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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-10, 12-14 and 17-21) in the reply filed on May 11, 2026 is acknowledged. Non-elected claims 15 and 22 are withdrawn from further consideration.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
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 1-10, 12-14 and 17-21 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.
On line 8 of claim 1, the phrase “the respective ion size” lacks antecedent basis. On lines 7-9 of claim 1, the phrase “wherein the at least one selectivity enhancer station separates ions based on the respective ion size comprises an ion mobility unit for separation ions with respect to their ion mobility” is indefinite since it does not make proper sense. It is suggested to change this phrase to -- wherein the at least one selectivity enhancer station separates ions based on respective ion size, and comprises an ion mobility unit for separating ions with respect to their ion mobility--. On lines 9-10 of claim 1, the phrase in parentheses “(AC/DC and/or RF)” is indefinite since it is not clear whether this limitation in parentheses is a part of the claimed invention. On line 14 of claim 1, the phrase “the ion detection system” lacks antecedent basis since line 11 of claim 1 positively recites “ an ion detection station”, not an ion detection system. Claim 1 is indefinite since there is no structural cooperation between the different recited components of the clinical diagnostic system. It is not clear whether each of the sample preparation station, the ion generation station, the at least one selectivity enhancer station, the ion detection station and the data processing station are all physically connected to one another so that a sample introduced to the clinical diagnostic system automatically flows or moves into and through each of the recited components of the system.
On lines 1-2 of claim 2, the phrase “the biological sample” lacks antecedent basis since line 2 of claim 1 recites plural” biological samples”. On line 2 of claim 2, the phrase “random-excess mode” is indefinite since it is not clear what a random-excess mode is and how it operates on the clinical diagnostic system.
On lines 1-2 of claim 3, the phrase “the biological sample” lacks antecedent basis since line 2 of claim 1 recites plural” biological samples”. On line 3 of claim 3, the word “liquor” is indefinite since it is not clear what type of body fluid constitutes this “liquor”.
On lines 2-3 and on line 3 of claim 5, the phrase “the biological sample” lacks antecedent basis since line 2 of claim 1 recites plural” biological samples”. On line 5 of claim 5, the phrase “sample pre-treatment unit, sample analytical unit” should be changed to -- sample pre-treatment unit, and sample analytical unit--.
On lines 1-2 of claim 6, the phrase “the sample delivery unit” lacks antecedent basis since claim 6 depends from claim 1, and claim 1 does not positively recite any “sample delivery unit”. In order for this phrase to have proper antecedent basis, claim 6 should depend from claim 5. On line 3 of claim 6, the phrase “the sample pre-treatment unit” lacks antecedent basis since claim 6 depends from claim 1, and claim 1 does not positively recite any “sample pre-treatment unit”. In order for this phrase to have proper antecedent basis, claim 6 should depend from claim 5. On line 5 of claim 6, the phrase “a supporting compound handling unit” is indefinite since it is not clear what constitutes “a supporting compound”. On line 8 of claim 6, the phrase “the sample analytical unit” lacks antecedent basis since claim 6 depends from claim 1, and claim 1 does not positively recite any “sample analytical unit”. In order for this phrase to have proper antecedent basis, claim 6 should depend from claim 5.
On lines 1-2 of claim 9, the phrase “the selectivity enhancer station” should be changed to –the at least one selectivity enhancer station—so as to recite the same terminology as recited in claim 1.
On line 2 of claim 10, the phrase “the mass spectrometer” lacks antecedent basis since claim 10 depends from claim 1, and claim 1 does not positively recite a mass spectrometer. Rather, claim 1 recites “an ion detection station”.
On line 1 of claim 12, the phrase “the presence or level” lacks antecedent basis. Step A) of the method recited on line 3 of claim 12 is indefinite since it is not clear what steps must be performed in the method to prepare the biological sample. What steps constitute the “preparation of the biological sample”?
Claim 13 is indefinite since it is not clear where and when the internal standard is added in the method. Is the internal standard added to the biological sample during the preparation of the biological sample in step A?
On line 2 of claim 19, the phrase “the mass spectrometer” lacks antecedent basis since claim 19 depends from claim 10, claim 10 depends from claim 1, and claim 1 does not positively recite a mass spectrometer. Rather, claim 1 recites “an ion detection station”.
Inventorship
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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.
Claim(s) 12-14 and 20-21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Manicke et al (US 2018/0033600, submitted in the IDS filed on September 30, 2023).
With regards to claim 12, Manicke et al teach of a method for analyzing a biological sample for a presence or level of at least one analyte therein (see paragraphs 0031-0035 in Manicke et al). The method comprises the steps of preparing a biological sample comprising an analyte of interest (see paragraph 0026 in Manicke et al where it states “Some embodiments of the present invention provide an inexpensive, single-use cartridge capable of performing a variety of sample preparation and analysis steps, including collecting an accurate volume of sample, depositing it on a porous substrate for storage as a dried sample, concentrating and separating analytes from a matrix, incorporating an IS (internal standard) to allow quantitative analysis, and performing final sample extraction and ionization for mass spectrometric analysis”), ion generation from at least one analyte of interest in the sample (see paragraphs 0088-0089 in Manicke et al where it states “In some embodiments, this process could be performed automatically using a properly designed MS interface system, wherein the system would slide sample holder 104 from a first to a second position…at programmed intervals. After a sample is dried, MS cartridge 100 is positioned in front of mass spectrometer atmospheric pressure inlet 170. Cover 160 is removed or pierced, and an elution/spray solvent is added to sample opening 130 to flow through through-hole 128 and into SPE column 134… the elution solvent extracts target analytes from SPE column 134… The solvent containing the analytes wicks through SPE column 134 and onto absorbent unit 150…once the elution solvent has completely wet absorbent unit 150, in the embodiment shown a paper-spray substrate, a high voltage… is applied to the absorbent unit 150…After voltage is applied, ionization of the extracted analytes is achieved by paper-spray ionization…”), separation of the ion or ions via their ion mobility using an electric field applied to one or more electrodes (see paragraphs 0133-0136 in Manicke et al where it states “In some embodiments of the present disclosure, non-chromatographic methods enhance selectivity in direct MS analyses. While in some embodiments paper-spray MS is utilized, in some embodiments coupling paper-spray MS to FAIMS can be applied.. FAIMS and other related methodologies such as differential mobility spectrometry (DMS) are ion mobility type methods that separate gas-phase ions at atmospheric pressure on the basis of analyte dependent variability in mobility at high electric fields…Because the mobility of an analyte ion changes as the electric field is varied, it will experience a drift toward one of the electrodes… First, the FAIMS device is inserted between the ion source (paper-spray in this case) and the inlet to the mass spectrometer…the data reported herein illustrates that paper-spray can be coupled to FAIMS-MS…”), and detecting and determining at least one ion of the at least one analyte of interest using mass spectrometry (see paragraph 0026 in Manicke et al where it states …performing final sample extraction and ionization for mass spectrometric analysis…”, paragraph 0031 in Manicke et al where it states “…positioning the first absorbent unit in front of a mass spectrometer pressure inlet, applying an electric potential to the first absorbent unit, and analyzing the sample by mass spectrometry”, and claims 21 and 33 in Manicke et al).
With regards to claims 13 and 21, Manicke et al teach that an internal standard is added to the biological sample during its preparation, and that the internal standard is isotopically labeled. See paragraph 0032 in Manicke et al where it states “…the cartridge further comprises a collection disc with an internal standard…”, paragraph 0131 in Manicke et al where it states “Results indicate that simply pipetting the IS solution on top of the sample collection punch can give acceptable analytical performance”, and paragraph 0180 in Manicke et al where it states “The SPE cartridge was evaluated for quantitative analysis of five drugs in plasma using stable isotopically labeled analogues as internal standards”.
With regards to claims 14 and 20, Manicke et al teach that the method is performed in a clinical diagnostic system which automatically prepares the biological sample. See paragraph 0022 in Manicke et al where it states “The general idea is to develop approaches that occur automatically when the sample is added to the cartridge”, wherein the cartridge 100 (see Figure 1) serves as a clinical diagnostic system, paragraph 0025 in Manicke et al where it states “Sample pre-concentration and extraction can occur automatically, requiring no human action or secondary device”, and paragraph 0088 in Manicke et al where it states “In some embodiments, this process could be performed automatically using a properly designed MS interface system…”.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-10 and 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Manicke et al (US 2018/0033600, submitted in the IDS filed on September 30, 2023) in view of Kobold et al (WO 2019/007868 A1). For a teaching of Manicke et al, see previous paragraphs in this Office action.
With regards to claim 1, Manicke et al teach of a clinical diagnostic system 100 comprising a sample cartridge 102 and a sample holder 104. The sample cartridge 102 and sample holder 104 serve as a sample preparation station for the automated preparation of a biological sample comprising at least one analyte of interest (see paragraph 0026 in Manicke et al where it states “Some embodiments of the present invention provide an inexpensive, single-use cartridge capable of performing a variety of sample preparation and analysis steps, including collecting an accurate volume of sample, depositing it on a porous substrate for storage as a dried sample, concentrating and separating analytes from a matrix, incorporating an IS (internal standard) to allow quantitative analysis, and performing final sample extraction and ionization for mass spectrometric analysis”, also see paragraphs 0083-0087 in Manicke et al which describe how a biological sample is added to a through hole 128 by a sample opening 130 in a solid phase extraction column (SPE) 134 of the sample holder 104, the sample wicks into an absorbent material 124 in the sample cartridge 102, the sample holder 104 is then moved in the cartridge 102 to position the SPE column 134 over an absorbent unit 150 which is a paper-spray substrate, and an elution solvent is applied to the SPE column 134 to extract target analytes from the column 134 into the paper-based substrate 150). The clinical diagnostic system taught by Manicke et al also comprises an ion generation station for generating at least one ion or ions of the at least one analyte of interest (see paragraphs 0088-0089 in Manicke et al where it states “In some embodiments, this process could be performed automatically using a properly designed MS interface system, wherein the system would slide sample holder 104 from a first to a second position…at programmed intervals. After a sample is dried, MS cartridge 100 is positioned in front of mass spectrometer atmospheric pressure inlet 170. Cover 160 is removed or pierced, and an elution/spray solvent is added to sample opening 130 to flow through through-hole 128 and into SPE column 134… the elution solvent extracts target analytes from SPE column 134… The solvent containing the analytes wicks through SPE column 134 and onto absorbent unit 150…once the elution solvent has completely wet absorbent unit 150, in the embodiment shown a paper-spray substrate, a high voltage… is applied to the absorbent unit 150…After voltage is applied, ionization of the extracted analytes is achieved by paper-spray ionization…”), at least one selectivity enhancer station for enhancing the selectivity of the at least one analyte of interest, wherein the at least one selectivity enhancer separates ions based on their respective ion size and comprises an ion mobility unit for separation of ions with respect to their ion mobility using electric or radio frequency fields applied to one or more electrodes (see paragraphs 0133-0136 in Manicke et al where it states “In some embodiments of the present disclosure, non-chromatographic methods enhance selectivity in direct MS analyses. While in some embodiments paper-spray MS is utilized, in some embodiments coupling paper-spray MS to FAIMS can be applied.. FAIMS and other related methodologies such as differential mobility spectrometry (DMS) are ion mobility type methods that separate gas-phase ions at atmospheric pressure on the basis of analyte dependent variability in mobility at high electric fields…Because the mobility of an analyte ion changes as the electric field is varied, it will experience a drift toward one of the electrodes… First, the FAIMS device is inserted between the ion source (paper-spray in this case) and the inlet to the mass spectrometer…the data reported herein illustrates that paper-spray can be coupled to FAIMS-MS…”), and an ion detection station for detecting at least one ion of the at least one analyte of interest, wherein the ion detection station comprises a mass spectrometer (see paragraph 0026 in Manicke et al where it states …performing final sample extraction and ionization for mass spectrometric analysis…”, and paragraph 0031 in Manicke et al where it states “…positioning the first absorbent unit in front of a mass spectrometer pressure inlet, applying an electric potential to the first absorbent unit, and analyzing the sample by mass spectrometry”).
Manicke et al fail to teach that the clinical diagnostic system also comprises a data processing station for processing and/or evaluation of at least one electronic signal received from the ion detection system/mass spectrometer.
Kobold et al (WO 2019/007868) teach of an automatic clinical diagnostic system and method which comprises a sample preparation module 20 for the automated preparation of samples, a liquid chromatography (LC) separation module 30 coupled to the sample preparation module 20 via an interface 40, a mass spectrometer module 50 coupled to the LC module 30 via an interface 60, and a result calculation module 70 for identifying and/or quantifying analytes in a sample applied to the diagnostic system. The sample preparation module 20 prepares a sample in the clinical diagnostic system by reducing or removing interfering matrix components in the sample, enriching analytes in the sample, pipetting fluids, pumping fluids, mixing with reagents, incubating the sample at a certain temperature, centrifuging, heating or cooling, separating, filtering, drying, washing, transferring, storing, etc. The sample preparation module may also comprise a reaction container transporting mechanism. The mass spectrometer module 50 may be a tandem mass spectrometer that generates fragments of analyte ions by collision induced fragmentation, and then separates the fragment ions according to their mass to charge ratio. The LC/MS interface may also further comprise an ion mobility module between the ionization source and the mass spectrometer. The ion mobility module may comprise an asymmetric waveform ion mobility spectrometer (FAIMS). This ion mobility module allows for gas-phase separation before mass spectrometry, which compensates for insufficient chromatographic separation and reduces overall background signal by preventing background and other non-specific ions to enter the mass spectrometer. Kobold et al teach that the result calculation module 70 comprises a memory and a processor for running a computer readable program designed for reading and storing analytical data generated during sample processing, and for analyzing the data to produce sample results that identify and/or quantify one or more analytes in a sample passed through the clinical diagnostic system. See the abstract and pages 4-5 and 8-9 of Kobold et al.
Based upon a combination of Manicke et al and Kobold et al, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include in the clinical diagnostic system taught by Manicke et al a data processing station for processing and/or evaluation of at least one electronic signal received from the ion detection system/mass spectrometer because Kobold et al teach that in a similar type of automated clinical diagnostic system comprising a sample preparation station, an ion generation station, a selectivity enhancer comprising an ion mobility unit, and a mass spectrometer as an ion detection station, it is advantageous to also include a data processing station in the form of a result calculation module since this type of module or station in the clinical diagnostic system allows for the automatic analysis of data produced by the mass spectrometer to produce sample results that identify and/or quantify one or more analytes in a sample passed through the clinical diagnostic system.
With regards to claims 2 and 7, Manicke et al teach that the clinical diagnostic system is automated, and that the sample preparation station is also partially or fully automated. See paragraph 0022 in Manicke et al where it states “The general idea is to develop approaches that occur automatically when the sample is added to the cartridge”, wherein the cartridge 100 (see Figure 1) serves as a clinical diagnostic system, paragraph 0025 in Manicke et al where it states “Sample pre-concentration and extraction can occur automatically, requiring no human action or secondary device”, and paragraph 0088 in Manicke et al where it states “In some embodiments, this process could be performed automatically using a properly designed MS interface system…”.
With regards to claim 3, Manicke et al teach that the biological sample analyzed using the clinical diagnostic system comprises blood or plasma. See paragraphs 0022, 0030 and 0097 in Manicke et al.
With regards to claims 4 and 18, Manicke et al teach that analytes having a molar mass of smaller than m/z=2000 or smaller than m/z=1000 are analyzed with the clinical diagnostic system. See Figures 20A-20D in Manicke et al.
With regards to claims 5-6, Manicke et al teach that the sample preparation station in the clinical diagnostic system serves to remove or reduce interfering matrix components in the biological sample. The sample preparation station comprises a sample pre-treatment unit that comprises a magnetic bead handling unit, an internal standard handling unit, and a sample analytical unit that comprises a solid-liquid support analyte enrichment unit. See paragraph 0030 in Manicke et al where it states “The solid phase extraction column may comprise material suitable for protein concentration. The material for protein concentration may comprise antibody derivatized magnetic beads. The antibody derivatized beads may be configured to couple to a protein analyte”. Also, see paragraph 0032 in Manicke et al where it states “…the cartridge further comprises a collection disc with an internal standard…”, paragraph 0131 in Manicke et al where it states “Results indicate that simply pipetting the IS solution on top of the sample collection punch can give acceptable analytical performance”, and paragraph 0180 in Manicke et al where it states “The SPE cartridge was evaluated for quantitative analysis of five drugs in plasma using stable isotopically labeled analogues as internal standards”. Also, see paragraph 0026 in Manicke et al where it states “Some embodiments of the present invention provide an inexpensive, single-use cartridge capable of performing a variety of sample preparation and analysis steps, including collecting an accurate volume of sample, depositing it on a porous substrate for storage as a dried sample, concentrating and separating analytes from a matrix, incorporating an IS (internal standard) to allow quantitative analysis, and performing final sample extraction and ionization for mass spectrometric analysis”.
With regards to claim 8, Manicke et al teach that the ion generation station comprises a steady analyte ion supply unit in the form of a paper-spray ionization unit. See paragraphs 0088-0089 in Manicke et al.
With regards to claim 9, Manicke et al teach that the selectivity enhancer station in the clinical diagnostic system comprises an ion mobility unit, but fail to teach that the selectivity enhancer station further comprises an ion fragmentation unit comprising a collision-induced dissociation (CID) fragmentation unit. However, based upon a combination of Manicke et al and Kobold et al, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include in the clinical diagnostic system taught by Manicke et al a collision-induced dissociation (CID) fragmentation unit because Manicke et al teach that fragments of the analyte ions are formed in the mass spectrometer of the diagnostic system (see paragraphs 0060 and 0097 in Manicke et al), and Kobold et al teach that analytes in a sample can be accurately and efficiently analyzed in a clinical diagnostic system comprising a tandem mass spectrometer that generates fragments of the analyte ions by collision induced fragmentation and then separates the fragment ions according to their mass to charge ratio.
With regards to claims 10 and 19, Manicke et al fail to specifically teach that the one or more analytes in the sample are present in the clinical diagnostic system, or in the mass spectrometer, or in the ion mobility unit for less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 seconds. However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to expect that the one or more analytes in the sample analyzed with the clinical diagnostic system taught by Manicke et al are present in the clinical diagnostic system, or in the mass spectrometer, or in the ion mobility unit for less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 seconds because Manicke et al teach that the separation of the analyte ions in the ion mobility device occurs very fast on a millisecond time scale. See paragraph 0135 in Manicke et al.
With regards to claim 17, Manicke et al fail to teach that the blood or plasma sample analyzed with the clinical diagnostic analyzer is obtained from a human mammal. However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to expect that the blood or plasma sample analyzed with the clinical diagnostic analyzer taught by Manicke et al is obtained from a human mammal because clinical diagnostic analyzers are widely known and generally used for analyzing blood samples obtained from humans in order to diagnose various conditions in the humans.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Please make note of: Franz et al (US 2018/0292368) who teach of an automated clinical diagnostic system and method comprising a sample preparation station, a liquid chromatography separation station, an ionization source, an ion mobility station and a mass spectrometer.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN M WALLENHORST whose telephone number is (571)272-1266. The examiner can normally be reached on Monday-Thursday from 6:30 AM to 4:30 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lyle Alexander, can be reached at telephone number 571-272-1254. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MAUREEN WALLENHORST/Primary Examiner, Art Unit 1797 May 27, 2026
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