DETAILED ACTION
Response to Arguments
Applicant's arguments filed on 17 September 2026 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Specifically, the remarks take the position that Hager does not discuss a 4 branched ion trap or suggest apply a resolving DC voltage to transverse branches of such a trap and instead teaches a dc resolving voltage applied to Q2 rods.
This has been found unpersuasive. Specifically, Hager was not relied upon for teaching a 4 branched ion trap. As discussed in the rejection of claim 1 Baba in view of Baba2 teaches a 4 branched ion trap where ions are fragmented, trapped and isolated in the transverse branches. Baba in view of Baba2 therefore disclose a trapping of isolated ions in transverse quadrupoles where fragmentation occurs. In other words, the combined device suggests a trapping of product or fragment ions isolated in the transverse quadrupole branches.
Baba in view of Baba2 fail to suggest any removal of unwanted fragment ions from the at least the portion of said plurality of fragment ions in said at least one said transverse branches by applying a resolving DC voltage to said at least one of said transverse branches.
However, it is well known to the art to apply a resolving DC potential to a quadrupole trapping fragment ions as evidenced by Hager [0055] which teaches “ions are trapped within Q2 [[i.e. a quadrupole]]”. Moreover Hager teaches that ions are moved (i.e. unwanted fragment ions) by the addition of a resolving DC voltage applied to the Q2 rods. Moreover, it is noted that any quadrupole may be interpreted as a transverse branch as it transverses a portion of the mass analyzer.
In otherwords, Hager is evidence that it was known to apply a resolving DC voltage to a quadrupole which has trapped ions to remove ions not of interest. While Q2 is a CID, it is more generally a fragmentation cell. The primary combination is also a fragmentation cell, therefore, since Baba in view of Baba2 already discloses the transverse branches that have product ions (cation and anions) trapped therein, the modification is to apply a resolving DC potential to the transverse quadrupoles of the combined device such that ions not of interest (or unwanted) may be removed such that only fragment ions of interest are retained for analysis. In other words, the combined device already discloses fragmenting, trapping product ions and isolating them into transverse quadrupoles, the modification is to apply a resolving DC voltage to the trapping quadrupoles, which was known to the art as evidenced by Hager.
As discussed in the last office action, such a modification to the trapping regions of the combined device would have been obvious so as to achieve better resolution mass spectra of only ions that are desired to be analyzed (see further evidence by Baba (US pgPub 2014/0374592) which teaches dc resolving voltages allows for the removal of impurities which increase the overall charge density within the ion trap and decrease the optimal performance see paragraphs [0004]-[0005]).
Lastly, it is noted here that applying resolving DC potentials to quadrupole ion traps is well known to the art. For instance, Collings et al. (US pgPub 2009/0121126) teaches at paragraph [0058] “ a resolving DC can be applied to remove fragments produced thereby. In this way, the m/z-space around the ion or ions of interest can be cleared of ion species that in some instances might interfere with recovery or detection of the desired species. In various embodiments, this step of applying a resolving DC can utilize the same resolving DC as was used to isolate the trapped ion subpopulation. The resolving DC employed in the radial excitation clean-up can have parameters identical to those of the resolving DC employed to remove ions outside the m/z window, as discussed above, and can be applied for a similar time.” (note paragraph [0003] teaches the trap is a quadrupole).
Similarly, US pgPub 2016/0247671 to Collings teaches in paragraph [0058] “ ions outside of region 1010 are removed by applying a resolving direct current (DC) potential to a mass analyzing quadrupole, such as quadrupole 411 of FIG. 4. In various embodiments, the amount of resolving DC potential that is applied is calculated based upon the desired mass range to be transmitted through the mass analyzing quadrupole.”
Additionally, Guna (US pgPub 2014/0131569) teaches similar subject matter in the abstract.
That is, not only does Hager teach applying a resolving DC potential to a trap, but also Collings publications and Guna above provide additional evidence that this was known to the art.
This provides further evidence that for a fragmentation cell (i.e. the ECD of the combined device), it was known to apply a resolving DC potential to the quadrupoles where fragment ions are trapped to remove unwanted ions and improve the resolution of the mass spectral data.
Therefore, the remarks are unpersuasive and the rejection stands as reiterated herein below.
With respect to Schoen, claim 7 was not previously considered because it was taught by Baba in view of Baba in view of Hager.
However, by amending claim 1 to include claim 7 the rejection in view of Schoen as necessitated a new grounds rejection necessitated by amendment discussed herein below.
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 1, 5-9, 13-14 and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Baba (WO 2017/221151) (copy of publication submitted with the office action of 12/10/2025) in view of Baba (US pgPub 2016/0322208) and further in view of Hager (US pgPub 2005/0006580).
Regarding claim 1, Baba teaches a method of performing mass spectrometry (fig. 2), comprising:
ionizing a sample to generate a plurality of precursor ions (201, [0037]),
passing said precursor ions through a mass filter to select at least one subset of said ions ([0037] teaches one or more mass analyzers upstream from ECD (step 202) operated as a conventional mass filter to select a range of precursor cations of interest for transmission therethrough),
introducing said selected ions into a branched radiofrequency (RF) ion trap (step 202, figure 3A shows branched ECD cell, paragraph [0037] last sentence teaches trapping the precursor cations within the ECD cell prior to being subject to ECD (i.e. ECD cell acts as an ion trap)) through an ion entrance port of the RF ion trap through which ions enter the RF ion trap (ions enter 310 via opening in 320a) from the mass filter (upstream mass analyzer operated as a mass filter [0037]) and
subjecting at least a portion of said selected precursor ions to fragmentation within said ion trap so as to generate a first plurality of fragment ions (step 203 ECD is a dissociation technique resulting in fragmentation of ions),
releasing at least a portion of said fragmented ions ([0039] product ions trapped in PTR cell after ECD, paragraph [0045] transmitting ions from ECD cell to Q2 operated as a cell for PTR or CID) and subjecting at least a portion thereof to fragmentation so as to generate a second plurality of fragment ions ([0045] transmitting ions from ECD to Q2 operated as a cell for CID)
wherein said branched RF ion trap comprises an axial section (313/314 in figure 3a) characterized by a central axis (316) extending axially from the ion entrance port of the RF ion trap to an ion exit port through which ions leave the RF ion trap (Axis “A” in figure 3 from entrance at 320a to exit at 320b), the RF ion trap further including a trap center and four branches extending from the trap center (four branches extending from center of ECD cell in figure 4a which acts as a trap as discussed above, therefore the center is interpreted as the trap center)
wherein two of said branches are positioned transverse to said central axis (branches 315a/315b are orthogonal to 313/314).
Baba teaches that alternatively the PTR may occur in the ECD cell itself after formation of product ions (last sentence of paragraph [0029]). Moreover, Baba teaches that PTR is a reaction between product ions and reagent cations ([0029]), wherein reagent ions have the opposite polarity of product ions (see abstract).
That is, while Baba suggests performing PTR on product ions in the ECD cell with reagent ions of opposite polarity, Baba fails to disclose isolating at least a portion of said first plurality of fragment ions wherein isolating at least a portion of said first plurality of fragment ions comprises causing said at least a portion of said first plurality of fragment ions to enter wherein said step of isolating at least a portion of said first plurality of fragment ions comprises causing said at least a portion of said first plurality of fragment ions to enter at least one of said transverse branches.
However, Baba2 teaches isolating at least a portion of said first plurality of ions (figs. 4a -6 shows the isolation of cations from anions in trapped in separate regions (18/20) see paragraph [0054]) wherein isolating at least a portion of said first plurality of ions comprises causing said at least a portion of said first plurality of fragment ions to enter at least one of said transverse branches (cations and anions (figures 3-6) in transverse branches 18 and 20 (see figure 2b)).
Baba2 teaches this accumulation of anions and cations (figures 4a-4b) and simultaneous trapping (fig. 6) is in preparation for the reaction period (fig. 7), in which cations and anions undergo mixing which leads to PTR ([0060]).
Baba2 modifies Baba by suggesting how to prepare charged particles of opposite polarity (i.e. cations and anions) for PTR in an ion trap.
Since both inventions are directed towards branched multipolar ion traps, it would have been obvious to one of ordinary skill in the art to apply the “charged particle species” (fig. 1 of Baba) to the ECD cell in Baba of opposite polarity to the product ions in Baba (see abstract), so as to isolate the anion and cations prior to PTR as suggested in Baba2 because trapping the ions of opposite polarity in the trapping ports 18 and 20 prevents thermally induced dissociation of the ions because the trapped ions are stably confined by the RF field ([0058], Baba2). CID results in incomplete fragmentation and loss of post translational modifications during the dissociation ([0004], Baba) as evidenced by Baba, therefore modifying Baba to include separation of the opposite polarity product and reagent ions of Baba as suggested by Baba2 would result in more complete fragmentation and retention of post translational modifications.
While Baba in view of Baba2 teaches a fragmentation cell of quadrupole form where fragment ions are isolated and trapped, Baba in view of Baba2 fails to disclose removing unwanted fragment ions from the at least the portion of said first plurality of fragment ions in said at least one transverse branch by applying a resolving DC voltage to said at least one transverse branch.
Hager teaches removing unwanted fragment ions from the fragment ions in said at least one branch by applying a resolving DC voltage to said at least one transverse branch ([0055] “Once trapped the RF voltage applied to the Q2 rods is adjusted such that all ions above a chosen mass are made unstable, that is there a,q values fall outside the normal Mathieu stability diagram. Removal of ions above the mass of a particular ion of interest is facilitated by the addition of a small amount of resolving DC voltage”).
Hager modifies the combined device by suggesting removal of unwanted (i.e. ions outside of the chosen range) while trapped in the quadrupole of Baba as modified by Baba2 (i.e. figures 4-6 showing ions trapped in transverse quadrupole of Baba2).
Since both inventions are directed towards quadrupole rod sets, it would have been obvious to one of ordinary skill in the art to modify the transverse ion trap of Baba in view of Baba2 to include a resolving DC potential so as to selectively remove unwanted ions so as to achieve better resolution mass spectra of only ions that are desired to be analyzed (see further evidence by Baba (US pgPub 2014/0374592) which teaches dc resolving voltages allows for the removal of impurities which increase the overall charge density within the ion trap and decrease the optimal performance see paragraphs [0004]-[0005])
Regarding claim 5, Baba in view of Baba2 teaches wherein said step of causing said at least a portion of said first plurality of fragment ions to enter one of said transverse branches comprises applying a DC voltage to an isolation electrode positioned in proximity of said branches (Baba teaches PTR to product ions with opposite polarity ions (see discussion above in claim 1), Baba2 suggests applying DC voltages to lenses 1 and 2 adjacent to branches 18/20 (see figure 4A and 2B) so that anions and cations separate see paragraphs [0054]-[0055]).
Regarding claim 6, Baba teaches wherein said isolation electrode extends from said proximal end to said distal end of the axial section (Baba2, lens 1 or lens 2 in figures 4B and 2B extends along the axis “A” of figure 2B, interpreting its extent to be the proximal and distal end of the axial section the limitation is met).
Regarding claim 8, Baba in view of Baba2 teaches wherein said step of releasing said selected isolated ions comprises adjusting a DC voltage applied to said isolation electrode Baba2 see paragraph [0059]).
Regarding claim 9, Baba teaches wherein said released ions undergo said second fragmentation in vicinity of said trap center (Baba teaches PTR after product ions are formed (last sentence of paragraph [0029]), wherein Baba2 teaches PTR at the center of the trap see paragraphs [0059]-[0060]).
Regarding claim 13, Baba teaches wherein said precursor ions are fragmented using any of collision induced dissociation (CID) and electron activation dissociation (EAD) ([0045] ECD and CID (note as evidenced by Zhang US pgPub 2024/0404646 ECD is a type of EAD see paragraph [0036])).
Regarding claim 14, Baba teaches wherein said first plurality of fragment ions are fragmented using any of CID and EAD ([0045] teaches ECD and collision induced dissociation (i.e. CID)).
Regarding claim 22, Baba in view of Baba2 teaches wherein releasing the at least the portion of the isolated ions comprises: releasing the at least the portion of the isolated ions from the at least one of the said transverse branches to the trap center (Baba2, see figure 7A anions and cations mix at center of trap see paragraph [0059]) to subject the at least the portion thereof to fragmentation to generate the second plurality of fragment ions (mixing results in PTR see paragraph [0060] of Baba2, wherein Baba teaches PTR of opposite polarity ions to product ions (see abstract and last sentence of paragraph [0029])); and transferring at least some of the second plurality of fragment ions downstream to a mass analyzer via the ion exit port defined along the central axis (Baba after PTR ions are transferred to exit port in 320b to a mass analyzers ([0040]) and step 206 om figure 2).
Regarding claim 23, Baba teaches wherein the two transverse branches are configured to receive electrons from an electron source (traverse branches along 316 in figure 3A receive electrons from electron source 330) located proximate to an entrance to one of the two transverse branches (330 is proximate entrance at 320c to upper transverse branch in figure 3A), to cause the fragmentation of the selected ions and of the first plurality of fragment ions (via ECD, see paragraph [0053]).
Claims 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Baba as evidenced by Zhang (US pgPub 2024/0404646) in view of Baba2 in view of Hager and further in view of Baba (US pgPub 2018/005810).
Regarding claim 10, Baba teaches wherein any of said precursor ions and said first plurality of fragment ions are dissociated via electron activation dissociation using an electron beam (electron beam seen in figure 3A, ECD is a type of EAD as evidenced by Zhang see paragraph [0036]).
Baba fails to disclose the energy of the electron beam.
However, Baba teaches ECD using an electron beam having an energy in a range of about 0 eV to about 50 eV ([0004] ECD 0-3 eV).
Baba modifies Baba by suggesting an appropriate electron beam energy for ECD.
Since both inventions are directed towards ECD, it would have been obvious to one of ordinary skill in the art to use the electron beam energy of Baba in the primary Baba method because it would resolve the problem of what beam energy would be appropriate to initiated electron capture dissociation.
Regarding claim 11, Baba teaches passing said second plurality of fragment ions through a mass analyzer so as to generate a mass spectrum thereof (implicit after CID in order to generate MS2 [0045]).
Regarding claim 12, Baba teaches wherein said mass analyzer comprises a time-of- flight mass analyzer (140 in figure 1 see paragraph [0034]).
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Schoen et al. (US pgPub 2009/0090853) in view of Schoen (US pgPub 2008/0073515) (herein Schoen2) and further in view of in view of Baba in view of Collings (US pgPub 2016/0247671).
Regarding claim 1, Schoen teaches a method of performing mass spectrometry (inherent to the apparatus of figure 1A/B), comprising:
ionizing a sample to generate a plurality of precursor ions (via ionization source 1, [0029]),
passing said precursor ions through a mass filter (mass filter Q1 or element 18 see paragraph [0031]) to select at least one subset of said ions ([0031] teaches Q1 is configured to select ions having m/z within a narrow range of values),
introducing said selected ions into a branched radiofrequency (RF) ion trap (Q2 comprising 42/45 and 48 and 12-14 see paragraph [0031] collisional cell requires trapping to cause fragmentation) through an ion entrance port of the RF ion trap through which ions enter the RF ion trap from the mass filter (ions entering q2 in figure 1 from mass filter q1), and subjecting at least a portion of said selected precursor ions to fragmentation within said ion trap so as to generate a first plurality of fragment ions ([0031] “the branched ion transfer device 15 may incorporate one or more collision cells 42/45/48 for the fragmentation of the selected ions”),
isolating at least a portion of said first plurality of fragment ions (via 30 which is a mass filter see paragraph [0031] “he resultant product ions are then directed to a selected one of a mass analyzer 30 (also labeled Q.sub.3,1) in the first branch, which may take the form of a quadrupole mass filter, and an ion trap mass analyzer 33 (also labeled IT.sub.3,2) in the second branch in a manner more fully described below”),
releasing at least a portion of said isolated ions (to additional stages QN see paragraph [0038] and figure 1a-b)
wherein said branched RF ion trap comprises an axial section (along 42) characterized by a central axis for receiving ions from an ion source (central axis along 42 receives ions from source 1) and the RF ion trap further including a trap center (center of 42) and four branches extending from the trap center ([0056] envisioned additional third and fourth stages, thus while only two branches shown, there could be four extending from center of q2),
wherein two of said branches are positioned transverse to said central axis (two branches transverse to center of 42), and wherein isolating at least a portion of said first plurality of fragment ions comprises causing said at least a portion of said first plurality of fragment ions to enter at least one of said transverse branches (see discussion with respect to paragraph [0031] above).
While Schoen teaches the central axis extending axially from the entrance port (from 19 in figure 1 in q2), Schoen fails to expressly suggest the central axis extending axially from the ion entrance port of the RF ion trap to an ion exit port through which ions leave the RF ion trap.
However Schoen2 teaches the central axis extending axially from the ion entrance port of the RF ion trap (fig. 4A entrance at 420b) to an ion exit port through which ions leave the RF ion trap (exit at 455).
Schoen2 modifies Schoen by demonstrating how four pathways could be incorporated into the Schoen.
Since both inventions are directed towards an ion trap with multiple branches, it would have been obvious to one of ordinary skill in the art to have the fourth branch form a central axis from entry to exit as suggested in Schoen2 because it would facilitate the structure for a four branch ion path envisioned by Schoen. Moreover, the secondary Schoen allow for switching that may be performed without an unacceptable degree of ions loss ([0007]).
While Schoen teaches additional stages after mass filtering, Schoen fails to teach subjecting at least a portion thereof to fragmentation so as to generate a second plurality of fragment ions.
However, Baba teaches at least a portion thereof to fragmentation so as to generate a second plurality of fragment ions ([0045] and figure 3A show a quadrupole Q2 for performing CID on product ions exiting the first cell).
Baba modifies Schoen by suggesting an additional CID cell downstream of the first fragmentation cell.
Since Schoen suggests additional stages after mass filtering after fragmentation and Baba suggests an additional fragmentation stage, it would have been obvious to one of ordinary skill in the art to add an additional fragmentation step of the fragment ions so as to facilitate MS2 analysis allowing for more structural information about the sample.
While Shoen teaches a mass analyzer 30 that isolates fragments, Schoen fails to disclose removing unwanted fragment ions from the at least the portion of said first plurality of fragment ions in said at least one transverse branch by applying a resolving DC voltage to said at least one transverse branch.
However, Collins teaches removing unwanted fragment ions from the at least the portion of said first plurality of fragment ions in said at least one transverse branch by applying a resolving DC voltage to said at least one transverse branch ([0058] teaches removing ions outside of a region by applying a DC resolving potential to a mass analyzing quadrupole 411).
Collins modifies the combined device by suggesting applying a resolving DC potential to the mass analyzing quadrupole 30 of Schoen modified by Schoen2 and Baba.
Since both inventions are directed towards mass analyzing quadrupoles, it would have been obvious to one of ordinary skill in the art
Relevant art
US20160126076 and US 20160322208 to Baba also teaches fragmentation and isolation of ions within the trap.
US20130026360 teaches fragmentation in a traverse section of an ion trap see figure 11 and associated text.
US2018/0005810 to Baba teaches in paragraph [0058] “it will be appreciated that the ion reaction devices described herein can be inserted in series in between two quadrupole filters, for example, between a quadrupole filter (Q1) upstream of the ion reaction device 600 (and disposed between the ion source and the ion reaction device), serves to trap/guide/etc. ions and provides a source of ions at the entrance of the device 600, and a downstream quadrupole (Q2), which can receive product ions and unreacted ions and either trap/guide/etc. in the quadrupole for further analysis or processing”
Satake et al. (US 2011/0204221) see figure 5 ECD by substituting 42 with an electron source ([0049]) and downstream CID 6.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action1. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/MICHAEL J LOGIE/Primary Examiner, Art Unit 2881
1 Note only the Schoen 103 rejection to claim 1 was necessitated by amendment. The rejection of claim 1 in view of Baba, Baba2 and further in view of Hager was not necessitated by amendment.
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