DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 17 December 2025 has been entered.
Response to Arguments
Applicant's arguments filed 17 December 2025 have been fully considered but they are not persuasive.
Rejections under 35 USC § 112(b)
By amendment, the indefinite rejections have been overcome.
Rejections under 35 USC § 102: Corr
The remarks take the position that a thermal wave is applied substantially co-axially with the axis of the ion beam and is in a direction toward the exit of the ion source. The remarks further take the position that the heaters 80 of Corr are directed towards the curtain plate aperture 14 and thus the thermal energy is not directed towards the exit of the ion source.
This has not been found persuasive. Specifically, the claim does not require the heater to be directed towards the ion source, only the thermal energy to be directed towards the ion source. Paragraph [0036] of Corr teaches the heater(s) 80 can be effective to raise the temperature of the ionization chamber to a temperature in a range of from 200 to 800 degrees Celsius. Therefore, thermal energy is directed towards the exit in order to raise the temperature of the entire chamber as the exit of ion source 40 is located in the ionization chamber.
Applicant is reminded that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Here, there is no requirement that the heater be directed towards the exit, only that thermal energy is directed towards the ion source. Since the entire chamber is heated, Corr directs thermal energy toward the exit of the ion source because the ion source is within the chamber that is heated.
However, in the event the claim was clarified to direct the heat source towards the ion source exit, it is noted that Covey et al. (USPN 6,759,650) teaches a heated gas jet heating gas to a temperature of 850 degrees C directed at a APCI source for vaporization and desolvation (see figure 7). Covey suggests directing the heated gas towards the exit of the ion source. Therefore, even if the claim were amended such that the heat source faces the ion source exit, such a limitation would be found obvious in view of Covey.
Rejections under 35 USC § 102: Covey/ Kostyukevich
Similar to Corr above, there is no requirement that the heater face the direction of the exit of the ion source, therefore thermal energy from the heating elements of Covey/ Kostyukevich radiates in all directions thus in the direction of the ion source.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 11, 13, 19, 21 and 35-37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Corr (WO2017103743).
Regarding claim 1, Corr teaches a method of fragmenting ions in a mass spectrometry system (figure 2 shows ion source 40 and heater 80. Paragraph [0036] teaches 80 can be effective to raise ethe temperature of the ionization chamber from 200 °C to about 800 °C. As evident from the instant specification such a temperature is sufficient to fragment ions ([0010] of the published application)1), comprising:
using an ion source (40) to ionize a sample so as to produce a plurality of ions (inherent to an ion source), wherein an ionization/fragmentation region is associated with the ion source (the location downstream of 40 where plume is shown in figure 2. Paragraph [0036] recites “The heater(s) 80 and the ion probe 42 can have a variety of configurations, but can in some aspects be generally positioned relative to one another and to the aperture 14b such that the heated gas flow directs the sample plume to the proximity of the aperture 14b”. Since the heated gas raises the temperature of the chamber to 800 degrees and is directed at the sample plume, the temperature at that location is sufficient for fragmentation as evident from the instant specification ([0010] of the published application). Note: MPEP 2112 recites “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. ”. Here since the temperature requirements are met, fragmentation inherently occurs. Paragraph [0036] also teaches that the ion population in the gap can be increased via heating, thus an ionization region), wherein the ionization/fragmentation region extends from an exit of the ion source (extending from end of 40) and is substantially along a portion of a surface-free path through which ions travel from the exit of the ion source to a vacuum chamber containing a mass analyzer (surface free between 40 and inlet 14b to vacuum chamber 16 of mass spectrometer 60), the vacuum chamber including an inlet coaxially aligned with the exit of the ion source to receive the ions traveling along the surface-free path (coaxial alignment seen in figure 1 between source 40 and inlet 14b/16b);
applying thermal energy, by a heat source (80) mounted at the ionization/fragmentation region ([0036] 80 positioned such that heat gas flow directs the sample plume to the proximity of aperture 14b, thus mounted at the ionization/fragmentation region) to the plurality of ions in the ionization/fragmentation region ([0036] 80 provides heated gas so as to direct sample plume and increases ion population. Since the temperature rises to 800 degrees, fragmentation inherently occurs, see discussion above) in a direction toward the exit of the ion source, and that is substantially co-axial the surface-free path defined by the coaxially aligned ion source exit and the vacuum chamber inlet ([0036] since the heated gas from 80 directs plume towards 14b, the heated gas is substantially co-axial with the ion source exit and vacuum chamber inlet. Note since the entire chamber is heated, thermal energy from the heated gas is directed towards the exit) to increase a temperature of the plurality of ions traveling within the ionization/fragmentation region ([0036]), to an elevated temperature of at least 550 degrees C (800 degrees C see paragraph [0036]), wherein the elevated temperature promotes thermally-induced dissociation of at least a portion of the plurality of ions at the exit (since the heated gas is provided directly at the plume and heats the chamber to 800 degrees C ([0036]), the requirements for TID at exit are met as evident from the instant disclosure (see paragraph [0010] of the instant published application) or by Makarov see discussion in footnote 1 above. Thus it is interpreted that fragmentation inherently occurs); and
transmitting the thermally dissociated ions along the surface-free path (through region between 40 and inlet 14b) to and through an inlet of the vacuum chamber (14b) containing the mass analyzer (60).
Regarding claim 2, Corr teaches wherein transmitting the thermally dissociated ions along the surface free path such that at least 50% of the thermally dissociated ions do not encounter a surface prior to reaching the inlet (no surfaces between exit of 40 and inlet 14b thus 100% of dissociated ions do not encounter a surface prior to reaching the inlet 14b. Note: heated gas directs plume towards inlet ([0036]) thus the plume of ions will not encounter any other surface because the plume is directed by heated gas towards the inlet).
Regarding 3, Corr teaches wherein the transmitted thermally dissociated ions are substantially free of undergoing diffusional losses, and wherein the thermally dissociated ions are substantially free of formation of cation adducts ([0018] of the instant published application teaches that by not encountering surfaces prior to reaching the inlet, diffusional losses of the ion fragments and formation of cation adducts are eliminated. Since the heat inherently causes fragmentation (see discussion above) and there are no surfaces upon which ions encounter prior to the inlet, therefore avoiding eliminating diffusional losses and formation of cations as in the instant specification. MPEP 2112 (II) recites: “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference.” Here, since the conditions of a substantially surface free fragmentation region is met by Corr, the result would be inherent to the reference).
Regarding claim 11, Corr as evidenced by Makarov (US pgPub 2021/0270773) teaches wherein the elevated temperature causes the thermal fragmentation at a fragmentation efficiency of at least about 70% (Corr teaches providing heated gas to the ionized plume of temperature risen to 800 degrees C. As evidenced by Makarov such a temperature results in 90% fragmentation efficiency [0161]).
Regarding claim 13, Corr teaches wherein the ion source is selected from the group consisting of atmospheric ion source ([0029] note ionization chamber 12 is maintained at atmospheric pressure.).
Regarding claim 19, Corr teaches wherein the plurality of ions comprises at least some multiply charged ions ([0004])
Claim 21 is the apparatus of claim 1 and taught in the citations herein above.
Regarding claim 35, Corr teaches wherein the elevated temperature of the plurality of ions is 800 degrees C ([0036] raising the temperature of the chamber to 800 degrees C, wherein the heated gas is directed at the plume, thus also heating the plume to 800 degrees C).
Regarding claim 36, Corr as evidenced by Makarov (US pgPub 2021/0270773) teaches wherein the elevated temperature causes the thermal fragmentation at a fragmentation efficiency of at least about 85% (Corr teaches providing heated gas to the ionized plume of temperature risen to 800 degrees C. As evidenced by Makarov such a temperature results in 90% fragmentation efficiency [0161]).
Regarding claim 37, Corr teaches wherein the elevated temperature at the exit of the ion source promotes thermally-induced dissociation of at least a portion of the plurality of ions concurrently with, or immediately after, ion formation (temperature of entire chamber raised to 800 degrees C, as evident from the instant specification and by Makarov, such a temperature is sufficient to achieve the claimed result).
Claims 1 and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Covey et al. (US pgPub 2011/0183431)
Regarding claim 1, Covey teaches method of fragmenting ions in a mass spectrometry system (fig. 10 ions heated to decluster (i.e. fragment) see paragraph [0096]), comprising:
using an ion source (208) to ionize a sample so as to produce a plurality of ions (inherent to an ion source), wherein an ionization/fragmentation region is associated with the ion source (1002 via resistive heating elements 1010 ([0096]). Note the number and location of heating elements may vary, for example heating elements may be located in the atmospheric pressure source region ([0097]), thus 1002 could extend from the ion source 208. The heating elements heat ions to a temperature of 750 degrees C ([0009]), thus operating in the same range as disclosed and thus interpreted to also perform ionization), wherein the ionization/fragmentation region extends from an exit of the ion source (1002 extends from ion source as seen in figure 10 or as modified by paragraph [0097] to include additional heating element in the atmospheric pressure ion source region 404) and is substantially along a portion of a surface-free path through which ions travel from the exit of the ion source to a vacuum chamber containing a mass analyzer (1002 (or as extended into the region 404 as suggested in paragraph [0097] to include heating elements in region 404) is substantially along a portion of a surface free path through which ions travel from the exit of ion source 208 to the entrance of MS via 210 (note “vacuum drag” in figure 10). That is the region 1002 overlaps with a surface free portion of the ion path to 204 from ion source 208); the vacuum chamber including an inlet (614) coaxially aligned with the exit of the ion source (614 aligned with ion source exit 208 as indicated by arrow) to receive the ions traveling along the surface free path (surface free between 208 and 614/210)
applying thermal energy, by a heat source (1010, note paragraph [0097] teaches the heating elements may be in the ion source region 404 and the chamber 604) mounted at the ionization/fragmentation region (since the heating elements cause fragmentation/ionization (see discussion above) they are mounted at the region) to the plurality of ions in the ionization/fragmentation region in a direction toward the exit of the ion source, and that is substantially coaxial to the surface-free path (figure 10 shows 110 coaxially aligned with the opening to DMS1 and paragraph [0097] suggests additional heating elements in region 404 thus along the ion path (i.e. coaxial from source to DMS1 to vacuum drag), wherein heat radiated from 1010 outside is in a direction of the exit (note: paragraph [0009] expressly teaches the source region where turbo heaters are operated to 750 degrees C. Therefore heating at the source)) to increase increasing a temperature of the plurality of ions traveling within the ionization/fragmentation region ([0096]), to an elevated temperature of 550 degrees C ([0009]), wherein the elevated temperature promotes thermally-induced dissociation at the exit of the ion source of at least a portion of the plurality of ions (since heating causes declustering of the sample ions, this is interpreted to be thermal dissociation of the plurality of ions (i.e. heat = thermal and decluster = dissociation), note paragraph [0009] teaches turbo heaters at source region operating at 750 degree C); and
transmitting the thermally dissociated ions along the surface-free path (through region 1002) to and through an inlet of the vacuum chamber (210) containing the mass analyzer (204).
Claim 21 is the apparatus of claim 1 and taught in the citations herein above.
Claims 1 and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kostyukevich et al. (Kostyukevich et al., “Thermal dissociation and H/D exchange of streptavidin tetramers at atmospheric pressure”, International Journal of Mass Spectrometry, 2018) (copy of publication submitted herewith).
Regarding claim 1, Kostyukevich teaches a method of fragmenting ions in a mass spectrometry system (fig. 1 and abstract), comprising steps of:
using an ion source to ionize a sample so as to produce a plurality of ions (inherent in the ESI seen in figure 1), wherein an ionization/fragmentation region is associated with the ion source (fig. 1, heating element 7 and capillary 6, abstract and right column on page 101, first full paragraph) wherein the ionization/fragmentation region extends from an exit of the ion source along a portion of a surface-free path through which ions travel from the exit of the ion source to a vacuum chamber containing a mass analyzer (inside capillary is surface free and capillary extends indirectly by alignment with ESI source as seen in figure 1 along a surface free path (inside capillary) that ions travel from exit of ESI 3 to inlet of MS 1) the vacuum chamber including an inlet (inlet seen at 1 in figure 1) coaxially aligned with the exit of the ion source (as seen in figure 1) to receive the ions traveling along the surface-free path (co-axial alignment between source and inlet surface-free path inside capillary);
applying thermal energy, by a heat source (heater applied to capillary) mounted at the ionization/fragmentation region (around the capillary thus at the ionization fragmentation region) to the plurality of ions in the ionization/fragmentation region in a direction toward the exit of the ion source (thermal energy from heated capillary radiates at exit of source) that is substantially coaxial to the surface-free path defined by the coaxial aligned ion source exit and the vacuum chamber inlet (heater heats metal capillary, since the capillary is coaxial to the surface free path inside the capillary from ion source to inlet, the heat from the heated capillary is also co-axially applied) to increase a temperature of at least 550 degrees C (page 101, right column, first two lines heat to 600 degrees C) of the plurality of ions traveling within the ionization/fragmentation region to an elevated temperature (via heating element 7 inside of the capillary (surface free path and fragmentation/ionization region) is heated to increase the temperature within the ionization/fragmentation region to an elevated temperature), wherein the elevated temperature at the exit of the ion source promotes thermally-induced dissociation of at least a portion of the plurality of ions (page 101, right column, first full paragraph and abstract, note heater at exit of ion source); and
transmitting the thermally dissociated ions along the surface free path to and through an inlet of a vacuum chamber containing a downstream mass analyzer (as indicated in figure 1).
Claim 21 is commensurate in scope and anticipated as discussed above.
Claim Rejections - 35 USC § 103
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.
Claims 5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Corr in view of Clemmer et al. (US pgPub 2021/0078004).
Regarding claims 5 and 7, while Corr teaches a heated gas wherein applying the thermal energy is performed such that at least 50% of ion fragmentation due to temperature increase occurs within the ionization/fragmentation region (Since the heated gas is applied directly to the plume such that the temperature of the chamber reaches 800 degrees C ([0036]), all TID occurs within the ionization/fragmentation region), Corr fails to specifically disclose wherein applying the thermal energy comprises exposing the plurality of ions to a source of electromagnetic radiation wherein the source of electromagnetic radiation comprises a thermal energy source.
However, Clemmer teaches as an alternative to heated drift gas ([0066]) using one or more IR lasers ([0064]) which are thermal energy sources.
Clemmer modifies Corr by suggestion of the substitution of heated drift gas for laser heating.
Since both inventions are directed towards applying a heat source to the ions, it would have been obvious to one of ordinary skill in the art to substitute the heated gas of Corr for the IR heating as suggested by Clemmer because it would lead to the predictable result of supplying heat to the ions (MPEP 2143.01 (I)(B)).
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Corr in view of Smith et al. (US pgPub 2008/0261258).
Regarding claim 17, Corr teaches wherein the sample comprises large macromolecules ionized via ESI ([0004]). Corr fails to expressly suggest any peptide and wherein the sample has a molecular weight of at least 40kDa.
However, Smith teaches ESI permits the ionization of large molecules exceeding 300 kDa such as peptides ([0042]).
Smith modifies Corr by suggestion of a specific large macromolecule.
Since both inventions are directed towards introducing a sample to an ESI ionization source, it would have been obvious to one of ordinary skill in the art to select peptides exceeding 300 kDa in mass because the ESI source of Corr is suitable for such a sample allowing the operator to study peptides in particular when analysis of peptides is desired.
Relevant art of interest to the applicant
Brown et al. (GB2538871)(copy of publication submitted herewith) teaches a similar device to Rockwood.
US6107628 teaches 100% transmission efficiency by using a ion funnel.
US20200111654 teaches an ion trap between an ion source and a TOF MS. The ion trap is disclosed to perform dissociation by heating electrodes ([0069])
Covey et al. (USPN 6,759,650) teaches a heated gas jet heating gas to a temperature of 850 degrees C directed at a APCI source for vaporization and desolvation (see figure 7 and 9). Covey suggests directing the heated gas towards the exit of the ion source.
a method of fragmenting ions in a mass spectrometry system (Figures 1 and 7 (note col. 8, lines 15-17 teach 60 of figure 2 (and figure 7) replaces the ion source 22 of figure 1). Figure 7 shows gas jets 104 heated by heaters 110 directed at the spray cone 106. The gas jets are heated to a temperature of 850 degrees Celcius (col. 11, lines 26-33). As evident from the instant specification such a temperature is sufficient to fragment ions ([0010] of the published application)2), comprising:
using an ion source (APCI 74 not annotated in figure 7, but shown and seen in figure 2) to ionize a sample so as to produce a plurality of ions (inherent to an ion source), wherein an ionization/fragmentation region is associated with the ion source (Fig. 7 shows region where 104 and 106 intersect downstream APCI 74 (fig. 2) held by 70. Since the heated gas is at a temperature of 850 degrees and is directed at the sample plume, the temperature at that location is sufficient for fragmentation as evident from the instant specification ([0010] of the published application or Makarov). Note: MPEP 2112 recites “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. ”. Here since the temperature requirements are met, fragmentation inherently occurs. Paragraph [0036] also teaches that the ion population in the gap can be increased via heating, thus an ionization region), wherein the ionization/fragmentation region extends from an exit of the ion source (extending from end of 40) and is substantially along a portion of a surface-free path through which ions travel from the exit of the ion source to a vacuum chamber containing a mass analyzer (fig. 7 shows housing 62, figure 6 shows a cross-sectional view of housing 62 wherein the spray 106 is surface free between the exit of 74 (only holder 70 shown in figure 6) and the inlet to mass spectrometer 24 (mass spectrometer seen in figure 1). Since the inherent fragmentation/ionization zone (i.e. area where 106 and 104 intersect in figure 7) occurs perpendicular to the mass spectrometer inlet, the zone of figure 7 is substantially surface free),
applying thermal energy, by a heat source (80) mounted at the ionization/fragmentation region ([0036] 80 positioned such that heat gas flow directs the sample plume to the proximity of aperture 14b, thus mounted at the ionization/fragmentation region) to the plurality of ions in the ionization/fragmentation region ([0036] 80 provides heated gas so as to direct sample plume and increases ion population. Since the temperature rises to 800 degrees, fragmentation inherently occurs, see discussion above) in a direction that is substantially co-axial the surface-free path defined by the coaxially aligned ion source exit and the vacuum chamber inlet ([0036] since the heated gas from 80 directs plume towards 14b, the heated gas is substantially co-axial with the ion source exit and vacuum chamber inlet) to increase a temperature of the plurality of ions traveling within the ionization/fragmentation region ([0036]), to an elevated temperature of at least 550 degrees C (800 degrees C see paragraph [0036]), wherein the elevated temperature promotes thermally-induced dissociation of at least a portion of the plurality of ions (since the heated gas is provided directly at the plume and heats the chamber to 800 degrees C ([0036]), the requirements for TID as evident from the instant disclosure are met (see paragraph [0010] of the instant published application). Thus it is interpreted that fragmentation inherently occurs); and
transmitting the thermally dissociated ions along the surface-free path (through region between 40 and inlet 14b) to and through an inlet of the vacuum chamber (14b) containing the mass analyzer (60).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL J LOGIE whose telephone number is (571)270-1616. The examiner can normally be reached M-F: 7:00AM-3:00PM.
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/MICHAEL J LOGIE/Primary Examiner, Art Unit 2881
1 Note Makarov (US pgPub 2021/0270773) is also evidence that such a temperature range results in fragmentation see paragraph [0161]
2 Note Makarov (US pgPub 2021/0270773) is also evidence that such a temperature range results in fragmentation see paragraph [0161]