IP Library › Granted Patent US 12,283,475
Granted Patent B2
US 12,283,475 · App. 18/190,168 · Granted Apr 22, 2025

Instrument, including an electrostatic linear ion trap, for analyzing ions

Inventors: Martin F. Jarrold (Bloomington, IN); Joanna A. Hogan (Hillsboro, OR)
Assignee: THE TRUSTEES OF INDIANA UNIVERSITY
H01J49/4245H01J49/0036H01J49/025H01J49/062H01J49/406H01J49/4235H01J49/4265H01J49/48
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,283,475
App. No.
18/190,168
Granted
Apr 22, 2025
Kind
B2
Abstract

An instrument for analyzing ions may include an ion source to generate ions, at least one ion processing instrument to process the generated ions by one or both of filtering the ions according to a molecular characteristic and dissociating the ions, and an electrostatic linear ion trap (ELIT) to receive and trap ions exiting the at least one ion processing instrument. The ELIT has first and second ion mirrors separated by a charge detection cylinder, and is configured such that trapped ions oscillate back and forth through the charge detection cylinder between the first and second ion mirrors with a duty cycle, corresponding to a ratio of time spent by the trapped ions traversing the charge detection cylinder and total time spent by the trapped ions traversing a combination of the first and second ion mirrors and the charge detection cylinder during one complete oscillation cycle, of approximately 50%.

Claims (53)

1. An instrument for analyzing ions, comprising:

an ion source configured to generate ions from a sample,

at least one ion processing instrument configured to receive the generated ions from the ion source and to process the generated ions by one or a combination of filtering the ions according to a molecular characteristic and dissociating the ions,

an electrostatic linear ion trap (ELIT) positioned to receive ions exiting the at least one ion processing instrument and configured to trap at least one of the received ions therein, the ELIT including first and second ion mirrors and a charge detection cylinder positioned between the first and second ion mirrors, and

at least one voltage source coupled to the first and second ion mirrors, the at least one voltage source configured to establish electric fields in each of the first and second ion mirrors configured to reflect the trapped at least one ion entering a respective one of the first and second ion mirrors from the charge detection cylinder back through the charge detection cylinder and toward the other of the first and second ion mirrors such the trapped at least one ion oscillates back and forth through the charge detection cylinder between the first and second ion mirrors with a duty cycle, corresponding to a ratio of time spent by the trapped at least one ion traversing the charge detection cylinder and total time spent by the trapped at least one ion traversing a combination of the first and second ion mirrors and the charge detection cylinder during one complete oscillation cycle, of approximately 50%.

2. The instrument of claim 1 , wherein the at least one ion processing instrument comprises:

a first ion processing instrument configured to receive the generated ions from the ion source and to filter the generated ions according to the molecular characteristic, and

a second ion processing instrument configured to receive the filtered ions and to dissociate the filtered ions,

wherein the ELIT receives the dissociated ions from the second ion processing instrument.

3. The instrument of claim 2 , further comprising at least one ion separation instrument positioned between the ion source and the first ion processing instrument, the at least one ion separation instrument configured to separate the generated ions as a function of at least one molecular characteristic and to pass the separated ions to the first ion processing instrument.

4. The instrument of claim 3 , wherein the at least one ion separation instrument comprises one or any combination of at least one instrument for separating ions as a function of mass-to-charge ratio, at least one instrument for separating ions as a function of ion mobility, at least one instrument for separating ions as a function of ion retention time and at least one instrument for separating ions as a function of molecule size.

5. The instrument of claim 1 , wherein the at least one ion processing instrument comprises:

a first ion processing instrument configured to receive the generated ions from the ion source and to dissociate the generated ions, and

a second ion processing instrument configured to receive the dissociated ions and to filter the dissociated ions according to the molecular characteristic,

wherein the ELIT receives the filtered ions from the second ion processing instrument.

6. The instrument of claim 5 , further comprising at least one ion separation instrument positioned between the ion source and the first ion processing instrument, the at least one ion separation instrument configured to separate the generated ions as a function of at least one molecular characteristic and to pass the separated ions to the first ion processing instrument.

7. The instrument of claim 6 , wherein the at least one ion separation instrument comprises one or any combination of at least one instrument for separating ions as a function of mass-to-charge ratio, at least one instrument for separating ions as a function of ion mobility, at least one instrument for separating ions as a function of ion retention time and at least one instrument for separating ions as a function of molecule size.

8. The instrument of claim 1 , further comprising at least one ion separation instrument positioned between the at least one ion processing instrument and the ELIT, the at least one ion separation instrument configured to separate ions exiting the at least one ion processing instrument as a function of at least one molecular characteristic and to pass the separated ions to the ELIT.

9. The instrument of claim 1 , further comprising a processor and a memory having instructions stored therein executable by the processor to cause the processor to control the at least one voltage source to produce at least one output voltage to establish the electric fields in the first and second ion mirrors.

10. The instrument of claim 1 , further comprising a charge pre-amplifier having an input coupled to the charge detection cylinder, wherein the trapped at least one ion induces a charge on the charge detection cylinder each time the trapped at least one ion passes therethrough, and the charge pre-amplifier produces charge detection signals corresponding to detections of the charges induced by the at least one trapped ion on the charge detection cylinder,

a processor having an input coupled to an output of the charge pre-amplifier, and

a memory having instructions stored therein executable by the processor to cause the processor to process a plurality of the charge detection signals, resulting from oscillation of the trapped at least one ion multiple times back and forth through the charge detection cylinder between the first and second ion mirrors, to determine a mass-to-charge ratio of the trapped at least one ion and to determine a charge of the trapped at least one ion, and to compute a mass of the trapped at least one ion based on the determined mass-to-charge ratio and the determined charge of the trapped at least one ion.

11. An instrument for analyzing ions, comprising:

an ion source configured to generate ions from a sample,

at least one ion processing instrument configured to receive the generated ions from the ion source and to process the generated ions by one or a combination of filtering the ions according to a molecular characteristic and dissociating the ions,

an electrostatic linear ion trap (ELIT) positioned to receive ions exiting the at least one ion processing instrument and configured to trap at least one of the received ions therein, the ELIT including first and second ion mirrors and a charge detection cylinder positioned between the first and second ion mirrors, and

at least one voltage source coupled to the first and second ion mirrors, the at least one voltage source configured to establish electric fields in each of the first and second ion mirrors configured to reflect the trapped at least one ion entering a respective one of the first and second ion mirrors from the charge detection cylinder back through the charge detection cylinder and into the other of the first and second ion mirrors such the trapped at least one ion oscillates back and forth between the first and second ion mirrors each time passing through the charge detection cylinder,

wherein time spent by the trapped at least one ion passing through the charge detection cylinder is approximately equal to a sum of time spent by the trapped at least one ion travelling from a stopped position within one of the first and second ion mirrors into a respective end of the charge detection cylinder and time spent by the trapped at least one ion traveling from an opposite respective end of the charge detection cylinder to a stopped position within the other of the first and second ion mirrors.

12. The instrument of claim 11 , further comprising at least one ion separation instrument positioned between the ion source and the at least one ion processing instrument, the at least one ion separation instrument configured to separate the generated ions as a function of at least one molecular characteristic and to pass the separated ions to the at least one ion processing instrument,

wherein the at least one ion separation instrument comprises one or any combination of at least one instrument for separating ions as a function of mass-to-charge ratio, at least one instrument for separating ions as a function of ion mobility, at least one instrument for separating ions as a function of ion retention time and at least one instrument for separating ions as a function of molecule size.

13. The instrument of claim 11 , wherein the at least one ion processing instrument comprises:

a first ion processing instrument configured to receive the generated ions from the ion source and to filter the generated ions according to the molecular characteristic, and

a second ion processing instrument configured to receive the filtered ions and to dissociate the filtered ions,

wherein the ELIT receives the dissociated ions from the second ion processing instrument.

14. The instrument of claim 11 , wherein the at least one ion processing instrument comprises:

a first ion processing instrument configured to receive the generated ions from the ion source and to dissociate the generated ions, and

a second ion processing instrument configured to receive the dissociated ions and to filter the dissociated ions according to the molecular characteristic,

wherein the ELIT receives the filtered ions from the second ion processing instrument.

15. The instrument of claim 11 , further comprising at least one ion separation instrument positioned between the at least one ion processing instrument and the ELIT, the at least one ion separation instrument configured to separate ions exiting the at least one ion processing instrument as a function of at least one molecular characteristic and to pass the separated ions to the ELIT,

wherein the at least one ion separation instrument comprises one or any combination of at least one instrument for separating ions as a function of mass-to-charge ratio, at least one instrument for separating ions as a function of ion mobility, at least one instrument for separating ions as a function of ion retention time and at least one instrument for separating ions as a function of molecule size.

16. A method for analyzing ions, comprising:

generating ions from a sample,

processing the generated ions by one of filtering the ions according to a molecular characteristic and dissociating the ions to produce first processed ions,

processing the first processed ions by the other of filtering the ions according to the molecular characteristic and dissociating the ions to produce second processed ions, and

analyzing the second processed ions with an electrostatic linear ion trap, having first and second ion mirrors and a charge detection cylinder positioned between the first and second ion mirrors, by (i) establishing a first electric field in the first ion mirror, the first electric field configured to stop in the first ion mirror at least one of the second processed ions exiting a first end of the charge detection cylinder, proximate to the first ion mirror, and traveling into the first ion mirror, and to accelerate the stopped at least one of the second processed ions in the first ion mirror back into the first end of the charge detection cylinder, and (ii) establishing a second electric field in the second ion mirror, the second electric field configured to stop in the second ion mirror the at least one of the second processed ions exiting a second end of the charge detection cylinder, proximate to the second ion mirror, and traveling into the second ion mirror, and to accelerate the stopped at least one of the second processed ions in the second ion mirror back into the second end of the charge detection cylinder, such that the at least one of the second processed ions oscillates back and forth between the first and second ion mirrors under the influence of the first and second electric fields each time passing through the charge detection cylinder,

wherein time spent by the at least one of the second processed ions passing through the charge detection cylinder is approximately equal to a sum of time spent by the at least one of the second processed ions travelling from a stopped position within one of first and second ion passageways into a respective end of the charge detection cylinder and time spent by the at least one of the second processed ions traveling from an opposite respective end of the charge detection cylinder to a stopped position within the other of the first and second ion passageways.

17. The method of claim 16 , further comprising, prior to processing the generated ions to produce the first processed ions, separating the generated ions as a function of at least one molecular characteristic,

wherein the first processed ions are produced by one of filtering the separated ions according to the molecular characteristic and dissociating the separated ions.

18. The method of claim 17 , wherein separating the generated ions as a function of at least one molecular characteristic comprises separating the generated ions as a function of one or more of mass-to-charge ratio, ion mobility, ion retention time and molecule size.

19. The method of claim 16 , wherein each passage of the at least one of the second processed ions through the charge detection cylinder induces a corresponding at least one charge on the charge detection cylinder,

and wherein the method further comprises (i) processing, with at least one processor, a plurality of the at least one charges induced on the charge detection cylinder resulting from oscillation of the at least one of the second processed ions multiple times back and forth through the charge detection cylinder between the first and second ion mirrors to determine a mass-to-charge ratio of the at least one of the second processed ions and to determine a charge of the at least one of the second processed ions, and (ii) to compute a mass of the at least one of the second processed ions based on the determined mass-to-charge ratio and the determined charge.

20. The method of claim 19 , further comprising amplifying each of the at least one charges induced on the charge detection cylinder to produce a corresponding at least one charge detection signal,

wherein processing the plurality of the at least one charges induced on the charge detection cylinder comprises processing, with the at least one processor, a plurality of the at least one charge detection signals.

Continuity (5)
Continuation 17468791 · Sep 8, 2021
Continuation 16960170
Provisional Application 62680343 · Jun 4, 2018
Provisional Application 62616860 · Jan 12, 2018
Related Publication 20230245879A1 · Aug 3, 2023
References Cited (263)
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 Wuijckhuijse · 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 11257665B2 · Jarrold et al. · 2022 [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 20090294655A1 · Ding 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 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 et al. · 2018 [cited by applicant]
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]
US 20210202225A1 · Jarrold · 2021 [cited by examiner]
US 20210210332A1 · Jarrold · 2021 [cited by examiner]
US 20210210335A1 · Jarrold · 2021 [cited by examiner]
US 20210217606A1 · Jarrold et al. · 2021 [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 2019236142A1 · 2019 [cited by applicant]
WO 2019231854A1 · 2019 [cited by applicant]
WO 2020117292A1 · 2020 [cited by applicant]
WO 2020219527A1 · 2020 [cited by applicant]
WO 2021158676A1 · 2021 [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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Walters, Robert W., “Structure of Adeno-Associated Virus Serotype 5”, Journal of Virology, vol. 78, No. 7, pp. B361-3371 (Apr. 2004). [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]
Winger, Brian E., et al., “Observation and Implications of High Mass-to-Charge Ratio lons from Electrospray Ionization Mass Spectrometry,” 1993 American Society for Mass Spectrometry 4, 536-545. [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]
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]
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]
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]
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]
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]
European Office Action dated Sep. 9, 2022 for application 19 702 771.7—5 pages. [cited by applicant]
European Office Action dated Sep. 9, 2022 for application 19 702 775.8—5 pages. [cited by applicant]
European Office Action dated Nov. 23, 2022 for application 19 702 773.3—5 pages. [cited by applicant]
Examination report No. 1 issued Oct. 21, 2022 in Australian Application No. 2019281255—4 pages. [cited by applicant]
PCT International Search Report and Written Opinion completed by the ISA/US on Aug. 26, 2022 issued in connection with PCT/US2022/073503. [cited by applicant]
Japanese Office Action dispatched Jan. 6, 2023 for application 2020-568366—9 pages. [cited by applicant]
Japanese Office Action dispatched Jan. 18, 2023 for application 2020-568469—16 pages. [cited by applicant]
Japanese Office Action dispatched Jan. 18, 2023 for application 2020-568379—11 pages. [cited by applicant]
Japanese Office Action dispatched Jan. 24, 2023 for application 2021-527871—4 pages. [cited by applicant]
Japanese Office Action dispatched Jan. 31, 2023 for application 2020-568364—9 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]
Office Action and Search Report for CN patent application No. 201980051696.1, dated Sep. 25, 2023. (translation appended). [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 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/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/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/EP on Jul. 14, 2020 and issued in connection with PCT/US2020/029287. [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/EP on Mar. 8, 2021 and issued in connection with PCT/US2020/065301. [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]
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, C., et al. “Chimeric Parvovirus B19 Capsids for the Presentation of Foreign Epitope”,; Virology 198, pp. 477-488 (1994). [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]
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]
European Office Action dated Jun. 26, 2024 and issued in connection with EP Patent Appln. No. 19707901.5, 8 pages. [cited by applicant]
Non-Final Office Action, mailed Sep. 29, 2024 and issued in connection with U.S. Appl. No. 17/781,483, 84 pages. [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]
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 lon 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 lon 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, … [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]
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. (2005). [cited by applicant]
Hogan, Joanna, et al. “Optimized Electrostatic Linear lon 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]
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]
Keifer, David Z., “Single-Molecule Mass Spectrometry”, Mass Spectrometry Reviews, vol. 36 pp. 715-733 (2017). [cited by applicant]
Keifer, David Z., et al. “Charge detection mass spectrometry: weighing heavier things” The Analyst, vol. 142, No. 10, Jan. 1, 2017, pp. 1654-1671. [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]
Keifer, David et al., “Charge Detection Mass Spectrometry of Bacteriophage P22 Procapsid Distributions Above 20MDa”, Rapid Communications in Mass Spectrometry, vol. 28, No. 5, Mar. 15, 2014. [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]
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]
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]
Kosaka, Nobuyoshi, et al., “Versatile roles of extracellular vesicles in cancer,” J Clin Invest. 2016; 126(4):1163-1172. https://doi.org/10.1172/JCI81130. [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]
English translation of an Office Action for Japanese Patent AppIn. 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]