupled to a different one of the plurality of charge detection cylinders and each configured to produce a charge detection signal corresponding to a magnitude of charge of one or more of the generated ions passing through a respective one of the plurality of charge detection cylinders.

Claims (50)

1. A mass spectrometer, comprising:

an ion source region including an ion generator configured to generate ions from a sample,

an ion detector configured to detect ions and produce corresponding ion detection signals,

an electric field-free drift region disposed between the ion source region and the ion detector through which the generated ions drift axially toward the ion detector,

a plurality of spaced-apart charge detection cylinders disposed in the drift region and through which the ions drifting axially through the drift region pass, and

a plurality of charge amplifiers each coupled to a different one of the plurality of charge detection cylinders and each configured to produce a charge detection signal corresponding to a magnitude of charge of one or more of the generated ions passing through a respective one of the plurality of charge detection cylinders.

2. The mass spectrometer of claim 1 , further comprising:

an ion region or instrument disposed between the ion source region and the drift region, and

at least one voltage source electrically connected to the ion region or instrument and configured to selectively produce at least one voltage to establish an electric field within the ion region or instrument oriented to accelerate the generated ions into the field-free drift region.

3. The mass spectrometer of claim 2 , further comprising:

at least one processor, and

at least one memory having instructions stored therein executable by the processor to control the at least one voltage source to produce the at least one voltage to establish the electric field within the ion region or instrument.

4. The mass spectrometer of claim 3 , wherein the instructions stored in the at least one memory further includes instructions executable by the processor to:

(a) control the at least one voltage source to produce the at least one voltage to establish the electric field within the ion acceleration region at a reference time RT,

(b) store in the at least one memory samples of the charge detection signals produced by each of the plurality of charge amplifiers as the accelerated ions drift axially through the field-free drift region toward the ion detector,

(c) monitor the ion detector and store detection times (DT) by the ion detector of each of the at least a subset of the accelerated ions,

(d) determine times-of-flight (TOF) of the at least a subset of the accelerated ions through the drift region each based on a respective one of the detection times DT relative to RT, and

(e) determine charge magnitudes or charge states of each of the at least a subset of the accelerated ions based on the respective TOF thereof, based on the magnitudes of the stored samples of the charge detection signals produced by the plurality of charge amplifiers, and based on axial lengths of the drift region, each of the plurality of charge detection cylinders and spacing therebetween.

5. The mass spectrometer of claim 4 , wherein the instructions stored in the at least one memory further includes instructions executable by the processor to determine the charge magnitudes or charge states of each of the at least a subset of the accelerated ions by

(i) determining velocities of the at least a subset of the accelerated ions each based on the respective TOF thereof and the axial length of the drift region,

(ii) for each of the at least a subset of the accelerated ions, determining a plurality of time windows based on the determined velocity of the ion and the axial lengths, each of the plurality of time windows corresponding to a time window, relative to RT or DT of the ion, during which the ion was passing through a different respective one of the plurality of charge detection cylinders,

(iii) for each of the plurality of charge amplifiers, processing the samples of the charge detection signal produced thereby during the respective time windows for each of the at least a subset of the accelerated ions to determine a set of equations relating magnitudes of the charge detection signal to magnitudes of the at least a subset of the accelerated ions, and

(iv) solving the plurality of sets of equations to determine charge magnitudes or charge states of each of the at least a subset of the accelerated ions.

6. The mass spectrometer of claim 4 , wherein the instructions stored in the at least one memory further includes instructions executable by the processor to determine mass-to-charge ratios of the at least a subset of the accelerated ions each based on the respective TOF thereof and on the axial length of the drift region.

7. The mass spectrometer of claim 6 , wherein the instructions stored in the at least one memory further includes instructions executable by the processor to determine mass values of the at least a subset of the accelerated ions each based on the respective determined mass-to-charge ratio thereof and on the respective determined charge magnitude or charge state thereof.

8. The mass spectrometer of claim 2 , wherein the ion region or instrument comprises an ion acceleration region having spaced apart first and second gates, the first gate adjacent to the ion source region and the second gate adjacent to the field-free drift region,

and wherein the at least one voltage source electrically connected to the first and second gates and is configured to selectively control voltage applied thereby to at least one of the first and second gates to establish the electric field within the ion acceleration region.

9. The mass spectrometer of claim 2 , wherein the ion region or instrument comprises an ion trap,

and wherein the at least one voltage source electrically connected to the ion trap and is configured to selectively control voltage applied thereto to establish the electric field within the ion trap.

10. The mass spectrometer of claim 2 , wherein the ion region or instrument comprises a mass-to-charge ratio filter,

and wherein the at least one voltage source electrically connected to the mass-to-charge ratio filter and is configured to selectively control voltage applied thereto to establish the electric field within the mass-to-charge ratio filter.

11. The mass spectrometer of claim 2 , further comprising a mass-to-charge ratio filter disposed between the ion source and the ion region or instrument,

wherein the ion region or instrument comprises an ion trap,

and wherein the at least one voltage source is electrically connected to the mass-to-charge ratio filter and to the ion trap, the at least one voltage source configured to selectively produce at least a first voltage to configure the mass-to-charge ratio filter to pass therethrough only ions having a selected mass-to-charge ratio or having mass-to-charge ratios within a selected range of mass-to-charge ratios, and to produce at least a second voltage to selectively establish the electric field within the ion trap.

12. The mass spectrometer of claim 2 , further comprising:

a first mass-to-charge ratio filter disposed between the ion source and the ion region or instrument,

a dissociation stage disposed between the first mass-to-charge ratio filter and the ion region or instrument and configured to dissociate ions passing therethrough, and

a second mass-to-charge ratio filter disposed between the ion source and the ion region instrument,

and wherein the at least one voltage source is electrically connected to each of the first and second mass-to-charge ratio filters, the at least one voltage source configured to selectively produce at least a first voltage to configure the first mass-to-charge ratio filter to pass therethrough only ions having a first selected mass-to-charge ratio or having mass-to-charge ratios within a first selected range of mass-to-charge ratios, and to produce at least a second voltage to configure the second mass-to-charge ratio filter to pass therethrough only ions having a second selected mass-to-charge ratio or having mass-to-charge ratios within a second selected range of mass-to-charge ratios.

13. The mass spectrometer of claim 1 , wherein the ion detector comprises a microchannel plate detector.

14. The mass spectrometer of claim 1 , wherein the ion detector comprises an ion-to-photon detector.

15. The mass spectrometer of claim 1 , wherein the ion detector comprises a Faraday cup detector.

16. The mass spectrometer of claim 1 , wherein the ion detector comprises an electron multiplier detector.

17. The mass spectrometer of claim 1 , further comprising:

at least one processor operatively coupled to the ion detector and to each of the plurality of charge amplifiers, and

at least one memory having stored therein instructions executable by the at least one processor to cause the at least one processor to determine mass-to-charge ratios of ions drifting through the drift region based on the ion detection signals and to determine corresponding charges of the ions based on the charge detection signals produced by one or more of the plurality of charge amplifiers.

18. The mass spectrometer of claim 1 , wherein the ion generator and the sample are both positioned within the ion source region.

19. The mass spectrometer of claim 1 , wherein the ion generator and the sample are positioned outside of the ion source region,

and wherein the ion generator is configured to generate ions from the sample and to supply the generated ions to the ion source region.

20. The mass spectrometer of claim 1 , wherein the ion generator comprises an electrospray ionization source.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 2, 2022
From: JARROLD, MARTIN F; CLEMMER, DAVID E
To: THE TRUSTEES OF INDIANA UNIVERSITY
Reel/Frame 060078/0221 →
Continuity (2)
Provisional Application 62949554 · Dec 18, 2019
Related Publication 20230013173A1 · Jan 19, 2023
References Cited (254)
US 3019168A · Taylor · 1962 [cited by applicant]
US 5285063A · Schwartz et al. · 1994 [cited by applicant]
US 5478745A · Samulski · 1995 [cited by applicant]
US 5572025A · Cotter · 1996 [cited by applicant]
US 5770857A · Fuerstenau et al. · 1998 [cited by applicant]
US 5863541A · Samulski et al. · 1999 [cited by applicant]
US 5869248A · Yuan et al. · 1999 [cited by applicant]
US 5877022A · Stinchcomb et al. · 1999 [cited by applicant]
US 5880466A · Benner · 1999 [cited by applicant]
US 5882652A · Valdes et al. · 1999 [cited by applicant]
US 5886346A · Makarov · 1999 [cited by applicant]
US 5905040A · Mazzara et al. · 1999 [cited by applicant]
US 5916563A · Young et al. · 1999 [cited by applicant]
US 5965358A · Carrion et al. · 1999 [cited by applicant]
US 6013487A · Mitchell · 2000 [cited by applicant]
US 6083702A · Mitchell et al. · 2000 [cited by applicant]
US 6156303A · Russell et al. · 2000 [cited by applicant]
US 6183950B1 · Madonna · 2001 [cited by applicant]
US 6583408B2 · Smith et al. · 2003 [cited by applicant]
US 6744042B2 · Zajfman et al. · 2004 [cited by applicant]
US 6753523B1 · Whitehouse · 2004 [cited by applicant]
US 6888130B1 · Gonin · 2005 [cited by applicant]
US 7314912B1 · Hallek et al. · 2008 [cited by applicant]
US 7829842B2 · Makarov · 2010 [cited by applicant]
US 8294085B2 · Ding · 2012 [cited by applicant]
US 8395112B1 · Bier · 2013 [cited by applicant]
US 8409870B2 · Van Wujickhuijse · 2013 [cited by applicant]
US 8766170B2 · Guna et al. · 2014 [cited by applicant]
US 8866074B2 · Okumura · 2014 [cited by applicant]
US 8963075B2 · Chen et al. · 2015 [cited by applicant]
US 9095793B2 · Flagan · 2015 [cited by applicant]
US 10056244B1 · Quarmby et al. · 2018 [cited by applicant]
US 10088451B2 · Giles et al. · 2018 [cited by applicant]
US 20020185606A1 · Smith et al. · 2002 [cited by applicant]
US 20030155502A1 · Grosshans et al. · 2003 [cited by applicant]
US 20040169137A1 · Westphall et al. · 2004 [cited by applicant]
US 20050236375A1 · Gefter et al. · 2005 [cited by applicant]
US 20070102634A1 · Frey et al. · 2007 [cited by applicant]
US 20070254352A1 · Schaffer et al. · 2007 [cited by applicant]
US 20090020694A1 · Florey · 2009 [cited by applicant]
US 20090078866A1 · Li et al. · 2009 [cited by applicant]
US 20090108194A1 · Page et al. · 2009 [cited by applicant]
US 20090189069A1 · Chen · 2009 [cited by applicant]
US 20090294641A1 · Konicek et al. · 2009 [cited by applicant]
US 20100084549A1 · Ermakov et al. · 2010 [cited by applicant]
US 20100084552A1 · Kawana · 2010 [cited by applicant]
US 20100090102A1 · Rather et al. · 2010 [cited by applicant]
US 20100227310A1 · Manalis et al. · 2010 [cited by applicant]
US 20100234837A1 · Alfano · 2010 [cited by applicant]
US 20100314538A1 · Makarov et al. · 2010 [cited by applicant]
US 20100320377A1 · Cotter · 2010 [cited by applicant]
US 20110095175A1 · Bateman · 2011 [cited by applicant]
US 20110240845A1 · Ding · 2011 [cited by applicant]
US 20120112056A1 · Brucker et al. · 2012 [cited by applicant]
US 20120282641A1 · Reilly et al. · 2012 [cited by applicant]
US 20120292498A1 · Jiang et al. · 2012 [cited by applicant]
US 20130068942A1 · Verenchikov · 2013 [cited by applicant]
US 20130124099A1 · Ecker et al. · 2013 [cited by applicant]
US 20130175440A1 · Perelman et al. · 2013 [cited by applicant]
US 20130200261A1 · Mizutani et al. · 2013 [cited by applicant]
US 20130234017A1 · Kaltashov et al. · 2013 [cited by applicant]
US 20130327934A1 · Makarov et al. · 2013 [cited by applicant]
US 20140197333A1 · Jolliffe et al. · 2014 [cited by applicant]
US 20140299766A1 · Anderson et al. · 2014 [cited by applicant]
US 20140346344A1 · Chen · 2014 [cited by applicant]
US 20150008316A1 · Guna · 2015 [cited by applicant]
US 20150021472A1 · Makarov · 2015 [cited by applicant]
US 20150325425A1 · Makarov · 2015 [cited by applicant]
US 20150331000A1 · Collier et al. · 2015 [cited by applicant]
US 20160005580A1 · Grinfeld · 2016 [cited by applicant]
US 20160035556A1 · Berkout et al. · 2016 [cited by applicant]
US 20160181084A1 · Smith · 2016 [cited by applicant]
US 20160336165A1 · Guna · 2016 [cited by applicant]
US 20170040152A1 · Makarov · 2017 [cited by applicant]
US 20170307565A1 · Clemmer et al. · 2017 [cited by applicant]
US 20170372883A1 · Verenchikov · 2017 [cited by applicant]
US 20180247805A1 · Continetti · 2018 [cited by examiner]
US 20190088459A1 · Takahashi · 2019 [cited by applicant]
US 20190236142A1 · Balakrishnan · 2019 [cited by applicant]
US 20200003739A1 · Yamamoto et al. · 2020 [cited by applicant]
US 20200243317A1 · Lopez-Hilfiker et al. · 2020 [cited by applicant]
US 20200357626A1 · Jarrold et al. · 2020 [cited by applicant]
CN 102714127A · 2012 [cited by applicant]
CN 107690690A · 2018 [cited by applicant]
CN 110506320A · 2019 [cited by applicant]
JP 11144675 · 1999 [cited by applicant]
JP 2008186730A · 2008 [cited by applicant]
JP 2011507194A · 2011 [cited by applicant]
JP 2011523172A · 2011 [cited by applicant]
JP 2014501429A · 2014 [cited by applicant]
JP 2014122908A · 2014 [cited by applicant]
JP 2014165053A · 2014 [cited by applicant]
JP 2016522401A · 2016 [cited by applicant]
JP 2019056598A · 2019 [cited by applicant]
WO 1998011244A1 · 1998 [cited by applicant]
WO 1999061601A1 · 1999 [cited by applicant]
WO 2000028004A1 · 2000 [cited by applicant]
WO 2000028061A1 · 2000 [cited by applicant]
WO 2001092551A2 · 2001 [cited by applicant]
WO 2003042704A1 · 2003 [cited by applicant]
WO 2006130474A2 · 2006 [cited by applicant]
WO 2010135830A1 · 2010 [cited by applicant]
WO 2012080352A1 · 2012 [cited by applicant]
WO 2012083031A1 · 2012 [cited by applicant]
WO 2012145037A1 · 2012 [cited by applicant]
WO 2016073850A1 · 2016 [cited by applicant]
WO 2017162779A1 · 2017 [cited by applicant]
WO 2017190031A1 · 2017 [cited by applicant]
WO 2018109895A1 · 2018 [cited by applicant]
WO 2019118242A1 · 2019 [cited by applicant]
WO 2019140233A1 · 2019 [cited by applicant]
WO 2019162687A1 · 2019 [cited by applicant]
WO 2019231854A1 · 2019 [cited by applicant]
WO 2019236142A1 · 2019 [cited by applicant]
WO 2019236143A1 · 2019 [cited by applicant]
WO 2020117292A1 · 2020 [cited by applicant]
WO 2020219527A1 · 2020 [cited by applicant]
Japanese Office Action dispatched Jan. 18, 2023 for 2020-568469—16 pages (References 1, 2, 3 and 5 , and prior art document JP 2010-515210 English equivalent US 2013/327934A1,cited in this document have been previously … [cited by applicant]
Japanese Office Action dispatched Jan. 18, 2023 for application 2020-568379—11 pages (Prior art documents David Keifer, U.S. Pat. No. 5,880,466, U.S. Pat. No. 6,888,130 and U.S. Publication 2011/0240845 have been previo… [cited by applicant]
Paul et al., Das elektrische massenfilter als massenspektromeler und isotopenlrenner. Z. Phys. 152, 143-182 (1958). [cited by applicant]
Paul, et al., Das elektrische massenfiller, Z. Phys. 140, 262-273 (1955). [cited by applicant]
Pierson, Elizabeth E., et al., Charge Detection Mass Spectrometry for Single Ions with an Uncertainty in the Charge Measurement of 0.65 e; Elizabeth E_ Pierson et al.; Journal American Society for Mass Spectrometry, vol… [cited by applicant]
Pierson, Elizabeth E., et al. “Charge Detection Mass Spectrometry Identifies Preferred Non-icosahedral Polymorphs in the Self-Assembly of Woodchuck Hepatitis Virus Capsids”, Jour. of Molecular Biology, vol. 428, Issue 2… [cited by applicant]
Pierson, Elizabeth E., et al., “Detection of 1-15 Late Intermediates in Virus Capsid Assembly by Charge Detection Mass Spectrometry”, Journal of the American Chemical Society, vol. 136, No. 9, Feb. 19, 2014, 3536-3541. [cited by applicant]
Pierson, Elizabeth, “Charge Detection Mass Spectrometry: Instrumentation & Applications to Viruses”, Proquest Dissertations and Theses; Thesis (Ph.D.) vol. 76-09(E), Section: B. 168, May 2015. [cited by applicant]
Richards et al., A new operating mode for the quadrupole mass filler. Int. J. Mass Spectrom. Ion Phys. 12, 317-339 1973). [cited by applicant]
Richards et al., Waveform parameter tolerances for the quadrupole mass filler with rectangular excitation. Int. J. Mass Spectrom. Ion Phys_ 15, 417-428 (1974). [cited by applicant]
Schlunegger et al., Frequency scan for the analysis of high mass ions generated by matrix-assisted laser esorption/ionization in a Paul trap_ Rapid Commun. Mass Spectrom. 13, 1792-1796 (1999). [cited by applicant]
Sonalikar, Hrishikesh S., et al. “Numerical analysis of segmented-electrode Orbitraps”, International Journal of Mass Spectrometry, Elsevier Science Publishers, Amsterdam, NL, vol. 395, Dec. 17, 2015 (Dec. 17, 2015), p.… [cited by applicant]
Shinholt, Deven L., et al., “A Frequency and Amplitude Scanned Quadrupole Mass Filter for the Analysis of High m/z Ions”, Review of Scientific Instruments 85, 113109 (2014) (accepted Oct. 17, 2014; published online Nov.… [cited by applicant]
Snijder, J., et al., “Defining the Stoichiometry and Cargo Load of Viral and Bacterial Nanoparticles by Orbitrap Mass Spectrometry”, J. Am. Chem. Soc. 2014, 136, 7295-7299. [cited by applicant]
Sobott et al., A tandem mass spectrometer for improved transmission and analysis of large macromolecular Assemblies. Anal. Chem. 74, 1402-1407 (2002). [cited by applicant]
Syed, et al., Quadrupole mass filler: Design and performance for operation in stability zone 3. J. Am. Soc. Mass Spectrom. 24, 1493-1500 (2013). [cited by applicant]
Shade, Rosemary, et al. “Nucleotide Sequence and Genome Organization of Human Parvovirus B19 Isolated from the Serum of a Child during plastic Crisis”, Journal of Virology, vol. 58, No. 3, pp. 921-936 (Jun. 1986). [cited by applicant]
Sharp, Phillip A., et al. “RNA Interference”, American Association for the Advancement of Science; Science, New Series, vol. 287, No. 5462, pp. 2431-2433 (Mar. 31, 2000). [cited by applicant]
Shi, Z., et al. “Insertional Mutagenesis at Positions 520 and 584 of Adena-Associated Virus Type 2 (MV2) Capsid Gene and Generation of MV2 Vectors with Eliminated Heparin-Binding Ability and Introduced Novel Tropism”, H… [cited by applicant]
Srivastava, Arun, et al., “Nucleotide Sequence and Organization of the Adena-Associated Virus 2 Genome”, Journal of Virology, vol. 45, No. 2, pp. 555-564 (Feb. 1983). [cited by applicant]
Tsao, Jun, et al., “The Three-Dimensional Structure of Canine Parvovirus and Its Functional Implications”, American Association for the Advancement of Science, Science, New Series, vol. 251, No. 5000, pp. 1456-1464 (Mar… [cited by applicant]
Todd, Aaron R., et al. “Implementation of a Charge-Sensitive Amplifier without a Feedback Resistor for Charge Detection Mass Spectrometry Reduces Noise and Enables Detection of Individual Ions Carrying a Single Charge”,… [cited by applicant]
Walters, Robert W., “Structure of Adeno-Associated Virus Serotype 5”, Journal of Virology, vol. 78, No. 7, pp. 3361-3371 (Apr. 2004). [cited by applicant]
Winger, Brian E., et al., “Observation and Implications of High Mass-to-Charge Ratio Ions from Electrospray Ionization Mass Spectrometry,” 1993 American Society for Mass Spectrometry 4, 536-545. [cited by applicant]
Wang, Lei, et al., “Expanding the Genetic Code”, Annual Review of Biophysics and Biomolecular Structure, vol. 35, pp. 25-249 (2006). [cited by applicant]
Weiss, Victor U., et al, “Analysis of a Common Cold Virus and Its Subviral Particles by Gas-Phase Electrophoretic Mobility Molecular Analysis and Native Mass Spectrometry”, Anal Chem. 2015. [cited by applicant]
Wright, J. Fraser, “Product-Related Impurities in Clinical-Grade Recombinant AAV Vectors: Characterization and Risk Assessment”, Biomedicines 2014, 2, 80-97. [cited by applicant]
Xie, Qing, et al., “Canine Parvovirus Capsid Structure, Analyzed at 2.9 A Resolution”, Journal of Molecular Biology, vol. 64, pp. 497-520 (1996). [cited by applicant]
Xie, Qing, et al., “The atomic structure of adeno-associated virus (MV-2), a vector for human gene therapy”, PNAS, vol. 99, No. 16, pp. 10405-10410 (Aug. 6, 2002). [cited by applicant]
Xiao, Weidong, et al., “Gene Therapy Vectors Based on Adena-Associated Virus Type 1”, Journal of Virology, vol. 73, No. 5, pp. 3994-4003 (May 1999). [cited by applicant]
Uetrecht et al., “Stability and Shape of Hepatitis B Virus Capsids in Vacuo”, Angew. Chem. Int. Ed. 2008, 47, 6247-6251. [cited by applicant]
Uetrecht et al., “High-resolution mass spectrometry of viral assemblies: Molecular composition and stability of dimorphic hepatitis B virus capsids”, PNAS 2008, vol. 105, 9216-9920. [cited by applicant]
Xiong, et al., The development of charge detection-quadrupole ion trap mass spectrometry driven by rectangular and riangularwaves, Analyst 137, 1199-1204 (2012). [cited by applicant]
Yang, et al., Development of a palm portable mass spectrometer. J. Amer. Soc. Mass Spec. 19, 1442-1448 (2008). [cited by applicant]
Yost, et al., Selected ion fragmentation with a tandem quadrupole mass spectrometer. J. Am. Chem. Soc. 100, 274-2275 (1978). [cited by applicant]
Bioconjugate Techniques; Hermanson;Academic Press, 1st Edition (1996), (book reference, chapter guide attached; book/specific chapter(s) to be made available upon request). [cited by applicant]
European Office Action dated Sep. 2, 2021 for application 19 707 901.5—5 pages. [cited by applicant]
Japanese Office Action dispatched Feb. 17, 2023 for application 2020-568389—11 pages. [cited by applicant]
European Office Action issued Mar. 3, 2023 for application 19732193.8—14 pages. [cited by applicant]
Chiorini, John A., et al. “Cloning of Adeno-Associated Virus Type 4 (MV4) and Generation of Recombinant MV4 Particles”,Journal of Virology, vol. 71, pp. 6823-6833 (Sep. 1997). [cited by applicant]
Chiorini, John A., “Cloning and Characterization of Adeno-Associated Virus Type 5”, Journal of Virology, vol. 73, DP-1309-1319 (Feb. 1999). [cited by applicant]
Chernushevich, et al., Collisional cooling of large ions in electrospray mass spectrometry. Anal. Chem 76. H54-1760 (2004). [cited by applicant]
Cleves, Ann E., “Protein transport: The nonclassical ins and outs”, Current Biology, vol. 7, No. 5, pp. 318-320 (1997). [cited by applicant]
Contino, Nathan Colby, “Ion trap charge detection mass spectrometry: Lowering limits of detection and improving signal to noise”, ISBN: 9781303535048, Jul. 30, 2013 (Jul. 30, 2013). [cited by applicant]
Ding, et al., A simulation study of the digital ion trap mass spectrometer. Int. J. Mass Spectrom. 221, 117-138 (2002). [cited by applicant]
Ding, et al., A digital ion trap mass spectrometer coupled with atmospheric pressure ion sources. J_ Mass Spectrom. 69, 471-484 (2004). [cited by applicant]
Douglas J_ Linear quadrupoles in mass spectrometry. Mass Spectrom. Rev. 28, 937-960 (2009). [cited by applicant]
Doussineau, Tristan, et al. “Infrared multiphoton dissociation tandem charge detection-mass spectrometry of single megadalton electrosprayed ions”, Review of Scientific Instruments, AIP, Melville, NY, US, vol. 82, No. 8… [cited by applicant]
Draper, Benjamin E., et al. “The Funpet—a New Hybrid Ion Funnel-Ion Carpet Atmospheric Pressure Interface for the Simultaneous Transmission of a Broad Mass Range”, Journal of the American Society for Mass Spectrometry, … [cited by applicant]
Draper, Benjamin E., et al., “Real-Time Analysis and Signal Optimization for Charge Detection Mass Spectrometry”, J. Am. Soc. Mass Spectrom. (2019) 30:898Y904. [cited by applicant]
El-Baba, Tarick J. et al., “Melting proteins confined in nanodroplets with 10.6 [mu]m light provides clues about early steps of denaturation”, Chemical Communications, vol. 54, No. 26, Mar. 8, 2018 (Mar. 8, 2018), p. 32… [cited by applicant]
Elliott, Andrew G., et al. “Simultaneous Measurements of Mass and Collisional Cross-Section of Single Ions with charge Detection Mass Spectrometry”, Analytical Chemistry, vol. 89, No. 14, Jun. 16, 2017, pp. 7701-7708. [cited by applicant]
Elliott, Andrew G., et al. “Single Particle Analyzer of Mass: A Charge Detection Mass Spectrometer with a Multi-Detector Electrostatic Ion Trap”, International Journal of Mass Spectrometry, Elsevier Science Publishers, … [cited by applicant]
Elliott, Andrew G., et al. “Effects of Individual Ion Energies on Charge Measurements in Fourier Transform Charge Detection Mass Spectrometry (FT-CDMS)”, Journal of the American Society for Mass Spectrometry.,Nov. 14, 2… [cited by applicant]
Fuerstenau, et al., “Mass Spectrometry of an Intact Virus”, Agnew. Chem. 2001, 559-562. [cited by applicant]
Gao, Guangping, et al. “Clades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues”, vol. 78, pp. 6381-6388 (Jun. 2004). [cited by applicant]
Gao, Guangping, et al. “Novel Adeno-Associated Viruses from Rhesus Monkeys as Vectors for Human Gene Therap”, .; National Academy of Sciences, vol. 99, No. 18, pp. 11854-11859 (Sep. 3, 2002). [cited by applicant]
Gorman, Linda, et al. “Stable Alteration of Pre-mRNA Splicing Patterns by Modified U7 Small Nuclear RNAs”, National Academy of Sciences, vol. 95, No. 9, pp. 4929-4934 (Apr. 28, 1998). [cited by applicant]
Grifman, M., et al. “Incorporation of Tumor-Targeting Peptides into Recombinant Adeno-associated Virus Capsids”,.; Molecular Therapy, vol. 3, No. 6, pp. 964-975 (Jun. 2001). [cited by applicant]
Grinfeld, Dmitry, et al. “Space-Charge Effects in an Electrostatic Multireflection Ion Trap”, European Journal of Mass Spectrometry,vol. 20, No. 2, Apr. 1, 2014 (Apr. 1, 2014), p. 131-142. [cited by applicant]
Hauck, B., et al. “Characterization of Tissue Tropism Determinants of Adeno-Associated Virus Type 1”, Journal of Virology, vol. 77, No. 4, pp. 2768-2774 (Feb. 2003). [cited by applicant]
Heller, Manfred, et al. “Mass spectrometry-based analytical tools for the molecular protein characterization of human plasma lipoproteins”, Proteomics, vol. 5, No. 19, Jul. 1 (205-97-91) , pp. 2619-2639. [cited by applicant]
Hogan, Joanna, et al. “Optimized Electrostatic Linear Ion Trap for Charge Detection Mass Spectrometry”, Jul. 9, 2018 (Jul. 9, 2018), vol. 29, No. 10, p. 2086-2095. [cited by applicant]
Hutchins, Patrick M., et al. “Quantification of HDL Particle Concentration by Calibrated Ion Mobility Analysis”, Clinical Chemistry 60:11, 1393-1401, 2014. [cited by applicant]
Keifer, David Z., “Single-Molecule Mass Spectrometry”, Mass Spectrometry Reviews, vol. 36 pp. 715-733 (2017). [cited by applicant]
Keifer, David et al., “Charge Detection Mass Spectrometry of Bacteriophage P22 Procapsid Distributions Above 20MDa”, Rapid Communications in Mass Spectrometry, vol. 28, No. 5 , 2014. [cited by applicant]
Keifer, David Z., et al. “Charge Detection Mass Spectrometry with Almost Perfect Charge Accuracy”, Analytical Chemistry, vol. 87, No. 20, Oct. 20, 2015, pp. 10330-10337. [cited by applicant]
Kelly, Ryan T., et al. “The ion funnel: Theory, implementations, and applications”, Mass Spectrometry Reviews., vol. 29, Apr. 23, 2009, pp. 294-312. [cited by applicant]
Kim et al., A multicapillary inlet jet disruption electrodynamic ion funnel interface for improved sensitivity using atmospheric pressure ion sources. Anal. Chem. 73, 4162-4170 (2001). [cited by applicant]
Koizumi et al., A novel phase-coherent programmable clock for high-precision arbitrary waveform generation applied o digital ion trap mass spectrometry_ Int. J_ Mass Spectrom_ 292, 23-31 (2010). [cited by applicant]
Konenkov et al., Matrix methods for the calculation of stability diagrams in quadrupole mass spectrometry. J. Amer. Soc. Mass Spec. 13, 597-613 (2002). [cited by applicant]
Kukreja, Alexander A., et al. “Structurally Similar Woodchuck and Human Hepadnavirus Core Proteins Having Distinctly Different Temperature Dependencies of Assembly” Journal of Virology, vol. 68, No. 24, 14105-14115, Sep… [cited by applicant]
Landais et al., Varying the radio frequency: A new scanning mode for quadrupole analyzers. Rapid Commun. Mass Spectrom. 12, 302-306 (1998). [cited by applicant]
Makarov, Alexander, “Electrostatic Axially Harmonic Orbital Trapping: A High-Performance Technique of Mass Analysis”, Analytical Chemistry, vol. 72, No. 6, Mar. 1, 2000 (Mar. 1, 2000), p. 1156-1162. [cited by applicant]
Marmet et al., A frequency-swept quadrupole mass filler. Int. J_ Mass Spectrom. Ion Proc. 42, 3-10 (1982). [cited by applicant]
Martin, Stability of doubly charged alkali halide clusters. J_ Chem. Phys. 76, 5467-5469 (1982). [cited by applicant]
Miyamura, K., et al. “Parvovirus Particles as Platforms for Protein Presentation”, National Academy of Sciences, vol. 1,No. 18,pp. 8507-8511 (Aug. 30, 1994). [cited by applicant]
Mori, Seiichiro, Mori, et al. “Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization of capsid protein”, Virology 330, pp. 375-383 (2004). [cited by applicant]
Muramatsu, S., et al. “Nucleotide Sequencing and Generation of an Infectious Clone of Adeno-Associated Virus 3”, Virology vol. 221; Article No. 0367; pp. 208-217 (1996). [cited by applicant]
Muzyczka, N., “Use of Adeno-Associated Virus as a General Transduction Vector for Mammalian Cells”, Current Topics n Microbiology and Immunology, vol. 158, pp. 97-129 (1992). [cited by applicant]
Nie et al., Frequency scan of a quadrupole mass analyzer in the third stability region for protein analysis. J. Chin. Chem_ Soc., 53, 47-52 (2006). [cited by applicant]
Padron, Eric, et al. “Structure of Adeno-Associated Virus Type 4”, Journal of Virology, vol. 79, No. 8, pp. 5047-5058 Apr. 2005). [cited by applicant]
Puttaraju, M., et al. “Spliceosome-mediated RNA trans-splicing as a tool for gene therapy”, Nature Biotechnology, vol. 17, pp. 246-252 (Mar. 1999). [cited by applicant]
Kosaka, Nobuyoshi, et al., “Versatile roles of extracellular vesicles in cancer,” J Clin Invest. 2016;126(4):1163-1172. https://doi.org/10.1172/JCl81130. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/US on Oct. 11, 2021 and issued in connection with PCT/US2021/034480. [cited by applicant]
Fernandez-Maestre et al. “Ammonia as a Modifier in Ion Mobility Spectrometry: Effects on Ion Mobilities and Potential as a Separation Tool”, J. Chil. Chem. Soc. 2014. 59, No. 1, especially: abstract; p. 2398, col. 1, pa… [cited by applicant]
Kafle et al. “Understanding gas phase modifier interactions in rapid analysis by Differential Mobility-Tandem Mass Spectrometry”, J Am Soc Mass Spectrom. 2014. 25(7): pp. 1098-1113, especially: p. 7, para 2; p. 10, para… [cited by applicant]
Kiss et al. “Size, weight and position: ion mobility spectrometry and imaging MS combined”, Anal Bioanal Chem. 2011. 399: pp. 2623-2634, especially: p. 2626, col. 1, para 1. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/US on Jan. 12, 2016 and issued in connection with PCT/US2015/059463. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/US on Jun. 19, 2017 and issued in connection with PCT/US2017/030163. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Feb. 14, 2019 and issued in connection with PCT/US2018/051944. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Apr. 18, 2019 and issued in connection with PCT/US2019/013251. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Apr. 16, 2019 and issued in connection with PCT/US2019/013274. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Mar. 27, 2019 and issued in connection with PCT/US2019/013277. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Jul. 24, 2019 and issued in connection with PCT/US2019/013278. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Sep. 9, 2019 and issued in connection with PCT/US2019/013279. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Mar. 28, 2019 and issued in connection with PCT/US2019/013280. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Aug. 27, 2019 and issued in connection with PCT/US2019/013281. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Mar. 27, 2019 and issued in connection with PCT/US2019/013283. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Mar. 29, 2019 and issued in connection with PCT/US2019/013284. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Jul. 26, 2019 and issued in connection with PCT/US2019/013285. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Aug. 27, 2019 and issued in connection with PCT/US2019/035381. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Sep. 9, 2019 and issued in connection with PCT/US2019/035379. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/US on Jan. 24, 2021 and issued in connection with PCT/US2020/054975. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Mar. 8, 2021 and issued in connection with PCT/US2020/065300. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/US on Nov. 23, 2020 and issued in connection with PCT/US2020/052009. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/US on Mar. 18, 2021 and issued in connection with PCT/US2021/016325. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/US on Apr. 5, 2021 and issued in connection with PCT/US2021/016435. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/EP on Jul. 14, 2020 and issued in connection with PCT/US2020/029287. [cited by applicant]
Supplemental European Search Report for European Patent Application No. 17790559.3 dated Nov. 12, 2019 (11 pages). [cited by applicant]
Anthony, Staci N. “MS /MS instrumentation for megadalton-sized ions”, 2016, XP055619426, ISBN: 978-1-369-02558-3 Retrieved from the Internet: URL:https://search.proquest.com/docview/18 30450391?accountid=29404. [cited by applicant]
Anthony, et al., A simple electrospray interface based on a DC ion carpet, Int. J. Mass Spectrom. 371, 1-7 (2014). [cited by applicant]
Bantel-Schaal, U., et al., “Human Adena-Associated Virus Type 5 Is Only Distantly Related to Other Known Primate Helper-Dependent Parvoviruses”, Journal of Virology, vol. 73, pp. 939-947 (Feb. 1999). [cited by applicant]
Beuhler, et al., Threshold studies of secondary electron emission induced by macro ion impact on solid surfaces. Nucl. Instrum. Methods. 170, 309-315 (1980). [cited by applicant]
Beuhler, et al., A study of the formation of high molecular weight water cluster ions (m/e < 59000) in expansion of onized gas mixtures, J. Chem. Phys. 77, 2549-2557 (1982). [cited by applicant]
Botamanenko, Daniel, et al., “Ion-Ion Interactions in Charge Detection Mass Spectrometry”, J Am Soc Mass Spectrom. Dec. 2019 ; 30(12): 2741-2749. doi:10.1007/s13361-019-02343-y. [cited by applicant]
Brancia, et al., Digital asymmetric waveform isolation (DAWI) in a digital linear ion trap. J_ Am. Soc_ Mass Spectrom. 1. 1530-1533 (2010). [cited by applicant]
Brown, Brooke Ann, et al., “Charge Detection Mass Spectrometry Measurements of Exosomes and other Extracellular Particles Enriched from Bovine Milk” Anal. Chem., Just Accepted Manuscript ⋅ DOI: 10.1021/acs.analchem.9b05… [cited by applicant]
Brown, C., et al. “Chimeric Parvovirus B19 Capsids for the Presentation of Foreign Epitope”,; Virology 198, pp. 477-488 (1994). [cited by applicant]
Burnham, et al. “Analytical Ultracentrifugation as an Approach to Characterize Recombinant Adena-Associated Viral Vectors”, Human Gene Therapy Methods, vol. 26, No. 6; pp. 228-242, Oct. 15, 2015. [cited by applicant]
Chao, Hengiun, et al. “Several Log Increase in Therapeutic Transgene Delivery by Distinct Adena-Associated Viral Serotype Vectors” Molecular Therapy vol. 2, No. 6, pp. 619-623 (Dec. 2000). [cited by applicant]
Japanese Office Action dispatched Jan. 6, 2023 for application 2020-568366—9 pages (References 1 and 2 and the Doussineau article cited in this document have been previously submitted). [cited by applicant]
Extended EP Search Report completed Aug. 29, 2024 and issued in connection with EP Appln. No. 24174366., 12 pages. [cited by applicant]
English translation of an Office Action for Japanese Patent Appln. No. 2022-547047, dated Aug. 1, 2024. [cited by applicant]
Japanese Office Action dispatched Jan. 24, 2023 for co-pending application 2021-527871—4 pages (Prior art reference Alexander Makarov has been previously submitted). [cited by applicant]
Japanese Office Action dispatched Jan. 31, 2023 for co-pending application 2020-568364—9 pages. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/US on Mar. 8, 2021 and issued in connection with PCT/US2020/065301. [cited by applicant]
Keifer, David Z., et al. “Charge Detection Mass Spectrometry: Weighing Heavier Things”, Analyst, vol. 142, No. 10, Apr. 26, 2017 (Apr. 26, 2017), pp. 1654-1671. [cited by applicant]
English translation of an Office Action for Japanese Patent Appln. No. 2022-537367, dated Oct. 8, 2024, 6 pages. [cited by applicant]
English translation of an Office Action for Japanese Patent Appln. No. 2022-537360, dated Oct. 8, 2024, 3 pages. [cited by applicant]
European Office Action dated Dec. 9, 2024 and issued in connection with EP Appln. No. 20839501.2, 5 pages. [cited by applicant]
European Office Action dated Dec. 9, 2024 and issued in connection with EP Appln. No. 20839500.4, 5 pages. [cited by applicant]
Japanese Office Action (including English translation) issued in App. No. JP2022537360, dated Oct. 8, 2024, 6 pages. [cited by applicant]
Japanese Office Action (including English translation) issued in App. No. JP2022537367, dated Oct. 8, 2024, 11 pages. [cited by applicant]
Japanese Office Action (including English translation) issued in App. No. JP2022518995, dated Dec. 3, 2024, 6 pages. [cited by applicant]
Chinese Office Action (including English translation) issued in App. No. CN202080096842.5, dated Dec. 12, 2024, 19 pages. [cited by applicant]
Chinese Office Action (including English translation) issued in App. No. CN202080096856.7, issued on Feb. 17, 2025. [cited by applicant]