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 .
Response to Amendment
The amendments filed 04/24/2026 have been entered. Claims 1-10 remain pending in the application.
Response to Arguments
Applicant’s amendments to the claims have overcome each and every objection previously set forth in the Non-Final Office Action dated 02/11/2026, hereinafter NFOA0211, however, Applicant’s amendments have introduced an additional typographical/clerical issue. See below for further details.
Applicant’s amendments to the claims have overcome each and every 35 U.S.C. 112(b) rejection previously set forth in NFOA0211.
Applicant’s invocation of 35 U.S.C. 102(b)(2)(A) and 35 U.S.C. 102(b)(2)(C) exceptions regarding the prior art Soltwisch are acknowledged. The 35 U.S.C. 103 rejection of record presented in NFOA0211 has thus been obviated. See below for new grounds of rejection.
Examiner notes for clarity of the record that Examiner did not take official notice in NFOA0211 (see p. 12); rather, the cited portion referred to in Applicant’s remarks was intended to indicate for the record the Examiner’s understanding of the knowledge of an ordinarily skilled artisan, and the general state of the laser/optical arts, hence Examiner’s qualifier indicating that this knowledge would not be sufficient to teach the limitation. Examiner notes that it is required to provide adequate documentary evidentiary basis to take official notice, which will be included if any such instances occur.
Claim Objections
Claim 10 is objected to because of the following informalities:
Claim 10 recites “…while varying an impingement position of the first energetic radiation to…”, however, the impingement position was previously initialized in the claim, as the claim previously requires ‘a first adjustment device for setting and changing an impingement position of the first energetic radiation’; Accordingly, this limitation should read ‘…while varying the impingement position of the first energetic radiation to…’.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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 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 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Bossmeyer (U.S. PGPub. No. US 20180174815 A1) in view of Soltwisch (DOI: 10.1021/acs.analchem.0c01747).
Examiner notes that Bossmeyer is Applicant provided prior art via the IDS dated 11/29/2023.
Regarding claim 1, Bossmeyer teaches a method for desorbing and ionizing sample material which is disposed on a sample support (Abstract; [0001]; [0068]), comprising:
- repeatedly locally impacting sample material on the sample support (See Fig. 6, beam 25 causing plume of ions 6; [0008]; [0068]; Examiner notes beams are disclosed as pulsed, i.e., repeated),
- impacting locally desorbed sample material using a pulsed second energetic radiation, which is aimed into the locally desorbed sample material, and triggering of ionization and/or increasing a degree of ionization of the locally desorbed sample material (See Fig. 6, beam 26 irradiating plume of ions 6; [0008]; [0068]; Examiner notes beams are disclosed as pulsed), with a direction of propagation of the second energetic radiation being in a plane that is substantially perpendicular to a surface normal of the sample support and positioned above the sample support (See Fig. 6, beam 26 propagating perpendicular to surface normal to sample support 5, and above beam 26 propagating above the sample support 5), and
- transferring ionized sample material, originating from the locally desorbed sample material which has been impacted with the second energetic radiation, into an ion-processing device (See Fig. 6, plume 6 being directed to ion funnel 7, into subsequent ion analysis stages such as 8, 9-11, and 11-16; [0008]-[0009]).
Bossmeyer does not teach repeatedly locally impacting sample material on the sample support at a plurality of impingement points on the sample material using a first energetic radiation which triggers local desorption of sample material into a gas phase above the sample support, while varying an impingement position of the first energetic radiation to each of the plurality of impingement points on the sample material on the sample support (Emphases added by Examiner) and does not explicitly teach with a focus position and/or a beam waist position of the second energetic radiation being controllably aligned above each respective impingement point on the sample material on the sample support.
However, Examiner notes that focusing a laser beam to a particular location is well represented in the prior art and an ordinarily skilled artisan would be reasonably apprised of the basic use of lenses to control a focus position to a particular location at least along the propagation of the beam (i.e., not lateral to the beam propagation). This does not necessarily mean that controllably aligning the focus position/the beam waist position above each of a plurality of impingement points on the sample would be known or obvious absent some teaching, suggestion, or motivation.
Nevertheless, Soltwisch teaches repeatedly locally impacting sample material on the sample support at a plurality of impingement points on the sample material using a first energetic radiation which triggers local desorption of sample material into a gas phase above the sample support (Introduction, Paragraphs 2-3; Experimental Section, Laser Irradiation Parameters Subsection; Examiner notes that the Laser Irradiation Parameters subsection discloses a pulsed laser, impinging at a plurality of points, including explicit disclosure of the ablation cloud; Experimental Section, MALDI-2 Modifications to the timsTOF fleX Subsection, Paragraph 1 discloses stage), while varying an impingement position of the first energetic radiation to each of the plurality of impingement points on the sample material on the sample support (Experimental Section, Laser Irradiation Parameters Subsection; Examiner notes this subsection teaches the laser being galvanometrically scanned across the sample) and with a focus position and/or a beam waist position of the second energetic radiation being controllably aligned above each respective impingement point on the sample material on the sample support (Experimental Section, MALDI-2 Modifications to the timsTOF fleX Subsection, Paragraphs 2-3; Examiner notes controllably aligning focus centrally above ablation sites, and synchronization of two laser sources).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Bossmeyer to include repeatedly locally impacting sample material on the sample support at a plurality of impingement points on the sample material using a first energetic radiation which triggers local desorption of sample material into a gas phase above the sample support, while varying an impingement position of the first energetic radiation to each of the plurality of impingement points on the sample material on the sample support (Emphases added by Examiner) and with a focus position and/or a beam waist position of the second energetic radiation being controllably aligned above each respective impingement point on the sample material on the sample support, as taught by Soltwisch.
Doing so represents combining known prior art elements according to known methods in order to yield predictable results, and would allow one, as taught by Soltwisch, to controllably vary the focus position of a laser beam in a MALDI system, which would allow one to improve the system of Bossmeyer by allowing for impingement on multiple sample positions synchronously with moving the sample stage, which is indicated by Soltwisch as desirable in Experimental Section, MALDI-2 Modifications to the timsTOF fleX Subsection, paragraph 1 due timing/speed considerations on measurement time, and which allow significant improvement to the desorption laser of Bossmeyer, and would allow the timing of the pulses to be properly synchronized while being scanned, as taught by Soltwisch above.
Examiner notes that galvanometric mirror systems are generally known within the prior art, and in particular for changing the position of lasers. For example, see prior art cited in NFOA0211.
Regarding claim 2, Bossmeyer in view of Soltwisch teaches the method according to Claim 1.
Soltwisch further teaches wherein a direction of incidence of the first energetic radiation is changed relative to a surface normal to the sample support (Experimental Section, Laser Irradiation Parameters Subsection; Examiner notes this subsection teaches the laser being galvanometrically scanned across the sample).
Regarding claim 3, Bossmeyer in view of Soltwisch teaches the method according to Claim 1.
Bossmeyer further teaches wherein the sample material is interspersed in a light-absorbent matrix substance ([0016]; [0019]; [0040]).
Regarding claim 4, Bossmeyer in view of Soltwisch teaches the method according to Claim 1.
Bossmeyer further teaches wherein the sample material comprises a plurality of spot preparations or a two-dimensional tissue section ([0001]; [0003]; [0006]; [0012]; [0019]; [0028]; [0040]).
Regarding claim 5, Bossmeyer in view of Soltwisch teaches the method according to Claim 1.
Bossmeyer further teaches wherein the sample support comprises a glass plate, a metal plate or a ceramic plate ([0019]).
Regarding claim 6, Bossmeyer in view of Soltwisch teaches the method according to Claim 1.
Bossmeyer further teaches wherein the first energetic radiation and/or the second energetic radiation is delivered by a pulsed laser ([0007]; [0010]; [0016]-[0017]; [0037]).
Regarding claim 7, Bossmeyer in view of Soltwisch teaches the method according to Claim 1.
Soltwisch further teaches wherein the position of the first energetic radiation relative to the sample support and/or the direction of propagation of the second energetic radiation relative to the sample support are/is changed or re-aligned using one or more mirrors and/or one or more lenses (Experimental Section, Laser Irradiation Parameters Subsection; Examiner notes this subsection teaches the laser being galvanometrically scanned across the sample; For completeness: Experimental Section, MALDI-2 Modifications to the timsTOF fleX Subsection, Paragraphs 2-3, which additionally discloses lenses and mirrors).
Regarding claim 8, as best understood in view of the 35 U.S.C. 112(b) issues identified above, Bossmeyer in view of Soltwisch teaches the method according to Claim 1.
Bossmeyer further teaches wherein the ion-processing device comprises a mobility analyzer, a mass analyzer, or a coupled mobility-mass analyzer (See Fig. 6; Abstract; [0004]-[0010]; [0057]; [0065]).
Regarding claim 9, as best understood in view of the 35 U.S.C. 112(b) issues identified above, Bossmeyer in view of Soltwisch teaches the method according to Claim 1.
Soltwisch further teaches wherein the focus position and/or the beam waist position of the second energetic radiation is adjusted (i) perpendicularly to and/or (ii) along the direction of propagation of the second energetic radiation (Experimental Section, MALDI-2 Modifications to the timsTOF fleX Subsection, Paragraphs 2-3; Examiner notes that the focus position is adjusted both along and perpendicular to the propagation direction of the PI laser, and discloses the synchronization of the two beams).
Regarding claim 10, Bossmeyer teaches a device for desorbing and ionizing sample material which is disposed on a sample support (Abstract; [0001]; [0068]), comprising:
- a desorption device for generating and guiding the first energetic radiation (See Fig. 6, beam 25 from laser system 24 desorbing plume of ions 6; [0008]; [0017]; [0047]; [0068]; Examiner notes a pulsed source is disclosed);
- an ionization device for generating and guiding the second energetic radiation (See Fig. 6, beam 26 from laser system 24 desorbing plume of ions 6; [0008]; [0017]; [0047]; [0068]; Examiner notes a pulsed source is disclosed);
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Bossmeyer does not teach a first adjustment device for setting and changing the position of the first energetic radiation relative to the sample support and a second adjustment device for setting and aligning the focus position and/or beam waist position of the second energetic radiation and does not explicitly teach a guidance system that communicates with the desorption device, the ionization device, the first adjustment device and the second adjustment device, and that is programmed to:
repeatedly locally impact the sample material on the sample support at a plurality of impingement points on the sample material using the first energetic radiation to trigger local desorption of sample material into a gas phase above the sample support, while varying an impingement position of the first energetic radiation to each of the plurality of impingement points on the sample material on the sample support;
impact locally desorbed sample material using a pulsing of the second energetic radiation, which is aimed into the locally desorbed sample material, and triggering of ionization and/or increasing a degree of ionization of the locally desorbed sample material, with a direction of propagation of the second energetic radiation being in a plane that is substantially perpendicular to a surface normal to the sample support and positioned above the sample support, and with a focus position and/or a beam waist position of the second energetic radiation being controllably aligned above each respective impingement point on the sample material on the sample support; and
transfer ionized sample material, originating from the locally desorbed sample material which has been impacted with the second energetic radiation, into an ion-processing device.
However, it is typical in the art for a laser system and/or a mass spectrometry system such as those disclosed by Bossmeyer to have some form of controller or processing device in order to function as intended, as would be understood by one of ordinary skill in the art, as Bossmeyer discloses (see, e.g., claim mapping of claim 1) several of the functionalities that the guidance system is required to be programmed to perform. Furthermore, under the broadest reasonable interpretation, a ‘guidance system’ is understood as some form of programmed processing system that could be comprised of several elements, and thus, the inherent control/processing structures of Bossmeyer that perform the method steps disclosed (see claim mapping of claim 1) could reasonably be interpreted as ‘a guidance system’ (e.g., in order to achieve ‘repeatedly locally impacting sample material’, ‘impacting locally desorbed sample material’, ‘transferring ionized sample material’). Typically, this is in the form of a computer system (having a processor and software) coupled to the mass spectrometry system, as would be known by an ordinarily skilled artisan.
Additionally, as discussed in claim 1, while not explicitly disclosed as being performed by a programmed processor, Bossmeyer teaches performing repeatedly locally impact the sample material on the sample support (See Fig. 6, beam 25 causing plume of ions 6; [0008]; [0068]; Examiner notes beams are disclosed as pulsed, i.e., repeated), and impact locally desorbed sample material using a pulsing of the second energetic radiation, which is aimed into the locally desorbed sample material, and trigger of ionization and/or increase a degree of ionization of the locally desorbed sample material (See Fig. 6, beam 26 irradiating plume of ions 6; [0008]; [0068]; Examiner notes beams are disclosed as pulsed), with a direction of propagation of the second energetic radiation being in a plane that is substantially perpendicular to a surface normal to the sample support and positioned above the sample support (See Fig. 6, beam 26 propagating perpendicular to surface normal to sample support 5, and above beam 26 propagating above the sample support 5), and and transfer ionized sample material, originating from the locally desorbed sample material which has been impacted with the second energetic radiation, into an ion-processing device (See Fig. 6, plume 6 being directed to ion funnel 7, into subsequent ion analysis stages such as 8, 9-11, and 11-16; [0008]-[0009]).
Accordingly, it is Examiner’s opinion that Bossmeyer disclosure of the above required structures performing the above functionality is sufficient, under the BRI, to disclose ‘a guidance system that communicates with the desorption device and the ionization device and that is programmed to perform’ the above disclosed method steps.
Soltwisch teaches a first adjustment device for setting and changing the position of the first energetic radiation relative to the sample support (Experimental Section, Laser Irradiation Parameters Subsection; Examiner notes this subsection teaches the laser being galvanometrically scanned across the sample, i.e., with one or more mirrors or lenses) and a second adjustment device for setting and aligning the focus position and/or beam waist position of the second energetic radiation (Experimental Section, MALDI-2 Modifications to the timsTOF fleX Subsection, Paragraphs 2-3; Examiner notes that the focus position is adjusted for the PI laser, with one or more mirrors or lenses) and a guidance system that communicates with the desorption device, the ionization device, the first adjustment device and the second adjustment device, and that is programmed (Experimental Section, MALDI-2 Modifications to the timsTOF fleX Subsection, Paragraphs 1-3; Examiner notes that Bruker timsTOF fleX has a programmed processor and communicated with the lasers and their optical elements, and Soltwisch further discloses synchronizing the elements) to:
repeatedly locally impact the sample material on the sample support at a plurality of impingement points on the sample material using the first energetic radiation to trigger local desorption of sample material into a gas phase above the sample support (Introduction, Paragraphs 2-3; Experimental Section, Laser Irradiation Parameters Subsection; Examiner notes that the Laser Irradiation Parameters subsection discloses a pulsed laser, impinging at a plurality of points, including explicit disclosure of the ablation cloud; Experimental Section, MALDI-2 Modifications to the timsTOF fleX Subsection, Paragraph 1 discloses stage), while varying an impingement position of the first energetic radiation to each of the plurality of impingement points on the sample material on the sample support (Experimental Section, Laser Irradiation Parameters Subsection; Examiner notes this subsection teaches the laser being galvanometrically scanned across the sample) and impact locally desorbed sample material using a pulsing of the second energetic radiation…with a focus position and/or a beam waist position of the second energetic radiation being controllably aligned above each respective impingement point on the sample material on the sample support (Experimental Section, MALDI-2 Modifications to the timsTOF fleX Subsection, Paragraphs 2-3; Examiner notes controllably aligning focus centrally above ablation sites, and synchronization of two laser sources).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Bossmeyer to include a first adjustment device for setting and changing the position of the first energetic radiation relative to the sample support and a second adjustment device for setting and aligning the focus position and/or beam waist position of the second energetic radiation and a guidance system that communicates with the desorption device, the ionization device, the first adjustment device and the second adjustment device, and that is programmed to:
repeatedly locally impact the sample material on the sample support at a plurality of impingement points on the sample material using the first energetic radiation to trigger local desorption of sample material into a gas phase above the sample support, while varying an impingement position of the first energetic radiation to each of the plurality of impingement points on the sample material on the sample support and impact locally desorbed sample material using a pulsing of the second energetic radiation…with a focus position and/or a beam waist position of the second energetic radiation being controllably aligned above each respective impingement point on the sample material on the sample support (Emphasis added by Examiner), as taught by Soltwisch, in order to achieve teach a first adjustment device for setting and changing the position of the first energetic radiation relative to the sample support and a second adjustment device for setting and aligning the focus position and/or beam waist position of the second energetic radiation and a guidance system that communicates with the desorption device, the ionization device, the first adjustment device and the second adjustment device, and that is programmed to: repeatedly locally impact the sample material on the sample support at a plurality of impingement points on the sample material using the first energetic radiation to trigger local desorption of sample material into a gas phase above the sample support, while varying an impingement position of the first energetic radiation to each of the plurality of impingement points on the sample material on the sample support; impact locally desorbed sample material using a pulsing of the second energetic radiation, which is aimed into the locally desorbed sample material, and triggering of ionization and/or increasing a degree of ionization of the locally desorbed sample material, with a direction of propagation of the second energetic radiation being in a plane that is substantially perpendicular to a surface normal to the sample support and positioned above the sample support, and with a focus position and/or a beam waist position of the second energetic radiation being controllably aligned above each respective impingement point on the sample material on the sample support; and transfer ionized sample material, originating from the locally desorbed sample material which has been impacted with the second energetic radiation, into an ion-processing device, by the combination
Doing so represents combining known prior art elements according to known methods in order to yield predictable results, and would allow one, as taught by Soltwisch, to controllably vary the focus position of a laser beam in a MALDI system, which would allow one to improve the system of Bossmeyer by allowing for impingement on multiple sample positions synchronously with moving the sample stage, which is indicated by Soltwisch as desirable in Experimental Section, MALDI-2 Modifications to the timsTOF fleX Subsection, paragraph 1 due timing/speed considerations on measurement time, and which allow significant improvement to the desorption laser of Bossmeyer, and would allow the timing of the pulses to be properly synchronized while being scanned, as taught by Soltwisch above. Finally, controlling the elements of the system using a programmed guidance system (e.g., a programmed control unit) also represents combining known prior art elements according to known methods in order to yield predictable results, and would allow one to control the optical elements of the system of Bossmeyer in view of Soltwisch using conventional control elements.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Spraggins (DOI: 10.1021/acs.analchem.9b03612);
Niehaus (cited in NFOA0211; DOI: 10.1038/s41592-019-0536-2);
Ogrinc Potočnik (DOI: 10.1002/rcm.7379);
Dreisewerd (DOI: 10.1007/978-1-0716-2030-4_2);
Schultz (US 20100200742 A1);
Murray (US 20200381235 A1);
Williams (US 20210183632 A1).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTOPHER J GASSEN whose telephone number is (571)272-4363. The examiner can normally be reached M-F 9-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, ROBERT H KIM can be reached at (571)272-2293. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTOPHER J GASSEN/Examiner, Art Unit 2881
/MICHAEL J LOGIE/ Primary Examiner, Art Unit 2881
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