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 .
Election/Restrictions
Applicant’s election without traverse of claims 1-9 in the reply filed on 1/16/2026 is acknowledged.
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.
Claim(s) 1, 2, 5, 7, and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jones et al. U.S. PGPUB No. 2021/0109069 in view of Gedcke et al. U.S. Patent No. 5,995,989.
Regarding claim 1, Jones discloses a method for performing mass analysis, the method comprising: ejecting, from a first well of a well plate (“Each ejection event may liberate approximately 20 nl of sample and so it is possible to repeatedly sample up to around 1000 times from each sample well” [0115]), a first sample into a transport fluid (“the spray of droplets which are ejected preferably comprise charged droplets which form or are released as a mist of droplets” [0106]); ionizing the first sample and the transport fluid to generate first ions (“The application of a high voltage to the sampling nozzle or sampling electrode 5 causes ions of a desired polarity (e.g. positively charged ions) to be drawn to the surface of the liquid sample 2 and then to be ejected or released from the upper surface of the liquid sample 2 as a fine mist of ionised particles” [0097]); detecting the first ions over a first period of time (“The selected parent ions of interest may then be fragmented in a collision or fragmentation cell or device and the resulting fragment ions may then be mass analysed. A determination may then be made that the fragment ion mass spectral data which has been obtained meets or exceeds a quality threshold” [0047]); storing the total accumulated count of first ions (“Each set of experiments may yield multiple data files associated with the sample, which may be identified, processed and stored appropriately” [0127]) as an intensity for the first well of the well plate (“the intensity of one or more fragment ions which are observed when parent ions of interest are fragmented and the resulting fragment, daughter or product ions are then mass analysed” [0029]); ejecting, from a second well of the well plate (“Each ejection event may liberate approximately 20 nl of sample and so it is possible to repeatedly sample up to around 1000 times from each sample well” [0115]), a second sample into the transport fluid (“the spray of droplets which are ejected preferably comprise charged droplets which form or are released as a mist of droplets” [0106]); ionizing the second sample and the transport fluid to generate second ions (“The application of a high voltage to the sampling nozzle or sampling electrode 5 causes ions of a desired polarity (e.g. positively charged ions) to be drawn to the surface of the liquid sample 2 and then to be ejected or released from the upper surface of the liquid sample 2 as a fine mist of ionised particles” [0097]); detecting the second ions over a second period of time (“The selected parent ions of interest may then be fragmented in a collision or fragmentation cell or device and the resulting fragment ions may then be mass analysed. A determination may then be made that the fragment ion mass spectral data which has been obtained meets or exceeds a quality threshold” [0047]); and storing the total accumulated count of second ions (“Each set of experiments may yield multiple data files associated with the sample, which may be identified, processed and stored appropriately” [0127]) as an intensity for the second well of the well plate (“the intensity of one or more fragment ions which are observed when parent ions of interest are fragmented and the resulting fragment, daughter or product ions are then mass analysed” [0029]). Jones discloses the claimed invention except that there is no explicit disclosure of, for each of the first and second ions, when a count rate of the detected second ions is above the background count rate threshold, accumulating a count of the detected ions.
Gedcke discloses a method for performing mass analysis, the method comprising: detecting ions over a first period of time (“a data acquisition period of 30 minutes” [col. 1; lines 32-33]); when a count rate of the detected first ions is above a background count rate threshold, accumulating a count of the detected ions (“The method of the present invention monitors the value of each data point as it is encountered and compares it to the previously encountered data to determine whether it is on or very near a peak. The y values for each data point are continuously summed and averaged to determine the average background level. The deviation Δi is determined for each subsequent data point and is used to determine a threshold” [Abstract]); storing the total accumulated count of ions as an intensity (“Each subsequent data point is compared to the threshold and, if found to be above the threshold, is assumed to be part of or very near a peak. At this point, the averaging is stopped until a subsequent data point is determined to be below the threshold. After any peaks have been detected, all or a portion of the data associated the background noise and scatter in the spectrum may be discarded, with only the data relevant to the peaks, and any other desired data kept” [Abstract]).
It would have been obvious to one possessing ordinary skill in the art before the effective filing date of the claimed invention to have modified Jones with the threshold method of Gedcke in order to remove background noise from acquired spectral data so as to distinguish between ions of interest and detected ions related to different compounds other than the sample that is desired to be analyzed.
Regarding claim 2, Jones discloses generating a report for the well plate, wherein the report includes the first intensity correlated with the first well and the second intensity correlated with the second well (“When the data is processed, these additional ejections may be summed to provide a spectrum for each sample with improved quality (i.e. more ions)” [0119]).
Regarding claim 5, Jones discloses the first sample is acoustically ejected as a droplet from the first well (“An Acoustic Mist Ionisation (“AMI”) ion source may be provided which is arranged and adapted to focus sound or acoustic waves 3 generated by an ultrasonic transducer 1 into a liquid sample 2. More particularly, the ultrasonic transducer 1 may be arranged to focus sound or acoustic waves into a region around the upper surface of the liquid sample 2 and in particular into a region around the meniscus which the liquid sample 2 forms with a sample well of a sample plate… The energy which is applied or focussed into the liquid sample 2 may be tuned so that a Taylor cone 4 is formed on the upper surface of the liquid sample 2 with the result that a mist of droplets is ejected or otherwise released from the upper surface of the liquid sample 2 and in particular from the cone region which forms, in use, upon the upper surface of the liquid sample 2” [0093-0094]).
Regarding claim 7, Jones discloses the claimed invention except that there is no explicit disclosure of, for each of the first and second ions, when a count rate of the detected second ions is above the background count rate threshold, accumulating a count of the detected ions.
Gedcke discloses a method for performing mass analysis, the method comprising: detecting ions over a first period of time (“a data acquisition period of 30 minutes” [col. 1; lines 32-33]); when a count rate of the detected first ions is above a background count rate threshold, accumulating a count of the detected ions (“The method of the present invention monitors the value of each data point as it is encountered and compares it to the previously encountered data to determine whether it is on or very near a peak. The y values for each data point are continuously summed and averaged to determine the average background level. The deviation Δi is determined for each subsequent data point and is used to determine a threshold” [Abstract]); storing the total accumulated count of ions as an intensity (“Each subsequent data point is compared to the threshold and, if found to be above the threshold, is assumed to be part of or very near a peak. At this point, the averaging is stopped until a subsequent data point is determined to be below the threshold. After any peaks have been detected, all or a portion of the data associated the background noise and scatter in the spectrum may be discarded, with only the data relevant to the peaks, and any other desired data kept” [Abstract]). Since Gedcke retroactively eliminates any peaks below the threshold, the remaining data represents only a time period that begins when the count rate of the detected first ions is first above the background count rate threshold and ends when the count rate of the detected first ions falls below the background count rate threshold.
It would have been obvious to one possessing ordinary skill in the art before the effective filing date of the claimed invention to have modified Jones with the threshold method of Gedcke in order to remove background noise from acquired spectral data so as to distinguish between ions of interest and detected ions related to different compounds other than the sample that is desired to be analyzed.
Regarding claim 9, Jones discloses that the method is performed as a multiple reaction monitoring (MRM) analysis of the sample (paragraph [0141] describes a specific example that is not suitable for MRM experiments, implying that at least one other example of the device does perform MRM analysis of the sample).
Claim(s) 3 and 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jones et al. U.S. PGPUB No. 2021/0109069 in view of Gedcke et al. U.S. Patent No. 5,995,989 in further view of Doherty et al. U.S. PGPUB No. 2009/0194679.
Regarding claim 3, Jones and Gedcke disclose the claimed invention except that while Jone discloses the sample is ejected from a transport liquid fluid (“an Acoustic Mist Ionisation ion source wherein acoustic energy is focussed into a liquid sample located in proximity to an electric field causing a mist of charged droplets to be ejected from the liquid sample and drawn towards a sampling nozzle or electrode” [Jones: 0060]), and Gedcke discloses the elimination of background counts in mass spectrometry (“The method and apparatus serves to recognize peak events and filter data associated with background noise, thereby reducing the volume of data to be transferred to storage and the data transfer rate required for storing the desired data” [Gedcke: [Abstract]), there is no explicit disclosure that the background count rate threshold is based on a count rate for the transport fluid.
Doherty discloses a method of mass spectrometry wherein: “the innovative concepts introduced herein can be applied to reduce noise in a mass spectrometer in connection with any sample that is accompanied by another species of gas or fluid that could generate noise, regardless of whether the species is part of the sample itself, part of a transport mechanism for the sample, or otherwise” [0102].
It would have been obvious to one possessing ordinary skill in the art before the effective filing date of the claimed invention to have modified Jones and Gedcke with the noise reduction of Doherty in order to remove noise generated by any liquid material used to store a sample in the liquid phase, thereby enabling more accurate measurement of the sample by mass spectrometry.
Regarding claim 4, Jones and Gedcke disclose the claimed invention except that while Jone discloses the sample is ejected from a transport liquid fluid (“an Acoustic Mist Ionisation ion source wherein acoustic energy is focussed into a liquid sample located in proximity to an electric field causing a mist of charged droplets to be ejected from the liquid sample and drawn towards a sampling nozzle or electrode” [Jones: 0060]), and Gedcke discloses generating a count rate threshold by: ionizing to generate ions; detecting the ions; determining an average count rate of the detected ions; and generating the count rate threshold based on the determined average count rate. (“The y values for each data point are continuously summed and averaged to determine the average background level. The deviation Δi is determined for each subsequent data point and is used to determine a threshold. Each subsequent data point is compared to the threshold and, if found to be above the threshold, is assumed to be part of or very near a peak. At this point, the averaging is stopped until a subsequent data point is determined to be below the threshold. After any peaks have been detected, all or a portion of the data associated the background noise and scatter in the spectrum may be discarded, with only the data relevant to the peaks, and any other desired data kept” [Gedcke: [Abstract]), there is no explicit disclosure of generating the background count rate threshold by: ionizing the transport fluid to generate transport ions; detecting the transport ions; determining an average count rate of the detected transport ions; and generating the background count rate threshold based on the determined average count rate.
Doherty discloses a method of mass spectrometry comprising: generating a background count rate threshold by: ionizing transport fluid to generate transport ions; detecting the transport ions (“Some background gasses (typically the expected environmental gasses, such as oxygen, nitrogen, carbon dioxide, argon, etc.) and fluids (most commonly water) virtually always manage to seep into the mass spectrometer… The carrier gas metastables can collide with the background gas molecules or collision gas molecules anywhere and at any time inside the mass spectrometer, creating ions of the background gasses” [0015-0016]); determining an average count rate of the detected transport ions; and generating the background count rate threshold based on the determined average count rate (“the innovative concepts introduced herein can be applied to reduce noise in a mass spectrometer in connection with any sample that is accompanied by another species of gas or fluid that could generate noise, regardless of whether the species is part of the sample itself, part of a transport mechanism for the sample, or otherwise” [0102]).
It would have been obvious to one possessing ordinary skill in the art before the effective filing date of the claimed invention to have modified Jones and Gedcke with the noise reduction of Doherty in order to remove noise generated by any liquid material used to store a sample in the liquid phase, thereby enabling more accurate measurement of the sample by mass spectrometry.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jones et al. U.S. PGPUB No. 2021/0109069 in view of Gedcke et al. U.S. Patent No. 5,995,989 in view of Satake et al. U.S. PGPUB No. 2013/0334416.
Regarding claim 8, Jones discloses the claimed invention except that there is no explicit disclosure that the first time period over which first ions are detected is between 0.2 to 2 seconds.
Satake discloses a method for performing mass analysis, the method comprising: ejecting, from a first well of a well plate, a first sample into a transport fluid (“the sample solution 5 is placed in the vessel 6 and disposed ahead of the inlet 21 of the mass spectrometer section 20 (S11)” [0065]); ionizing the first sample and the transport fluid to generate first ions (“the sample solution is ionized every time the probe electrode 1 of the sample transport electrode 7 passes in front of the inlet 21 (S16)” [0065]); detecting the first ions over a first period of time (“In the detector, ions are detected for 3 seconds, which is the measurement time (S17)” [0065]); when a count rate of the detected first ions is above a background count rate threshold, accumulating a count of the detected first ions (“The ions to be measured may be only ions of a certain m/z value” [0065]). Satake discloses that “the time t is a measurement time, and may be any time” [0065] and that “the actual measurement is initiated for about several seconds to several minutes this time (S22). This optimization is preferably performed fully automatically under the control of the computer” [0065].
It would have been obvious to one possessing ordinary skill in the art before the effective filing date of the claimed invention to have modified Jone and Gedcke with the detection time of Satake in order to optimize the detection time so as to be long enough to accumulate enough ions for an accurate measurement of a sample, but such that the detection time is not too long, slowing down throughput of analysis of multiple samples. Although Satake discloses that “the time t is a measurement time, and may be any time” [0065] and that “the actual measurement is initiated for about several seconds to several minutes this time (S22). This optimization is preferably performed fully automatically under the control of the computer” [0065], there is no explicit disclosure that the first time period is between 0.2 to 2 seconds. It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to set the first time period between 0.2 to 2 seconds since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. One would have been motivated to set the first time period between 0.2 to 2 seconds for the purpose of optimizing the detection time so as to be long enough to accumulate enough ions for an accurate measurement of a sample, but such that the detection time is not too long, slowing down throughput of analysis of multiple samples. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235.
Allowable Subject Matter
Claim 6 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claim 6; Jones et al. U.S. PGPUB No. 2021/0109069 discloses a method for performing mass analysis, the method comprising: ejecting, from a first well of a well plate (“Each ejection event may liberate approximately 20 nl of sample and so it is possible to repeatedly sample up to around 1000 times from each sample well” [0115]), a first sample into a transport fluid (“the spray of droplets which are ejected preferably comprise charged droplets which form or are released as a mist of droplets” [0106]); ionizing the first sample and the transport fluid to generate first ions (“The application of a high voltage to the sampling nozzle or sampling electrode 5 causes ions of a desired polarity (e.g. positively charged ions) to be drawn to the surface of the liquid sample 2 and then to be ejected or released from the upper surface of the liquid sample 2 as a fine mist of ionised particles” [0097]); detecting the first ions over a first period of time (“The selected parent ions of interest may then be fragmented in a collision or fragmentation cell or device and the resulting fragment ions may then be mass analysed. A determination may then be made that the fragment ion mass spectral data which has been obtained meets or exceeds a quality threshold” [0047]); storing the total accumulated count of first ions (“Each set of experiments may yield multiple data files associated with the sample, which may be identified, processed and stored appropriately” [0127]) as an intensity for the first well of the well plate (“the intensity of one or more fragment ions which are observed when parent ions of interest are fragmented and the resulting fragment, daughter or product ions are then mass analysed” [0029]); ejecting, from a second well of the well plate (“Each ejection event may liberate approximately 20 nl of sample and so it is possible to repeatedly sample up to around 1000 times from each sample well” [0115]), a second sample into the transport fluid (“the spray of droplets which are ejected preferably comprise charged droplets which form or are released as a mist of droplets” [0106]); ionizing the second sample and the transport fluid to generate second ions (“The application of a high voltage to the sampling nozzle or sampling electrode 5 causes ions of a desired polarity (e.g. positively charged ions) to be drawn to the surface of the liquid sample 2 and then to be ejected or released from the upper surface of the liquid sample 2 as a fine mist of ionised particles” [0097]); detecting the second ions over a second period of time (“The selected parent ions of interest may then be fragmented in a collision or fragmentation cell or device and the resulting fragment ions may then be mass analysed. A determination may then be made that the fragment ion mass spectral data which has been obtained meets or exceeds a quality threshold” [0047]); and storing the total accumulated count of second ions (“Each set of experiments may yield multiple data files associated with the sample, which may be identified, processed and stored appropriately” [0127]) as an intensity for the second well of the well plate (“the intensity of one or more fragment ions which are observed when parent ions of interest are fragmented and the resulting fragment, daughter or product ions are then mass analysed” [0029]). Jones discloses the claimed invention except that there is no explicit disclosure that the first time period is based on a time of ejection of the first sample and a time of ejection of the second sample.
The prior art fails to teach or reasonably suggest, in combination with the other claim limitations, a method for performing mass analysis, the method comprising: detecting first ions, ejected from a first well of a well plate and ionized, over a first period of time based on a time of ejection of the first sample and a time of ejection of a second sample from a second well of the well plate.
Conclusion
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/JASON L MCCORMACK/ Examiner, Art Unit 2881