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 .
Claim Objections
The Claims are objected to because of the following informalities:
In Claim 5, lines 4-5, the term “driving the coil to apply an inhibitory protocol of magnetic stimulation to the subject’s brain” should be replaced with -- driving the at least one coil to apply an inhibitory protocol of magnetic stimulation to the subject’s brain -- for claim consistency with Claim 1.
In Claim 11, lines 3-4, the term “driving the coil to apply an inhibitory protocol of magnetic stimulation to the subject’s brain” should be replaced with -- driving the at least one coil to apply an inhibitory protocol of magnetic stimulation to the subject’s brain -- for claim consistency with Claim 1.a
Appropriate correction is required and applicant should carefully review the Claims for any other informalities.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 5-12, and 14-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Regarding Claim 1, the claim(s) is directed to the abstract idea of measuring a slope between a negative peak at about 100 ms after the stimulation and a positive peak at about 180 ms after the stimulation, at least partially in response to the slope between the negative peak and the positive peak, generate an output that is indicative of the subject being at risk of dementia which are considered steps of a mental process.
This judicial exception is not integrated into a practical application because:
- The claims fail to outline an improvement to the technical field.
- The claims fail to apply the judicial exception to effect a particular treatment.
- The claims fail to apply the judicial exception with a particular machine.
- The claims fail to effect a transformation or reduction of a particular article to a different state or thing.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they seem to merely generally link the use of the judicial exception to a particular technological environment.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because driving a coil to apply a magnetic stimulation to the subject’s brain and receiving a magnetic-stimulation-evoked-potential signal from the electrodes are insignificant extrasolution data gathering activities.
Furthermore, coils and electrodes are general fields of use and computer processors are generic computer elements used to perform generic computer functions and don’t add significantly more and are well-understood, routine, and previously known to the industry.
None of these limitations, considered as an ordered combination provide eligibility because the claim taken as a whole, does not amount to significantly more than the underlying abstract idea of mentally analyzing parameters of a stimulation response curve to judge a risk of dementia and does not purport to improve the functioning of the signal processing, or to improve any other technology or technical field. Use of a generic signal processing does not amount to significantly more than the abstract idea itself.
Dependent claims 5-11 and 21 also do not add significantly more to the exception as they merely specify how the extrasolution data gathering is performed, identify how the mental steps are performed, or adds mental steps to the mental process.
Regarding Claim 12, the claim(s) is directed to the abstract idea of measuring a slope between a negative peak at about 100 ms after the stimulation and a positive peak at about 180 ms after the stimulation, at least partially in response to the slope between the negative peak and the positive peak, generate an output that is indicative of the subject being at risk of dementia which are considered steps of a mental process.
This judicial exception is not integrated into a practical application because:
- The claims fail to outline an improvement to the technical field.
- The claims fail to apply the judicial exception to effect a particular treatment.
- The claims fail to apply the judicial exception with a particular machine.
- The claims fail to effect a transformation or reduction of a particular article to a different state or thing.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they seem to merely generally link the use of the judicial exception to a particular technological environment.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because driving a coil to apply a magnetic stimulation to the subject’s brain and receiving a magnetic-stimulation-evoked-potential signal from the electrodes are insignificant extrasolution data gathering activities.
Furthermore, coils and electrodes are general fields of use and computer processors are generic computer elements used to perform generic computer functions and don’t add significantly more and are well-understood, routine, and previously known to the industry.
None of these limitations, considered as an ordered combination provide eligibility because the claim taken as a whole, does not amount to significantly more than the underlying abstract idea of mentally analyzing parameters of a stimulation response curve to judge a risk of dementia and does not purport to improve the functioning of the signal processing, or to improve any other technology or technical field. Use of a generic signal processing does not amount to significantly more than the abstract idea itself.
Dependent claims 14-20 and 23 also do not add significantly more to the exception as they merely specify how the extrasolution data gathering is performed, identify how the mental steps are performed, or adds mental steps to the mental process.
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 and 7-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferreri et al (“Sensorimotor Cortex Excitability and Connectivity in Alzheimer’s Disease: A TMS-EEG Co-Registration Study”) (“Ferreri”) in view of Scheib (US 2011/0118620) as noted in Applicant IDS dated 12/13/2022 and further in view of De Bruin et al (US 2011/0119212) (“De Bruin”) as noted in Applicant IDS dated 12/13/2022 and further in view of Feiweier et al (US 2009/0030304) (“Feiweier”).
Regarding Claim 1, while Ferreri teaches an apparatus (p2083, Abstract, p2085-2086, Materials and Methods, the combined structure of the transcranial magnetic stimulation and EEG recordings make up apparatus, Alzheimer’s disease is a type of dementia), comprising:
at least one coil (p2085, Transcranial Magnetic Stimulation, “Single pulse TMS (monophasic pulse configuration; Magstim Company Limited, Whitland, UK) of the left M1 was performed during a multi-channel EEG recording by means of a standard figure-of-eight double 70 mm coil oriented to elicit a posterolateral-anteromedial current flow in the brain.”);
a plurality of electrodes configured to be placed in contact with a subject's head (p2085, EEG recordings, “The EEG activity was continuously acquired from 32 scalp sites using electrodes positioned according to the 10–10 International System.”); and
at least one computer processor (p2086, Data Analysis and Statistics, “Computer scientist engineers (L.V., F.V., S.P., D.P) and a biostatistician (P.P) with expertise in TMS and EEG analysis performed the data processing and statistical analysis. Data analysis was conducted with MATLAB 2008b version 7.7 (MathWorks, Natick, Mass.) and the public license toolbox EEGLAB [Delorme and Makeig, 2004].”) configured to:
drive the at least one coil to apply a magnetic stimulation to the subject's brain (p2087, Results, “As already well described [lmoniemi et al., 1997; Massimini et al., 2005; Ferreri et al., 2011b,,b; for review see Ferreri and Rossini, 2013], the supra-threshold single pulse TMS of the left MI evoked in both the experimental groups EEG activity lasting up to 300 ms [for review Komssi and Kähkönen, 2006] and peaking on the GMFP at approximately 30, 44, 60, 100 and 180 ms post-TMS, as illustrated in Figures 1 and 2.”);
receive a magnetic-stimulation-evoked-potential signal from the plurality of electrodes (p2087, Results), the signal including a negative peak at about 100 ms after the stimulation and a positive peak at about 180 ms after the stimulation (p2087, Results, “The GMFP analysis revealed an increase in amplitude between 20 and 150 ms post-stimulus in AD patients,… Moreover, when looking at the individual latencies (the polarity according to that observed at the vertex: N7, P30, N44, P60, N100 and P180), the maps analysis showed a significant group difference in some waves, with AD showing a clear increase in the cortical excitability.”);
at least partially in response to evoked activity characteristics, generate an output that is indicative of the subject being at risk of dementia (p2087, Results, “The GMFP analysis revealed an increase in amplitude between 20 and 150 ms post-stimulus in AD patients,… Moreover, when looking at the individual latencies (the polarity according to that observed at the vertex: N7, P30, N44, P60, N100 and P180), the maps analysis showed a significant group difference in some waves, with AD showing a clear increase in the cortical excitability.”),
wherein evoked activity characteristics differences are indicative of the subject being at risk of dementia (p2087, Results, “The GMFP analysis revealed an increase in amplitude between 20 and 150 ms post-stimulus in AD patients,… Moreover, when looking at the individual latencies (the polarity according to that observed at the vertex: N7, P30, N44, P60, N100 and P180), the maps analysis showed a significant group difference in some waves, with AD showing a clear increase in the cortical excitability.”),
wherein differences are noted in the amplitude of the P30 wave, amplitude of the P60 wave, and the latency of the N100 wave (p2087, Col. 2),
Ferreri fails to teach measuring a slope between the negative peak and the positive peak;
At least partially in response to the slope between the negative peak and the positive peak, generating an output that is indicative of the subject suffering from damaged gray matter and/or white matter.
However Scheib teaches a EEG-based analysis (Abstract) where EEG derived waveform may be judged by slope values of portions of a curve ([0006]) where the slopes are an indication of a brain state ([0028]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that changes in an EEG curve may represent a neurological condition (Ferreri: dementia, Scheib: pain) and thus a slope, representing that change, may be a way to create a metric for the neurological condition. One of ordinary skill in the art would further consider Ferreri’s Fig. 3 and would consider what other distinctions in TMS evoked activity between the Alzheimer’s patients and the control group are present and how to quantify these differences to further bolster the identification of patients at risk of dementia. Traditional characterization metrics such as slopes and integrals would be obvious choices to use to create repeatable tests for caregivers to distinguish between healthy patient and dementia patient. One notices a difference in slope between the N100 peak and the P180 peak, where the slope in the control patient is greater, and would be motivated to add this as another quantifying metric to increase confidence in a final dementia test. Finally, it would be obvious to use slope as slope may be interpreted a test of multiple amplitudes simultaneously and is therefore in line with the amplitude metrics already found in Ferreri.
Yet their combined efforts fail to teach at least partially in response to the slope between the negative peak and the positive peak, generate an output that is indicative of the subject suffering from damaged gray matter and/or white matter.
However De Bruin teaches a neurological medical analysis (Abstract) and further teaches that a diagnosis of a condition can be performed by using thresholds for specific parameters related to the condition ([0111]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that a slope of the magnetic-stimulation-evoked-potential signal characteristic of Alzheimer’s as, taught by Ferreri and Scheib, differs from a control patients by a certain threshold, and thus could be utilized to make a diagnosis of a risk of the subject experiencing dementia. Further, it would be obvious to note that the slope around 150 ms of the control signal shows a greater value than the slope around 150 ms of the Alzheimer’s patients and use this as the basis of a threshold relationship to generate an output of dementia risk in a subject.
Yet their combined efforts fail to teach the subject being at risk of dementia indicates a risk of suffering from damaged gray matter and/or white matter.
However Feiweier teaches neurodegenerative analysis (Abstract) that notes that Alzheimer’s disease is linked to neurodegenerative damage in grey matter ([0010], [0043]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to recognize the formalized analysis of Alzheimer’s in Ferreri by the teachings of Scheib and De Bruin could also be understood as an analysis of gray matter as neurodegenerative changes, i.e. damage, in grey matter occur in Alzheimer’s disease as taught by Feiweier.
Regarding Claim 2, Ferreri, Scheib, De Bruin, and Feiweier teach the apparatus according to claim 1, wherein the at least one computer processor is configured to measure the slope of the late portion of the curve of the magnetic-stimulation- evoked-potential signal by measuring a slope of a portion of the curve of the magnetic-stimulation- evoked-potential signal measured between 100 ms and 180 ms after the magnetic stimulation (See Claim 1 Rejection, distinct slope differences between control patients and Alzheimer’s patients at 150 ms, can be applied for diagnostic purposes).
Regarding Claim 7, while Ferreri teaches a method (p2083, Abstract, Alzheimer’s disease is a type of dementia), comprising:
using at least one computer processor (p2086, Data Analysis and Statistics, “Computer scientist engineers (L.V., F.V., S.P., D.P) and a biostatistician (P.P) with expertise in TMS and EEG analysis performed the data processing and statistical analysis. Data analysis was conducted with MATLAB 2008b version 7.7 (MathWorks, Natick, Mass.) and the public license toolbox EEGLAB [Delorme and Makeig, 2004].”):
driving a coil to apply a magnetic stimulation to a subject's brain (p2087, Results, “As already well described [lmoniemi et al., 1997; Massimini et al., 2005; Ferreri et al., 2011b,,b; for review see Ferreri and Rossini, 2013], the supra-threshold single pulse TMS of the left MI evoked in both the experimental groups EEG activity lasting up to 300 ms [for review Komssi and Kähkönen, 2006] and peaking on the GMFP at approximately 30, 44, 60, 100 and 180 ms post-TMS, as illustrated in Figures 1 and 2.”);
receiving a magnetic-stimulation-evoked-potential signal from electrodes that are placed in contact with the subject's head (p2087, Results), the signal including a negative peak at about 100 ms after the stimulation and a positive peak at about 180 ms after the stimulation (p2087, Results, “The GMFP analysis revealed an increase in amplitude between 20 and 150 ms post-stimulus in AD patients,… Moreover, when looking at the individual latencies (the polarity according to that observed at the vertex: N7, P30, N44, P60, N100 and P180), the maps analysis showed a significant group difference in some waves, with AD showing a clear increase in the cortical excitability.”);
measure a late portion of a curve of the magnetic-stimulation- evoked-potential signal (p2087, Results, “The GMFP analysis revealed an increase in amplitude between 20 and 150 ms post-stimulus in AD patients,… Moreover, when looking at the individual latencies (the polarity according to that observed at the vertex: N7, P30, N44, P60, N100 and P180), the maps analysis showed a significant group difference in some waves, with AD showing a clear increase in the cortical excitability.”);
at least partially in response to evoked activity characteristics, generate an output that is indicative of the subject being at risk of dementia (p2087, Results, “The GMFP analysis revealed an increase in amplitude between 20 and 150 ms post-stimulus in AD patients,… Moreover, when looking at the individual latencies (the polarity according to that observed at the vertex: N7, P30, N44, P60, N100 and P180), the maps analysis showed a significant group difference in some waves, with AD showing a clear increase in the cortical excitability.”),
wherein evoked activity characteristics differences are indicative of the subject being at risk of dementia (p2087, Results, “The GMFP analysis revealed an increase in amplitude between 20 and 150 ms post-stimulus in AD patients,… Moreover, when looking at the individual latencies (the polarity according to that observed at the vertex: N7, P30, N44, P60, N100 and P180), the maps analysis showed a significant group difference in some waves, with AD showing a clear increase in the cortical excitability.”),
wherein differences are noted in the amplitude of the P30 wave, amplitude of the P60 wave, and the latency of the N100 wave (p2087, Col. 2),
Ferreri fails to teach measuring a slope between the negative peak and the positive peak;
At least partially in response to the slope between the negative peak and the positive peak, generating an output that is indicative of the subject being at risk of suffering from damaged gray matter and/or white matter.
However Scheib teaches a EEG-based analysis (Abstract) where EEG derived waveform may be judged by slope values of portions of a curve ([0006]) where the slopes are an indication of a brain state ([0028]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that changes in an EEG curve may represent a neurological condition (Ferreri: dementia, Scheib: pain) and thus a slope, representing that change, may be a way to create a metric for the neurological condition. One of ordinary skill in the art would further consider Ferreri’s Fig. 3 and would consider what other distinctions in TMS evoked activity between the Alzheimer’s patients and the control group are present and how to quantify these differences to further bolster the identification of patients at risk of dementia. Traditional characterization metrics such as slopes and integrals would be obvious choices to use to create repeatable tests for caregivers to distinguish between healthy patient and dementia patient. One notices a difference in slope between the N100 peak and the P180 peak, where the slope in the control patient is greater, and would be motivated to add this as another quantifying metric to increase confidence in a final dementia test. Finally, it would be obvious to use slope as slope may be interpreted a test of multiple amplitudes simultaneously and is therefore in line with the amplitude metrics already found in Ferreri.
Yet their combined efforts fail to teach at least partially in response to the slope between the negative peak and the positive peak, generate an output that is indicative of the subject suffering from damaged gray matter and/or white matter.
However De Bruin teaches a neurological medical analysis (Abstract) and further teaches that a diagnosis of a condition can be performed by using thresholds for specific parameters related to the condition ([0111]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that a slope of the magnetic-stimulation-evoked-potential signal characteristic of Alzheimer’s as, taught by Ferreri and Scheib, differs from a control patients by a certain threshold, and thus could be utilized to make a diagnosis of a risk of the subject experiencing dementia. Further, it would be obvious to note that the slope around 150 ms of the control signal shows a greater value than the slope around 150 ms of the Alzheimer’s patients and use this as the basis of a threshold relationship to generate an output of dementia risk in a subject.
Yet their combined efforts fail to teach the subject being at risk of dementia indicates a risk of suffering from damaged gray matter and/or white matter.
However Feiweier teaches neurodegenerative analysis (Abstract) that notes that Alzheimer’s disease is linked to neurodegenerative damage in grey matter ([0010], [0043]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to recognize the formalized analysis of Alzheimer’s in Ferreri by the teachings of Scheib and De Bruin could also be understood as an analysis of gray matter as neurodegenerative changes, i.e. damage, in grey matter occur in Alzheimer’s disease as taught by Feiweier.
Regarding Claim 8, Ferreri, Scheib, De Bruin, and Feiweier teach the method according to claim 7, wherein measuring the slope of the late portion of the curve of the magnetic-stimulation- evoked-potential signal by measuring a slope of a portion of the curve of the magnetic-stimulation- evoked-potential signal measured between 100 ms and 180 ms after the magnetic stimulation (See Claim 7 Rejection, distinct slope differences between control patients and Alzheimer’s patients at 150 ms, can be applied for diagnostic purposes).
Claim(s) 3-4 and 9-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferreri in view of Scheib and further in view of De Bruin and further in view of Feiweier and further in view of Pless et al (US 2011/0118661) (“Pless”) as noted in Applicant IDS 12/13/2022.
Regarding Claim 3, while Ferreri, Scheib, De Bruin, and Feiweier teach the apparatus according to claim 1, wherein the at least one computer processor is further configured to determine a slope of a portion of the magnetic-stimulation- evoked-potential signal (See Claim 1 Rejection),
their combined efforts fail to teach wherein the at least one computer processor is further configured to:
determine a slope of an early portion of the curve in the magnetic-stimulation- evoked-potential signal.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that multiple slopes of the magnetic-stimulation-evoked-potential signal characteristic of Alzheimer’s and grey matter damage as, taught by Ferreri, Scheib, and Feiweier, differ from control signal by a certain threshold, and thus could be utilized to make a diagnosis of a risk of the subject experiencing dementia. Further, it would be obvious to note that the slope between 40 ms to 100 ms of the control signal shows a near constant value and the slope between 40 ms to 100 ms of the Alzheimer’s patients shows a largely negative value. One can use this as the basis of a second threshold relationship outlined in De Bruin that may differentiate between healthy patients and patients with dementia.
Yet their combined efforts fail teach at least partially in response to detecting that a ratio between the slope of the early portion in the magnetic-stimulation-evoked-potential signal and the slope between the negative peak and the positive peak is below a given threshold.
However Pless teaches a brain analysis for pain (Abstract) and teaches that an EEG-based determination of pain can be done based on a ratio of EEG-based diagnostic parameter ([0126]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that the multiple slopes of the magnetic-stimulation-evoked-potential signal characteristic of Alzheimer’s and gray matter damage, as taught by Ferreri, Scheib, and Feiweier could be utilized together as multiple positive signs indicating a risk of grey matter damage to increase the confidence in a final determination of the risk of gray matter damage. Furthermore, utilizing a ratio for the multiple slopes means a single risk assessing metric will be output, which will be more readily understood by a practitioner of the art. Finally, it would be obvious that the ratio will be can be judged as higher risk of grey matter damage if below a given threshold when one considers the slopes of the control and Alzheimer’s evoked potentials in Ferreri. Specifically, an Alzheimer’s patient’s evoked potential has an early portion with a distinctly negative slope, a later portion with a distinctly positive slope meaning a ratio will be a small negative value. A healthy control patient’s evoked potential has an early portion with a negligibly positive slope, a later portion with a distinctly positive slope meaning a ratio will be a large positive value. Setting a threshold with this relationship in mind will have a greater likelihood of Alzheimer’s when the ratio is below a given threshold.
Regarding Claim 4, Ferreri, Scheib, De Bruin, and Pless teach the apparatus according to claim 3, wherein the at least one computer processor is configured to measure the slope of the early portion of the curve of the magnetic-stimulation- evoked-potential signal by measuring a slope of a portion of the curve of the magnetic-stimulation- evoked-potential signal measured between 60 ms and 100 ms after the magnetic stimulation (See Claim 3 Rejection).
Regarding Claim 9, while Ferreri, Scheib, De Bruin, and Feiweier teach the method according to claim 7, configured to determine a slope of a portion of the magnetic-stimulation- evoked-potential signal (See Claim 7 Rejection),
their combined efforts fail to teach wherein the at least one computer processor is further configured to:
determine a slope of an early portion of the curve in the magnetic-stimulation- evoked-potential signal.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that multiple slopes of the magnetic-stimulation-evoked-potential signal characteristic of Alzheimer’s and grey matter damage as, taught by Ferreri, Scheib, and Feiweier, differ from control signal by a certain threshold, and thus could be utilized to make a diagnosis of a risk of the subject experiencing dementia. Further, it would be obvious to note that the slope between 40 ms to 100 ms of the control signal shows a near constant value and the slope between 40 ms to 100 ms of the Alzheimer’s patients shows a largely negative value. One can use this as the basis of a second threshold relationship outlined in De Bruin that may differentiate between healthy patients and patients with dementia.
Yet their combined efforts fail teach at least partially in response to detecting that a ratio between the slope of the early portion in the magnetic-stimulation-evoked-potential signal and the slope between the negative peak and the positive peak is below a given threshold.
However Pless teaches a brain analysis for pain (Abstract) and teaches that an EEG-based determination of pain can be done based on a ratio of EEG-based diagnostic parameter ([0126]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that the multiple slopes of the magnetic-stimulation-evoked-potential signal characteristic of Alzheimer’s and gray matter damage, as taught by Ferreri, Scheib, and Feiweier could be utilized together as multiple positive signs indicating a risk of grey matter damage to increase the confidence in a final determination of the risk of gray matter damage. Furthermore, utilizing a ratio for the multiple slopes means a single risk assessing metric will be output, which will be more readily understood by a practitioner of the art. Finally, it would be obvious that the ratio will be can be judged as higher risk of grey matter damage if below a given threshold when one considers the slopes of the control and Alzheimer’s evoked potentials in Ferreri. Specifically, an Alzheimer’s patient’s evoked potential has an early portion with a distinctly negative slope, a later portion with a distinctly positive slope meaning a ratio will be a small negative value. A healthy control patient’s evoked potential has an early portion with a negligibly positive slope, a later portion with a distinctly positive slope meaning a ratio will be a large positive value. Setting a threshold with this relationship in mind will have a greater likelihood of Alzheimer’s when the ratio is below a given threshold.
Regarding Claim 10, Ferreri, Scheib, De Bruin, Feiweier, and Pless teach the method according to claim 9, wherein the at least one computer processor is configured to measure the slope of the early portion of the curve of the magnetic-stimulation- evoked-potential signal by measuring a slope of a portion of the curve of the magnetic-stimulation- evoked-potential signal measured between 60 ms and 100 ms after the magnetic stimulation (See Claim 9 Rejection).
Claim(s) 13 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferreri as evidence by Farreh (WO 2018/203944) in view of Scheib and further in view of De Bruin.
Regarding Claim 13, while Ferreri teaches an apparatus (p2083, Abstract, p2085-2086, Materials and Methods, the combined structure of the transcranial magnetic stimulation and EEG recordings make up apparatus, Alzheimer’s disease is a type of dementia), comprising:
at least one coil (p2085, Transcranial Magnetic Stimulation, “Single pulse TMS (monophasic pulse configuration; Magstim Company Limited, Whitland, UK) of the left M1 was performed during a multi-channel EEG recording by means of a standard figure-of-eight double 70 mm coil oriented to elicit a posterolateral-anteromedial current flow in the brain.”);
a plurality of electrodes configured to be placed in contact with a subject's head (p2085, EEG recordings, “The EEG activity was continuously acquired from 32 scalp sites using electrodes positioned according to the 10–10 International System.”); and
at least one computer processor (p2086, Data Analysis and Statistics, “Computer scientist engineers (L.V., F.V., S.P., D.P) and a biostatistician (P.P) with expertise in TMS and EEG analysis performed the data processing and statistical analysis. Data analysis was conducted with MATLAB 2008b version 7.7 (MathWorks, Natick, Mass.) and the public license toolbox EEGLAB [Delorme and Makeig, 2004].”) configured to:
drive the at least one coil to apply a magnetic stimulation to the subject's brain (p2087, Results, “As already well described [lmoniemi et al., 1997; Massimini et al., 2005; Ferreri et al., 2011b,,b; for review see Ferreri and Rossini, 2013], the supra-threshold single pulse TMS of the left MI evoked in both the experimental groups EEG activity lasting up to 300 ms [for review Komssi and Kähkönen, 2006] and peaking on the GMFP at approximately 30, 44, 60, 100 and 180 ms post-TMS, as illustrated in Figures 1 and 2.”);
receive a magnetic-stimulation-evoked-potential signal from the plurality of electrodes (p2087, Results), the signal including a negative peak at about 100 ms after the stimulation and a positive peak at about 180 ms after the stimulation (p2087, Results, “The GMFP analysis revealed an increase in amplitude between 20 and 150 ms post-stimulus in AD patients,… Moreover, when looking at the individual latencies (the polarity according to that observed at the vertex: N7, P30, N44, P60, N100 and P180), the maps analysis showed a significant group difference in some waves, with AD showing a clear increase in the cortical excitability.”);
at least partially in response to evoked activity characteristics, generate an output that is indicative of the subject being at risk of dementia (p2087, Results, “The GMFP analysis revealed an increase in amplitude between 20 and 150 ms post-stimulus in AD patients,… Moreover, when looking at the individual latencies (the polarity according to that observed at the vertex: N7, P30, N44, P60, N100 and P180), the maps analysis showed a significant group difference in some waves, with AD showing a clear increase in the cortical excitability.”),
wherein evoked activity characteristics differences are indicative of the subject being at risk of dementia (p2087, Results, “The GMFP analysis revealed an increase in amplitude between 20 and 150 ms post-stimulus in AD patients,… Moreover, when looking at the individual latencies (the polarity according to that observed at the vertex: N7, P30, N44, P60, N100 and P180), the maps analysis showed a significant group difference in some waves, with AD showing a clear increase in the cortical excitability.”),
wherein differences are noted in the amplitude of the P30 wave, amplitude of the P60 wave, and the latency of the N100 wave (p2087, Col. 2),
where dementia can be understood as a chronic brain injury (Farreh: [0050]).
Ferreri fails to teach measuring a slope between the negative peak and the positive peak;
At least partially in response to the slope between the negative peak and the positive peak, generating an output that is indicative of the subject suffering from damaged gray matter and/or white matter.
However Scheib teaches a EEG-based analysis (Abstract) where EEG derived waveform may be judged by slope values of portions of a curve ([0006]) where the slopes are an indication of a brain state ([0028]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that changes in an EEG curve may represent a neurological condition (Ferreri: dementia, Scheib: pain) and thus a slope, representing that change, may be a way to create a metric for the neurological condition. One of ordinary skill in the art would further consider Ferreri’s Fig. 3 and would consider what other distinctions in TMS evoked activity between the Alzheimer’s patients and the control group are present and how to quantify these differences to further bolster the identification of patients at risk of dementia. Traditional characterization metrics such as slopes and integrals would be obvious choices to use to create repeatable tests for caregivers to distinguish between healthy patient and dementia patient. One notices a difference in slope between the N100 peak and the P180 peak, where the slope in the control patient is greater, and would be motivated to add this as another quantifying metric to increase confidence in a final dementia test. Finally, it would be obvious to use slope as slope may be interpreted a test of multiple amplitudes simultaneously and is therefore in line with the amplitude metrics already found in Ferreri.
Yet their combined efforts fail to teach at least partially in response to the slope between the negative peak and the positive peak, generate an output that is indicative of the subject suffering from damaged gray matter and/or white matter.
However De Bruin teaches a neurological medical analysis (Abstract) and further teaches that a diagnosis of a condition can be performed by using thresholds for specific parameters related to the condition ([0111]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that a slope of the magnetic-stimulation-evoked-potential signal characteristic of Alzheimer’s as, taught by Ferreri and Scheib, differs from a control patients by a certain threshold, and thus could be utilized to make a diagnosis of a risk of the subject experiencing dementia. Further, it would be obvious to note that the slope around 150 ms of the control signal shows a greater value than the slope around 150 ms of the Alzheimer’s patients and use this as the basis of a threshold relationship to generate an output of dementia risk in a subject.
Regarding Claim 16, Ferreri, Farreh, Scheib, and De Bruin teach the method according to claim 13, wherein the at least one computer processor is configured to measure the slope of the early portion of the curve of the magnetic-stimulation- evoked-potential signal by measuring a slope of a portion of the curve of the magnetic-stimulation- evoked-potential signal measured between 60 ms and 100 ms after the magnetic stimulation (See Claim 13 Rejection).
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferreri as evidence by Farreh in view of Scheib and further in view of De Bruin as evidenced by Chicchi (US 10,987,521).
Regarding Claim 14, Ferreri, Farreh, Scheib, and De Bruin teach the apparatus according to claim 13, wherein the computer processor is configured to generate an output indicating that the brain injury is in at least one region selected from the group consisting of: a corticospinal track, a frontal lobe, and a temporal lobe (See Claim 13 Rejection, Alzheimer’s is a brain injury related to the frontal lobe as noted in Chicchi’s Col. 10, L. 37-43).
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferreri as evidence by Farreh in view of Scheib and further in view of De Bruin as evidenced by Engreitz et al (US 2020/0143907) (“Engreitz”).
Regarding Claim 15, Ferreri, Farreh, Scheib, and De Bruin teach the apparatus according to claim 13, wherein the computer processor is configured to generate an output indicating that the brain injury is in at least one region selected from the group consisting of: basal ganglia and brain stem (See Claim 13 Rejection, Alzheimer’s is a brain injury that shows a relation to the basal ganglia as noted in Engreitz [0640]).
Claim(s) 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferreri as evidence by Farreh in view of Scheib and further in view of De Bruin and further in view of Pless.
Regarding Claim 17, while Ferreri, Farreh, Scheib, and De Bruin teach the method according to claim 13, configured to determine a slope of a portion of the magnetic-stimulation- evoked-potential signal (See Claim 13 Rejection),
their combined efforts fail to teach wherein the at least one computer processor is further configured to:
determine a slope of an early portion of the curve in the magnetic-stimulation- evoked-potential signal.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that multiple slopes of the magnetic-stimulation-evoked-potential signal characteristic of Alzheimer’s and grey matter damage as, taught by Ferreri, Scheib, and Feiweier, differ from control signal by a certain threshold, and thus could be utilized to make a diagnosis of a risk of the subject experiencing dementia. Further, it would be obvious to note that the slope between 40 ms to 100 ms of the control signal shows a near constant value and the slope between 40 ms to 100 ms of the Alzheimer’s patients shows a largely negative value. One can use this as the basis of a second threshold relationship outlined in De Bruin that may differentiate between healthy patients and patients with dementia.
Yet their combined efforts fail teach at least partially in response to detecting that a ratio between the slope of the early portion in the magnetic-stimulation-evoked-potential signal and the slope between the negative peak and the positive peak is below a given threshold.
However Pless teaches a brain analysis for pain (Abstract) and teaches that an EEG-based determination of pain can be done based on a ratio of EEG-based diagnostic parameter ([0126]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, that the multiple slopes of the magnetic-stimulation-evoked-potential signal characteristic of Alzheimer’s and gray matter damage, as taught by Ferreri, Scheib, and Feiweier could be utilized together as multiple positive signs indicating a risk of grey matter damage to increase the confidence in a final determination of the risk of gray matter damage. Furthermore, utilizing a ratio for the multiple slopes means a single risk assessing metric will be output, which will be more readily understood by a practitioner of the art. Finally, it would be obvious that the ratio will be can be judged as higher risk of grey matter damage if below a given threshold when one considers the slopes of the control and Alzheimer’s evoked potentials in Ferreri. Specifically, an Alzheimer’s patient’s evoked potential has an early portion with a distinctly negative slope, a later portion with a distinctly positive slope meaning a ratio will be a small negative value. A healthy control patient’s evoked potential has an early portion with a negligibly positive slope, a later portion with a distinctly positive slope meaning a ratio will be a large positive value. Setting a threshold with this relationship in mind will have a greater likelihood of Alzheimer’s when the ratio is below a given threshold.
Regarding Claim 18, Ferreri, Farreh, Scheib, De Bruin, and Pless teach the apparatus according to claim 17, wherein the at least one computer processor is configured to measure the slope of the early portion of the curve of the magnetic-stimulation- evoked-potential signal by measuring a slope of a portion of the curve of the magnetic-stimulation- evoked-potential signal measured between 60 ms and 100 ms after the magnetic stimulation (See Claim 17 Rejection).
Allowable Subject Matter
Claim(s) 5-6, 11-12, and 18-20 would be allowable if rewritten to overcome the rejection(s) under 35 USC 101 rejections set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Conclusion
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/JAIRO H. PORTILLO/
Examiner
Art Unit 3791
/PUYA AGAHI/Primary Examiner, Art Unit 3791
