Detailed Action
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show the “linac electrodes 115a/115b” as described on Page 20, the fourth paragraph of the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 recites a final limitation that links a particular source of energy, namely “a space charge generated in said region in proximity of said potential barrier due to accumulation of ions,” to a particular effect, namely imparting “sufficient kinetic energy” to product ions “so as to overcome said potential barrier,” without setting forth how one of ordinary skill in the art would determine that the claimed effect is caused by the recited source of energy. The claim does not clearly identify which ions are accumulating to generate the recited space charge, whether the relevant ions are precursor ions, fragment ions, or both, or how to distinguish the claimed mechanism from other possible mechanisms by which product ions may acquire sufficient energy to overcome the barrier. Accordingly, the claim fails to provide an objective boundary by which one of ordinary skill in the art could determine whether a given process falls within or outside the scope of the claim, and therefore the scope of claim 1 is not reasonably certain. For the purposes of compact prosecution, they will be interpreted as best understood in light of the specification.
Claim 14 recites the limitation “at least a portion of said first plurality of product ions trapped in said region.” There is insufficient antecedent basis for this limitation in the claim. For the purposes of compact prosecution, claim 14 will be interpreted as dependent on claim 13 in light of the specification (Spec. Page 26, the third paragraph).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 1-4, 8-12, 15-17, and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2019/0157065 A1 [hereinafter Stewart].
Regarding Claim 1:
The term “collision cell” in claim 1 is not interpreted as requiring actual collision-induced dissociation in every embodiment, because the specification expressly teaches maintaining the collision cell at a pressure suitable for collisional cooling of precursor ions “without causing their collisional fragmentation” (see Spec. Page 2, fourth Paragraph), while separately teaching that ion energy and pressure may be selected so that “at least a portion of the precursor ions will undergo fragmentation before reaching the potential barrier” (see Spec. Page 2, fifth Paragraph). Accordingly, “collision cell” is reasonably interpreted as a gas-containing ion cell in which ion-neutral collisions occur at least for collisional cooling, with collisional dissociation being an optional mode rather than a requirement of claim 1.
Stewart teaches a method for fragmenting ions in a mass spectrometer (para. [0136]: “a mass spectrometer suitable for carrying out a UVPD method”), comprising:
introducing a plurality of precursor ions into a collision cell (Figs. 9/10- fragmentation chamber 700/800) of a mass spectrometer (paras. [0136, 0152]: precursor ions are injected into the fragmentation chamber 700/800 via one axial end; figs. 10 and 11A-11B show details of an exemplary fragmentation chamber 800 of the one (700) shown in fig. 9),
generating a potential barrier in the collision cell to cause at least a portion of ions in the collision cell to be trapped within a region in proximity of said potential barrier (Fig. 10; paras. [0152-0155]: initial DC bias on first and second end electrodes 810/812 axially confines the precursor ions, and a first DC bias applied to at least one first electrode of elongate PCB electrode assembly 814 so that “a first potential well is formed in the central region of the elongate ion channel which confines the precursor ions in a central region of the elongate ion channel”), and
applying ultraviolet (UV) radiation to said trapped ions so as to cause fragmentation of at least a portion of any of said precursor ions and fragment ions thereof to generate a plurality of product ions such that a space charge generated in said region in proximity of said potential barrier due to accumulation of ions will impart sufficient kinetic energy to at least a portion of the product ions so as to overcome said potential barrier, thereby exiting said region (paras. [0159-0161]: “… to cause the ultraviolet radiation source 710 to emit UV radiation…to irradiate a substantial portion of the volume of the precursor ions confined within the potential well…By exposing the precursor ions to the UV radiation, the precursor ions may absorb the UV radiation and undergo a fragmentation reaction. As such, the precursor ions may dissociate into product ions as a result of the absorption of UV radiation…the product ions generated by the UVPD reaction may escape the first potential well…because the product ions … may be more energetic than the precursor ion”).
The “fragmentation chamber” in Stewart encompasses a gas-containing ion cell in which ion–neutral collisions occur at least for collisional cooling (see Stewart para. [0156] “A cooling gas may also be provided within the fragmentation chamber. The cooling gas allows the precursor ions confined within the first potential well to cool at a faster rate through interactions with the molecules of the cooling gas. Preferably, the cooling gas is an inert gas”). Accordingly, Stewart’s fragmentation chamber falls within the above interpretation of the claimed “collision cell.”
Regarding Claim 2:
Stewart teaches the method of claim 1. Stewart further teaches wherein said potential barrier is created in the collision cell in proximity of an outlet of the collision cell (para. [0152]: “… apply an initial DC bias to the second end electrode 812 to repel the precursor ions towards the centre of the elongate ion channel,” i.e., end-electrode bias defines potential barrier proximate the outlet, since absent such confining potentials the ions would not be repelled from the axial ends towards the chamber center).
Regarding Claim 3:
Stewart teaches the method of claim 1. Stewart further teaches wherein said potential barrier is coupled to the collision cell in proximity of an inlet of the collision cell (para. [0153]: “the initial DC bias may also be applied to the first end electrode 810… to repel the precursor ions towards the central region of the elongate ion channel,” i.e., end-electrode bias defines potential barrier proximate the inlet, since absent such confining potentials the ions would not be repelled from the axial ends towards the chamber center).
Regarding Claim 4:
Stewart teaches the method of claim 1. Stewart further teaches wherein said potential barrier is coupled to the collision cell at a location between an inlet and an outlet of the collision cell (para. [0154]: “apply a first DC bias to at least one first electrode of the elongate PCB electrode assembly 814”, i.e., the electrodes located between the inlet and the outlet of the chamber, “As such the first potential well is defined by a first DC bias applied to a first electrode with respect to the elongate multipole electrode assembly 820”).
Regarding Claim 8:
Stewart teaches the method of claim 1. Stewart further teaches introducing a plurality of ions into a mass filter positioned upstream of said collision cell so as to select a plurality of precursor ions having m/z ratios within a target range for transmission into said collision cell for causing fragmentation thereof via exposure to the UV radiation (para. [0042]: the precursor ions may be mass selected precursor ions selected by a quadrupole mass filter before injected for fragmentation).
Regarding Claim 9:
Stewart teaches the method of claim 1. Stewart further teaches transmitting said product ions into a mass analyzer disposed downstream of said collision cell for generating a mass spectrum thereof (Fig. 9; para. [0165]: “once the precursor ions have been fragmented… eject the product ions into the mass analyser 690 for mass analysis (i.e. an MS2 scan),” see also Fig. 9 showing mass analyser 690 downstream of fragmentation chamber 700).
Regarding Claim 10:
Stewart teaches the method of claim 1. Stewart further teaches wherein said mass analyzer comprises any of a quadrupole mass analyzer and a time-of-flight mass analyzer, and wherein optionally said mass analyzer comprises an ion trap (para. 0069]: “the mass analyser may be a time of flight (TOF) mass analyser”).
Regarding Claim 11:
Stewart teaches the method of claim 3. Stewart further teaches wherein said step of coupling the potential barrier comprises coupling at least one electrically conductive electrode to said collision cell and applying any of a DC and RF voltage to said electrode so as to generate said potential barrier (para. [0153]: initial DC bias is applied to first end electrode 810 to repel the precursor ions towards the central region of the elongate ion channel, thereby providing confining potentials within the fragmentation chamber).
Regarding Claim 12:
The term “ion lens” is interpreted broadly to refer to an ion-optics electrode positioned along the ion path, such as near the inlet or outlet of the collision cell, that shapes the electric field so as to guide, retard, or trap ions. This interpretation is consistent with the specification, which explains that the potential barrier in proximity of the outlet may be generated by applying a DC and/or RF voltage to an “electrode/IQ3 electrode/exit ion lens”, for trapping ions in a region near the electrode (see Spec. Page 17, third and fourth paragraphs).
Stewart teaches the method of claim 11. Stewart further teaches wherein said electrode comprises an ion lens positioned in proximity of any of an inlet and an outlet of said collision cell (electrode 810/812 located on either axial end of the fragmentation chamber, steering and trapping the ions to the center of the chamber when applying DC potentials to such electrodes).
The electrodes 810/812 in Stewart are positioned at the axial ends of the fragmentation chamber adjacent the inlet/outlet regions and, when biased, control ion motion and provide confining/retarding potentials in the same manner as the inlet/outlet electrode described in the instant application. Accordingly, Stewart’s end electrodes reasonably correspond to the claimed ion lens.
Regarding Claim 15:
The “collision cell” recites in claim 15 is interpreted the same as the term in claim 1.
Stewart teaches a mass spectrometer (para. [0136]: “a mass spectrometer suitable for carrying out a UVPD method”), comprising:
a collision cell (Figs. 9/10- fragmentation chamber 700/800) having an inlet for receiving ions and an outlet through which ions can exit the collision cell (paras. [0136, 0152]: ions are injected into the fragmentation chamber 700/800 via one axial end 810 and exited through the other axial end 812),
at least one electrode coupled to said collision cell and configured for application of a DC and RF voltage thereto to generate a potential barrier for trapping at least a portion of ions in the collision cell within a region in proximity of said electrode (Fig. 10; paras. [0151-0155]: initial DC bias on first and second end electrodes 810/812 axially confines the precursor ions, apply an RF pseudopotential to the elongate multipole electrode assembly 820, and a first DC bias applied to at least one first electrode of elongate PCB electrode assembly 814 so that “a first potential well is formed in the central region of the elongate ion channel which confines the precursor ions in a central region of the elongate ion channel which confines the precursor ions in a central region of the elongate ion channel”), and
a UV radiation source (Fig.9 - ultraviolet radiation source 710) radiatively coupled to said collision cell to irradiate at least a portion of said trapped ions so as to cause fragmentation of at least a portion thereof, thereby generating a plurality of product ions such that at least a portion of the product ions can overcome the potential barrier to exit said region (paras. [0159-0161]: “… to cause the ultraviolet radiation source 710 to emit UV radiation…to irradiate a substantial portion of the volume of the precursor ions confined within the potential well…By exposing the precursor ions to the UV radiation, the precursor ions may absorb the UV radiation and undergo a fragmentation reaction. As such, the precursor ions may dissociate into product ions as a result of the absorption of UV radiation…the product ions generated by the UVPD reaction may escape the first potential well…because the product ions … may be more energetic than the precursor ion”).
Regarding Claim 16:
Stewart teaches the mass spectrometer of claim 15. Stewart further teaches a mass analyzer (Fig. 9- mass analyser 690) positioned downstream of said collision cell for receiving at least a portion of the product ions and generating a mass spectrum thereof (Fig. 9; para. [0165]: “once the precursor ions have been fragmented… eject the product ions into the mass analyser 690 for mass analysis (i.e. an MS2 scan)”).
Regarding Claim 17:
Stewart teaches the mass spectrometer of claim 15. Stewart further teaches a mass filter positioned upstream of said collision cell, said mass filter being configured to receive a plurality of ions and allowing passage of a plurality of precursor ions having m/z ratios within a target range to said collision cell (para. [0042]: the precursor ions may be mass selected precursor ions selected by a quadrupole mass filter before injected for fragmentation).
Regarding Claim 19:
The “ion lens” in claim 19 is interpreted the same as it in claim 12.
Stewart teaches the mass spectrometer of claim 15. Stewart further teaches wherein said electrode comprises an ion lens positioned in proximity of an outlet of said collision cell (electrode 810/812 located on either end of the fragmentation chamber and steer the ions to the center of the chamber when applying DC potentials to such electrodes).
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 5-6, 18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Stewart in view of US 2010/0207023 A1 [hereinafter Loboda].
Regarding Claim 5:
Stewart teaches the method of claim 1. Stewart further teaches such said potential barrier is capable of trapping at least a portion of the cooled ions (paras. [0154-0156]: a fragmentation chamber in which a first potential well confines ions which are cooled by a cooling gas before UV fragmentation). However, Stewart does not specifically note maintaining said collision cell at a pressure suitable for cooling the ions introduced into the collision cell.
Loboda teaches maintaining said collision cell at a pressure suitable for cooling the ions introduced into the collision cell (para. [0031]: “A photo-fragmentation region 188 having a higher pressure than the filtering region 186 can be provided to generate fragment ions predominantly by prompt fragmentation... An inlet 190 can provide gas 192, referred to as cooling gas, to the photo-fragmentation region 188 to maintain the higher pressure in the photo-fragmentation region 188 than the pressure in the filtering region 186”).
Stewart teaches after the precursor ions are confined within the first potential well, a cooling time period may be provided to allow the precursor ions to cool through a reduction in their kinetic energy (para. [0156]), and further teaches that the cooling gas allows the confined ions to cool at a faster rate. Loboda teaches introducing a cooling gas into a photo-fragmentation region to maintain the region at a higher pressure. Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to modify Stewart’s fragmentation chamber to use Loboda’s cooling-gas, higher-pressure arrangement, in order to increase ion-neutral collision frequency and thereby reduce the cooling time required for ions confined in Stewart’s potential well before UV fragmentation.
Regarding Claim 6:
Stewart in view of Loboda teaches the method of claim 5. Loboda further teaches wherein said pressure is in a range of about 1 torr to about 15 torr (para. [0032]: “the pressure in the photo-fragmentation region 208… preferably from about 10 mTorr to about 10 Torr,” i.e., a pressure range overlapping the claimed range).
Regarding Claim 18:
Stewart teaches the mass spectrometer of claim 15. Stewart further teaches so as to allow said cooled ions to be trapped via said potential barrier (paras. [0154-0156]: a fragmentation chamber in which ions are confined in a first potential well and cooled by a cooling gas before UV fragmentation). However, Stewart wherein said collision cell contains a gas at a pressure suitable for causing collisional cooling of at least a portion of the received ions, wherein optionally said pressure is in a range of about 1 torr to about 15 torr.
Loboda teaches wherein said collision cell contains a gas at a pressure suitable for causing collisional cooling of at least a portion of the received ions, wherein optionally said pressure is in a range of about 1 torr to about 15 torr (paras. [0031-0032]: “A photo-fragmentation region 188 having a higher pressure than the filtering region 186 can be provided to generate fragment ions predominantly by prompt fragmentation….An inlet 190 can provide gas 192, referred to as cooling gas, to the photo-fragmentation region 188 to maintain the higher pressure in the photo-fragmentation region 188 than the pressure in the filtering region 186;” “the pressure in the photo-fragmentation region 208… preferably from about 10 mTorr to about 10 Torr”).
Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to modify Stewart’s fragmentation chamber to use Loboda’s cooling-gas, higher-pressure arrangement, in order to increase ion-neutral collision frequency so that ions introduced into Stewart’s chamber are cooled more effectively before or during confinement.
Regarding Claim 20:
Stewart teaches the method of claim 15. However, Stewart does not specifically note wherein said collision cell has a curved profile extending from said inlet to said outlet, and wherein optionally said curved profile is a semi-circular profile.
Loboda teaches wherein said collision cell has a curved profile extending from said inlet to said outlet, and wherein optionally said curved profile is a semi-circular profile (Fig. 8a shows photofragmentation region 208 has a curved, semi-circular profile extending between the inlet side adjacent filtering region 206 and the outlet side adjacent mass analyzer 218; see also Fig. 8b showing a curved photo-fragmentation region 228).
Therefore, it would have been obvious for an ordinary skilled person in the art, before the time of effective filing, to configure Stewart’s fragmentation chamber with the curved profile taught by Loboda as a matter of design choice, since the instant specification does not attribute any particular technical effect or criticality to the curved shape, and using a curved or semi-circular chamber would have been a predictable variation in the physical layout of the fragmentation region while preserving the same ion-fragmentation function.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Stewart in view of US 2003/0006370 A1[hereinafter Bateman].
Regarding Claim 7:
Stewart teaches the method of claim 1. Stewart further teaches a potential barrier / first potential well that confines ions within the fragmentation chamber (paras. [0154-0161]). However, Stewart does not specifically note a potential barrier is in a range of about 0.1 volts to about 1.5 volts.
Bateman teaches a potential barrier is in a range of about 0.1 volts to about 1.5 volts (paras. [0014, 0043]: an ion tunnel ion trap in which a downstream portion is “separated from the upstream portion by a potential barrier” and further teaches that “the axial DC voltage difference maintained along a portion of the ion tunnel ion trap is selected from the group consisting of: (i) 0.1-0.5 V; (ii) 0.5-1.0 V; (iii) 1.0-1.5 V …”)
Thus, the combination teaches a potential barrier in a range of about 0.1 volts to about 1.5 volts).
Stewart teaches trapping ions in a potential well within a fragmentation chamber and then allowing resulting product ions to escape the well after fragmentation, so Stewart already implies that the barrier should be high enough to retain ions yet not so high as to prevent later ion release. Bateman teaches specific small axial DC voltage differences within the claimed range and explains that such a DC gradient is beneficial because it urges ions toward the downstream exit region and, when the trapping potential at the exit is removed, urges ions out of the ion tunnel ion trap. Therefore, it would have been obvious for an ordinary skilled person in the art, before the effective time of filing, to use the small barrier-related voltages taught by Bateman in Stewart’s trapping fragmentation chamber because they provide a known way to retain ions temporarily while still facilitating downstream release, making the selection of a barrier within the claimed range a predictable optimization of Stewart’s trapping-and-release operation.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Stewart in view of US2011/0084205A1 [hereinafter Makarov].
Regarding Claim 13:
Stewart teaches the method of claim 1. However, Stewart does not specifically note wherein an energy of the ions introduced into the collision cell is selected such that at least a portion of said ions is fragmented via collisional dissociation to generate a first plurality of product ions, wherein said potential barrier is capable of trapping at least a portion of said plurality of product ions in said region.
Makarov teaches wherein an energy of the ions introduced into the collision cell is selected such that at least a portion of said ions is fragmented via collisional dissociation to generate a first plurality of product ions, wherein said potential barrier is capable of trapping at least a portion of said plurality of product ions in said region (paras. [0066-0067, 0104]: ions are sent “directly to the HCD collision cell 50, in which they are fragmented” and “[t]he collision energy is selected by the energy offset between the ion trap and the collision cell”, and the collision cell “comprises a set of trapping electrodes, which generate an electric field, such that ions can be stored in a trapping volume”, i.e., the selected collision energy causes collisional dissociation in the collision cell to generate product ions, and the trapping electrodes / potential barriers of the collision cell are capable of trapping at least a portion of those product ions in the trapping region).
Stewart teaches trapping ions in a fragmentation chamber and fragmenting the trapped ions by UV radiation, while Makarov teaches selecting the collision energy of ions entering an HCD collision cell so that the ions undergo collisional dissociation and further teaches that the collision cell includes trapping electrodes capable of storing ions in a trapping volume. Therefore, it would have been obvious for an ordinary skilled person in the art, before the time of effective filing, to incorporate Makarov’s CID operation into Stewart’s trapping fragmentation chamber so that precursor ions can first undergo collisional dissociation in the collision cell before UV irradiation. Doing so would have been desirable because generating product ions by CID prior to UV irradiation provides additional structural information about the analyte ions, which is a known objective in tandem mass spectrometry analysis, while Stewart’s trapping region would allow at least a portion of those product ions to be retained for subsequent processing.
Regarding Claim 14:
As discussed in the 112b rejection section, this claim is interpreted as dependent on claim 13.
Stewart in view of Makarov teaches the method of claim 13. Stewart in view of Makarov further teaches wherein said step of applying the UV radiation comprises exposing at least a portion of said first plurality of product ions trapped in said region to said UV radiation so as to cause fragmentation of at least a portion thereof so as to generate a second plurality of product ions such that said second plurality of the product ions can overcome said potential barrier (as previously discussed, the combined references teaches claim 13 which recites the first-stage CID fragmentation. Claim 14 adds a second-stage UV fragmentation of the first product ions trapped in the collision cell, which is taught by Stewart as previously discussed (e.g., in claims 1& 15); thus, claims 13 and 14 together recite an MS3-type fragmentation workflow taught by the combined references).
Conclusion
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/JING WANG/Examiner, Art Unit 2881
/WYATT A STOFFA/Primary Examiner, Art Unit 2881