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 .
Status of Claims
Claims 1, 3-8, and 11-17 are currently pending and under examination. Claims 2 and 9-10 are canceled. As per the amendments filed on 12/19/2025, claims 1, 11, 16, and 17 are amended.
Response to Arguments
Applicant's arguments, see Remarks pages 10-15 (Claim Rejections - 35 USC § 103), filed
12/19/2025, with respect to the rejections of Claims 1 and 3-17 under 35 U.S.C. § 103 have been fully considered. Claims 9 and 10 are canceled. Regarding claims 1, 16, and 17, Applicant argues:
First, Applicant has amended claims 1, 16, and 17 to recite "by ignoring a sensed combined stimulation" based on paragraphs [0287] to [0289] of the specification. The specification describes that noise filtering is performed by ignoring a sensed combined stimulation from the EEG signal to obtain a first response signal. Additionally, Applicant has amended claims 1, 16, and 17, based on claims 9 and 10, to recite "a second combined stimulation according to a 1-1 frequency that is lower than the PRF of the first combined stimulation to induce the gamma oscillation," and the processor is configured to "based on the gamma oscillation not derived according to the second combined stimulation, control the electrical stimulation part to transfer to a third combined stimulation according to a 1-2 frequency that is lower than the 1-1 frequency to be transferred to the brain of the object."
In an embodiment of the present application, an electrical stimulation part transfers a first combined stimulation in which a burst signal is repeatedly turned on and off at a PRF between 30 Hz and 50 Hz. During the on-state of the burst signal, the burst signal is applied at a burst frequency higher than the PRF. The processor is configured to ignore the burst signal ( on-signal) and to measure the remaining portion (off-signal) as a response of the brain. As a result, a clear brain response signal can be obtained. See FIG. 7 and paragraphs [0288] and [0289] of the specification.
These distinct features are not disclosed in any of the cited references. For example, the cited references, whether individually or combined, do not teach the combination of (i) applying the first combined stimulation in which the burst frequency is higher than the PRF, and (ii) filtering out the sensed combined stimulation from the EEG signal as a noise signal in order to obtain the first response signal.
Fitzgerald merely discloses applying transcranial alternating current stimulation (tACS) at frequencies corresponding to intrinsic brainwave frequency bands. It describes removing or reducing stimulation artifacts in a measured EEG signal by signal conditioning, subtraction, or optional filtering to recover underlying neural activity. However, Fitzgerald does not teach or suggest a processor configured to filter out a noise signal by intentionally ignoring a sensed combined stimulation itself from the EEG signal to obtain a first response signal.
De Ridder is primarily directed to the generation and delivery of nested or multifrequency stimulation waveforms and, at most, discusses general frequency-domain analysis (such as FFT or band-pass filtering) to isolate neural oscillations. De Ridder neither discloses an electrical stimulation part configured to transfer tACS in combination with an EEG sensing part, nor teaches a processor-side logic in which a sensed combined stimulation is deliberately treated as a noise signal and ignored when defining a first response signal from an EEG signal.
Thiele addresses the problem of stimulation artifacts during concurrent stimulation and recording and proposes amplitude-modulated tACS (AM-tACS) so that a high-frequency carrier component can be suppressed by conventional low-pass filtering. In Thiele, two frequency components that coexist in the same time window are separated in the frequency domain. As a result, the separated frequency component may still be affected by residual contamination due to spectral overlap, filter roll-off, or imperfect separation.
Thiele and the other cited references do not teach separating stimulation and brain response in the time domain by intentionally ignoring the burst signal applied during a very short on-time, and measuring an EEG signal obtained during the remaining off-time as a brain response signal. Consequently, the cited references do not teach that, during the off-time, no stimulation is present and a substantially clean brainwave signal can be obtained without contamination from the stimulation signal. (12/19/2025 Remarks, pages 10-13)
This argument is not persuasive. The argument refers to the amended limitation “a processor configured to filter out a noise signal by ignoring a sensed combined stimulation from the EEG signal to obtain a first response signal” in claims 1, 16, and 17. Fitzgerald discloses a device which stimulates at the pulse repetition frequency (i.e. matching the endogenous neural oscillations) in order to promote entrainment ([0109], [0113-0114]). Fitzgerald uses filtering to isolate the endogenous signal from the measured signal, which includes the stimulation artifact ([0047, [0108]).
De Ridder teaches the production of nested signals for multifrequency stimulation where a lower carrier signal contains a higher frequency component ([0052]). Waveforms with an on/off carrier frequency and a nested high-frequency burst signal during the “on” phase are illustrated in Figures 8A ([0067]) and 9 ([0089-0092]). Filtering to isolate different neural frequencies is described ([0114]).
In light of the signals produced in Fitzgerald and De Ridder, Thiele teaches an amplitude modulated technique for removing the stimulation artifact from measured EEG signals. This filtering is accomplished using a stimulation waveform containing a high frequency carrier contained in the envelope of a low frequency amplitude modulation, where the high frequency component is higher than stimulation frequencies relevant to entrainment and used to identify and filter out the stimulation artifact (page 2, paragraphs 2 and 3). Thiele teaches that, in the combined signal, the amplitude modulation component (the frequency relevant to entrainment) in the artifact does not have any spectral power to interfere with the endogenous component of the EEG (page 2, paragraphs 2 and 3). This is interpreted by the Examiner as teaching, with the broadest reasonable interpretation, “a processor configured to filter out a noise signal by ignoring a sensed combined stimulation from the EEG signal to obtain a first response signal” from the amended independent claims.
Applicant additionally argues:
Accordingly, none of the cited references teaches or suggests the claimed technical configuration in which a combined stimulation applied for a relatively short on-time is intentionally ignored as a noise signal at the processor level, and an EEG signal obtained during the remaining off-time is defined and used as a first response signal.
In an embodiment of the present application, in the case of a patient with Alzheimer's disease, a measured gamma wave of oscillation appears abnormally due to an imbalance between GABAergic and glutamatergic agents secreted from inhibitory and excitatory neurons. Subsequently, the GABAergic and glutamatergic agents decrease, while amyloid and tau proteins accumulate, thereby further lowering the gamma oscillation and significantly degrading cognitive function compared to that of a normal person. See paragraph [0242] of the specification. To treat Alzheimer's disease patients, entrainment is induced while gradually lowering the frequency of the PRF.
Typically, when the PRF is initially applied at 40 Hz but entrainment is not induced, entrainment may be induced by sequentially applying signals at 38 Hz, 36 Hz, 34 Hz, and 32 Hz while gradually lowering the frequency. Through continuous use of the present apparatus, the patient's brain function is improved, allowing entrainment to be induced at the normal 40 Hz band in a patient for whom entrainment is initially induced only at a lower frequency band, such as 32 Hz. See paragraphs [0297] to [0299] of the specification.
In contrast, Fitzgerald discloses applying stimulation at predetermined frequencies corresponding to intrinsic brainwave bands but does not teach or suggest adaptively lowering a PRF in a stepwise manner based on whether a gamma oscillation is derived from a measured EEG signal. Fitzgerald lacks any teaching of sequentially adjusting stimulation frequency in response to a failure to induce entrainment.
Further, De Ridder is primarily concerned with generating and delivering nested or multifrequency stimulation waveforms, and does not disclose a control strategy in which a stimulation frequency is gradually reduced over time based on a brain response. De Ridder neither teaches monitoring whether a gamma oscillation is derived nor adjusting a PRF according to such a determination.
Likewise, Thiele focuses on enabling concurrent stimulation and recording by suppressing stimulation artifacts using amplitude-modulated tACS and frequency domain filtering. Thiele applies a fixed modulation frequency and does not disclose or suggest gradually lowering a PRF in response to a failure to derive a gamma oscillation, nor does it teach a closed loop frequency adjustment strategy as recited in the present claims.
Accordingly, none of the cited references teaches or suggests the claimed configuration in which the PRF is adaptively and stepwise lowered from an initial value (e.g., 40 Hz) based on whether a gamma oscillation is derived, in order to induce entrainment in a subject whose brain does not initially respond at the target frequency. (12/19/2025 Remarks, pages 13-15)
This argument is not persuasive. This argument is related to the amended limitation “control the electrical stimulation part to transfer a second combined stimulation according to a 1-1 frequency that is lower than the PRF of the first combined stimulation, to induce the gamma oscillation, and based on the gamma oscillation not derived according to the second combined stimulation, control the electrical stimulation part to transfer to a third combined stimulation according to a 1-2 frequency that is lower than the 1-1 frequency to be transferred to the brain of the object” in independent claims 1, 16, and 17. While De Ridder and Thiele are relied upon to teach combined stimulation signals (e.g. where a higher frequency component is nested in a lower frequency component), Fitzgerald is relied upon to disclose the entrainment feature.
Fitzgerald discloses:
In some embodiments the adjusting of the set of first oscillation parameters of the stimulation signal may be based on a modulation parameter, in addition to the one or more second oscillation parameters that are determined. The modulation parameter may be a chirp, for example. Thus, during application of the stimulation signal, the frequency of the stimulation signal may be increased (up-chirp) or decreased (down-chirp). Chirping of the stimulation signal may be reflected in the oscillating activity signals of the brain due to neural entrainment, i.e. the oscillation parameters of the activity signals of the brain may adjust to synchronize with the changing parameters of the stimulation signal. ([0048])
This is interpreted as allowing for multiple frequency down-chirps to decrease the stimulation frequency based on observed entrainment activity signals. The stepwise process described in the arguments in not required by the amended claim language (see MPEP 2111.01.II – “It Is Improper To Import Claim Limitations from the Specification”), where the claim language only requires the mechanism to be able to successively decrease frequency based on the brain activity signal. Additionally, based on MPEP 2114 (II) and MPEP 2115 (II), the results of the stimulation for producing a specific effect in a brain region (such as a treatment outcome) are related to how the apparatus is used (intended use) rather than the apparatus structure itself.
The rejections of claims 1, 16, and 17 over Fitzgerald in view of De Ridder are withdrawn. However, the combination of Fitzgerald in view of De Ridder and Thiele is found to teach all the limitations of amended claims 1, 16, and 17, see “Claim Rejections - 35 USC § 103” section.
Regarding claims 3-8 and 11-15, Applicant argues:
In view of the above, Applicant respectfully submits that Claims 1, 16 and 17 are patentable over the cited references. Claims 3-8 and 11-15 are believed to be patentable at least by virtue of their dependencies from Claim 1. (12/19/2025 Remarks, page 15)
This argument is not persuasive. Claims 3-8 and 11-15 are dependent on the arguments for independent claim 1, which were not found persuasive. The rejections of claims 3-5 over Fitzgerald in view of De Ridder are withdrawn. However, the combination of Fitzgerald in view of De Ridder and Thiele is found to teach all the limitations of claims 3-5, see “Claim Rejections - 35 USC § 103” section. Additionally, the rejections of claims 6-8 and 11-15 are maintained.
Summary: The 35 U.S.C. § 103 rejections for claims 1, 3-5, and 16-17 over Fitzgerald in view of De Ridder are withdrawn. 35 U.S.C. § 103 rejections for claims 1, 3-8, and 11-17 over Fitzgerald in view of De Ridder and Thiele are added (see “Claim Rejections - 35 USC § 103”).
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or non-obviousness.
Claims 1, 3-8, and 11-17 are rejected under U.S.C 103 as being unpatentable over Fitzgerald (US PG Pub 2019/0134395 A1, see previously cited) in view of De Ridder (US PG Pub 2016/0074663 A1, see previously cited) and Thiele (NPL, “Amplitude Modulated Transcranial Alternating Current Stimulation (AM‑TACS) Efficacy Evaluation via Phosphene Induction,” see previously cited).
Regarding Claim 1, Fitzgerald discloses an apparatus ([0002]) comprising:
• an electrical stimulation part configured to transfer a transcranial alternating current stimulation (tACS) ([0097] – tACS signal applied via a stimulation part) to a brain of an object ([0080] – stimulation signal applied transcranially to the brain), wherein the tACS is a first stimulation in which a signal is repeatedly turned on and off at a pulse repetition frequency (PRF) ([0113]) between 30 Hz to 50 Hz ([0114]) (According to MPEP 2144.05: “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” There is no evidence of an “unexpected result or criticality” on the analysis from the discussed range interpretations for frequency);
• a sensing part comprising an electroencephalogram (EEG) sensor ([0047] – EEG device/sensor) configured to measure an EEG signal as a response of the brain ([0095] – receiving brain signal activity 240 after stimulation signal 220, which would constitute a response to the stimulation in the brain); and
• a processor ([0101] – the different functions of the processor are listed) configured to:
filter out a noise signal from the EEG signal ([0047] – “Where an EEG device is employed to receive a brain activity signal/monitor brain activity, the EEG device can collect EEG signals via bio-amplifiers, which signals are conditioned and optionally filtered, in real-time, into the frequency bands of interest”) to obtain a first response signal ([0028] – the brain activity measured by EEG is considered a response to the stimulation);
determine whether a gamma oscillation synchronized in a plurality of brain areas of the object is derived or not ([0134] – “Various characteristics of the brain activity signal may be the focus of analysis, including the peak frequencies in specific frequency bands such as the alpha, theta and gamma frequency bands. The brain activity signal may also be analyzed to determine information about the involvement of multiple brain regions in generating the relevant activity and/or to determine information about the anatomical sites of the generation of oscillations in specific frequency bands”), based on the first response signal ([0095] – an artifact-free signal is calculated as the modified activity signal 260. If a difference is detected between the modified activity signal and external stimulation, the stimulation parameters are adjusted: “Thus an adjusted stimulation signal can then be generated at 210 that is based on features of the modified activity signal, which in turn correspond to features of the endogenous brain activity”);
based on the gamma oscillation not being derived, control the electrical stimulation part to transfer a second stimulation ([0095] – “At 280, the set of first oscillation parameters of the stimulation signal are adjusted based on the one or more second oscillation parameters of the modified activity signal. Thus an adjusted stimulation signal can then be generated at 210 that is based on features of the modified activity signal, which in turn correspond to features of the endogenous brain activity”), according to a 1-1 frequency that is lower than the PRF of the first stimulation ([0048] – “up-chirp” and “down-chirp” allows for frequency adjustment during subsequent stimulation; [0116] – “Within one or more frequency bands of interest, the generation and adjusting of the stimulation signal may be matched and optimized for a best fit with the endogenous brain activity of the patient, e.g., by having a corresponding frequency and/or phase to the modified activity signal. The generation of a stimulation signal with an appropriate fit may be carried out over a period of time, e.g. iteratively”), to induce the gamma oscillation ([00134] – gamma frequency bands are included in this process), and
based on the gamma oscillation ([0134-0135] – gamma frequency assessed for content in signals) not derived according to the second stimulation, control the electrical stimulation part to transfer to a third stimulation according to a 1-2 frequency that is lower than the 1-1 frequency to be transferred to the brain of the object ([0048] – “up-chirp” and “down-chirp” allows for frequency adjustment during subsequent sets of stimulation), and.
Fitzgerald discloses: “Stimulation with tACS in the EEG range (conventionally: 0.1-80 Hz) is believed to directly modulate cortical oscillations, with a growing number of studies showing entrainment of endogenous oscillations at the frequency of stimulation. The ability of tACS to entrain endogenous oscillations at the frequency of stimulation is significant as it allows for more direct enhancement of processes underlying cognition” ([0004]). Entraining is interpreted as the phenomenon of brain signals naturally synchronizing with externally applied stimulation. Fitzgerald also discloses “By determining a frequency of the modified activity signal, for example, a frequency of the stimulation signal can be adjusted, e.g., at 280 of FIG. 2, to have the same frequency as the modified activity signal (and generally, therefore, the endogenous brain activity). This can provide for entrainment of the endogenous oscillations at the frequency of stimulation” ([0109]). This process is in line with the limitations in Claim 1 where an analysis of entrainment between endogenous brain activity and the stimulation signal is used to modify the stimulation signal to promote entrainment.
However, Fitzgerald does not disclose:
a combined stimulation in which a burst signal is repeatedly turned on and off at a pulse repetition frequency between 30 Hz to 50 Hz, and during an on state of the burst signal, the burst signal is applied to the brain at a burst frequency higher than the PRF
a second and third combined signal in the same fashion as the first combined signal
filter out a noise signal by ignoring a sensed combined stimulation from the EEG signal to obtain a first response signal
De Ridder, in the same field of endeavor of applying neurostimulation to the brain ([0006]), teaches a nested signal composed of multiple frequency components ([0052] – “more than one level of coupling or nesting may be achieved such as through a nesting hierarchy in which one or more high frequency ranges nest with one or more low frequency ranges. For example, combinations of the following frequency ranges may couple/nest with one another: infraslow (0.01-1 Hz), delta (1-3 Hz), theta (4-7 Hz), alpha (8-12 Hz), beta (13-30 Hz), gamma (31-100 Hz) to ultrafast waves (>100 Hz-1200 Hz)”). In this case the higher frequencies are contained within the lower frequencies, which become carrier waves ([0052]). De Ridder teaches: “As used herein, the term ‘burst firing’ or ‘burst mode’ refers to an action potential that is a burst of high frequency spikes/pulses (e.g. 400-1000 Hz)” ([0042]) and the use of nested stimulation to provide a pulse burst within a carrier waveform (Fig. 8A, [0067], Fig. 9, [0089-0092]). It has been established in [0052] that the gamma range 31-100 Hz can serve as a carrier wave for the higher burst frequency.
De Ridder further teaches the use of high frequency burst signals to address particular frequency-dependent features of neurological conditions:
Recently, new stimulation configurations such as burst stimulation and high frequency stimulation, have been developed, in which closely spaced high frequency pulses are delivered. In general, conventional neurostimulation systems seek to manage pain and other pathologic or physiologic disorders through stimulation of select nerve fibers that carry pain related signals. However, nerve fibers and brain tissue carry other types of signals, not simply pain related signals. A need remains for methods and systems that deliver therapies that stimulate brain tissue, in order to override or alter pathological neural oscillations to treat a neurological condition. [0004-0005]
De Ridder notes burst firing is a natural mechanism in some portions of the brain ([0047-0048]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to alter Fitzgerald’s stimulator for entraining endogenous brain oscillations by incorporating the nested stimulation signal in De Ridder. This would have been obvious because both Fitzgerald and De Ridder discuss applying neurostimulation to the brain and De Ridder provides a solution/improvement to provide high frequency burst signals nested in lower frequency signals to modulate neuronal pathways which communicate using burst signals. Therefore, a person of ordinary skill in the art would be motivated to improve the apparatus of Fitzgerald by incorporating the nested stimulation signal in De Ridder.
Thiele, in the same field of endeavor of transcranial stimulation (Abstract, page 1), teaches the use of amplitude modulated tACS where a stimulation waveform contains a high frequency component and low frequency envelope (Page 2 – “A different approach to circumvent the artefact problem was proposed by Witkowski et al who used amplitude modulated tACS (AM-tACS). This method uses a stimulation waveform that consists of two components: a high-frequency (> 150 Hz) sinusoidal carrier and a low-frequency (e.g., 10 Hz) amplitude modulation. When combined, the modulation signal leads to a sinusoidally rising and falling amplitude of the carrier signal, often referred to as the envelope, generating an amplitude modulated waveform”). This method is discussed as being useful for minimizing the spectral power magnitude (noise) at the lower amplitude modulated frequency which overlaps with the EEG frequency (Page 2 – “AM-tACS aims to allow for the analysis of online stimulation effects, by theoretically avoiding the contamination of the recorded brain oscillations at the frequency of interest with a stimulation artefact. When using AM-TACS, the recorded signal should only be contaminated by the carrier frequency, which is way beyond the frequency of interest. The frequency of the amplitude modulation on the other hand exhibits no spectral power, thus not introducing an artefact into the signal”).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to alter Fitzgerald’s stimulator for entraining endogenous brain oscillations by incorporating the amplitude modulated tACS stimulation waveform and noise filter in Thiele. This would have been obvious because both Fitzgerald and Thiele discuss applying transcranial stimulation to the brain and Thiele provides a solution/improvement to minimize stimulation artifact noise from an EEG signal by reducing the spectral power of the stimulation artifact at EEG frequencies. Therefore, a person of ordinary skill in the art would be motivated to improve the system of Fitzgerald by incorporating the amplitude modulated tACS stimulation waveform and noise filter in Thiele.
Therefore, Claim 1 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 3, the transcranial stimulation apparatus in Claim 1 is obvious over Fitzgerald in view of De Ridder and Thiele, as indicated hereinabove. Fitzgerald further discloses the PRF is applied to induce the gamma oscillation synchronized in the plurality of brain areas of the object ([0004]). Fitzgerald does not disclose the burst frequency is applied to induce a membrane action potential and brain oscillation in the plurality of brain areas of the object.
De Ridder, in the same field of endeavor of applying neurostimulation to the brain ([0006]), teaches a nested signal composed on multiple frequency components ([0052]). In this case the higher frequencies are contained within the lower frequencies, which become carrier waves ([0052]). De Ridder teaches: “As used herein, the term ‘burst firing’ or ‘burst mode’ refers to an action potential that is a burst of high frequency spikes/pulses (e.g. 400-1000 Hz)” ([0042]) and the use of nested stimulation to provide a pulse burst within a carrier waveform (Fig. 8A, [0067], Fig. 9, [0089-0092]). It has been established in [0052] that the gamma range 31-100 Hz can serve as a carrier wave for the higher burst frequency. De Ridder teaches the high-frequency waveforms can be used to affect electrophysiologic neuron parameters and brain oscillations ([0071]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to alter Fitzgerald’s stimulator for entraining endogenous brain oscillations by incorporating the nested stimulation signal in De Ridder. This would have been obvious because both Fitzgerald and De Ridder discuss applying neurostimulation to the brain and De Ridder provides a solution/improvement to provide high frequency burst signals nested in lower frequency signals to modulate neuronal pathways which communicate using burst signals. Therefore, a person of ordinary skill in the art would be motivated to improve the system of Fitzgerald by incorporating the nested stimulation signal in De Ridder.
Therefore, Claim 3 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 4, the transcranial stimulation apparatus in Claim 3 is obvious over Fitzgerald in view of De Ridder and Thiele, as indicated hereinabove. Fitzgerald further discloses the electrical stimulation part stimulates the brain of the object according to a stimulation mode determined corresponding to a condition of the object, the condition of the object denotes a disease relating to the object and a progressive degree of the disease, and the disease includes Alzheimer's disease, Parkinson's disease, and schizophrenia ([0131] – monitoring and stimulation protocol to treat a “diverse range of disorders including schizophrenia, depression, Parkinson's disease and Alzheimer's disease”). Fitzgerald does not explicitly teach stroke and epilepsy as diseases.
The transcranial stimulator using EEG feedback in Fitzgerald is placed to deliver transcranial stimulation ([0097] – tACS signal applied via a stimulation part to the brain). MPEP 2114 (II) states:
[A]pparatus claims cover what a device is, not what a device does." Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469, 15 USPQ2d 1525, 1528 (Fed. Cir. 1990) (emphasis in original). A claim containing a "recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus" if the prior art apparatus teaches all the structural limitations of the claim.
MPEP 2115 (II) states:
Claim analysis is highly fact-dependent. A claim is only limited by positively recited elements. Thus, "[i]nclusion of the material or article worked upon by a structure being claimed does not impart patentability to the claims." In re Otto, 312 F.2d 937, 136 USPQ 458, 459 (CCPA 1963); see also In re Young, 75 F.2d 996, 25 USPQ 69 (CCPA 1935).
The results of stimulation for a specific disease are related to how the apparatus is used (intended use) rather than the apparatus structure itself. Therefore, the apparatus of Fitzgerald modified with the stimulation waveform of De Ridder is inherently capable of being applied to brain stimulation to treat stroke and epilepsy in the same manner as the transcranial apparatus in the instant application, consistent with guidelines in MPEP 2114 (II) and MPEP 2115 (II).
Therefore, Claim 4 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 5, the transcranial stimulation apparatus in Claim 4 is obvious over Fitzgerald in view of De Ridder and Thiele, as indicated hereinabove. Fitzgerald further teaches the stimulation frequency is a frequency for entraining the gamma oscillation synchronized in the plurality of brain areas of the object including the prefrontal cortex (PFC) ([0105]). Fitzgerald does not disclose a burst frequency or the hippocampus as an area of the brain.
De Ridder, in the same field of endeavor of applying neurostimulation to the brain ([0006]), teaches a nested signal composed on multiple frequency components ([0052]). In this case the higher frequencies are contained within the lower frequencies, which become carrier waves ([0052]). De Ridder teaches: “As used herein, the term ‘burst firing’ or ‘burst mode’ refers to an action potential that is a burst of high frequency spikes/pulses (e.g. 400-1000 Hz)” ([0042]) and the use of nested stimulation to provide a pulse burst within a carrier waveform (Fig. 8A, [0067], Fig. 9, [0089-0092]). It has been established in [0052] that the gamma range 31-100 Hz can serve as a carrier wave for the higher burst frequency. De Ridder teaches the high-frequency waveforms can be used to affect electrophysiologic neuron parameters and brain oscillations entrainment ([0071]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to alter Fitzgerald’s stimulator for entraining endogenous brain oscillations by incorporating the nested stimulation signal in De Ridder. This would have been obvious because both Fitzgerald and De Ridder discuss applying neurostimulation to the brain and De Ridder provides a solution/improvement to provide high frequency burst signals nested in lower frequency signals to modulate neuronal pathways which communicate using burst signals. Therefore, a person of ordinary skill in the art would be motivated to improve the system of Fitzgerald by incorporating the nested stimulation signal in De Ridder.
The transcranial stimulator using EEG feedback in Fitzgerald is placed to deliver transcranial stimulation ([0097] – tACS signal applied via a stimulation part to the brain). Based on MPEP 2114 (II) and MPEP 2115 (II), the results of stimulation for producing a specific effect in a brain region are related to how the apparatus is used (intended use) rather than the apparatus structure itself. Therefore, the apparatus of Fitzgerald modified with the stimulation waveform of De Ridder is inherently capable of being applied to brain stimulation to regulate electrochemical reactions in the hippocampus in the same manner as the transcranial apparatus in the instant application, consistent with guidelines in MPEP 2114 (II) and MPEP 2115 (II).
Therefore, Claim 5 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 6, the transcranial stimulation apparatus in Claim 5 is obvious over Fitzgerald in view of De Ridder and Thiele, as indicated hereinabove. Fitzgerald discloses removal of a feedback signal, originating from the stimulation, from the EEG signal ([0094]). Fitzgerald discloses, “By subtracting the feedback signal from the brain activity signal, which feedback signal is based on the monitored stimulation signal as applied to the patient, the modified activity signal can be substantially artefact-free and can therefore be more closely indicative of the endogenous oscillating activity in the brain of the patient. One or more second oscillation parameters of the modified activity can subsequently be determined, which second oscillation parameters can therefore correspond more closely to endogenous oscillation parameters, and the stimulation signal can be adjusted accordingly” ([0094]). Fitzgerald therefore discloses instructions for removing the stimulation signal artifact from the brainwave signal in order to more accurately correct the stimulation signal for entrainment. Fitzgerald does not disclose an interference signal by the first combined stimulation is ignored based on a magnitude of the EEG signal having a difference of a predetermined numeric value or more as compared to a magnitude of a resulting signal obtained by removing the noise signal from the EEG signal.
Thiele, in the same field of endeavor of transcranial stimulation (Abstract, page 1), teaches the use of amplitude modulated tACS where a stimulation waveform contains a high frequency component and low frequency envelope (Page 2 – “A different approach to circumvent the artefact problem was proposed by Witkowski et al who used amplitude modulated tACS (AM-tACS). This method uses a stimulation waveform that consists of two components: a high-frequency (> 150 Hz) sinusoidal carrier and a low-frequency (e.g., 10 Hz) amplitude modulation. When combined, the modulation signal leads to a sinusoidally rising and falling amplitude of the carrier signal, often referred to as the envelope, generating an amplitude modulated waveform”). This method is discussed as being useful for minimizing the spectral power magnitude (noise) at the lower amplitude modulated frequency which overlaps with the EEG frequency (Page 2 – “AM-tACS aims to allow for the analysis of online stimulation effects, by theoretically avoiding the contamination of the recorded brain oscillations at the frequency of interest with a stimulation artefact. When using AM-TACS, the recorded signal should only be contaminated by the carrier frequency, which is way beyond the frequency of interest. The frequency of the amplitude modulation on the other hand exhibits no spectral power, thus not introducing an artefact into the signal”).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to alter Fitzgerald’s stimulator for entraining endogenous brain oscillations by incorporating the amplitude modulated tACS stimulation waveform and noise filter in Thiele. This would have been obvious because both Fitzgerald and Thiele discuss applying transcranial stimulation to the brain and Thiele provides a solution/improvement to minimize stimulation artifact noise from an EEG signal by reducing the spectral power of the stimulation artifact at EEG frequencies. Therefore, a person of ordinary skill in the art would be motivated to improve the system of Fitzgerald by incorporating the amplitude modulated tACS stimulation waveform and noise filter in Thiele.
Therefore, Claim 6 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 7, the transcranial stimulation apparatus in Claim 6 is obvious over Fitzgerald in view of De Ridder and Thiele as indicated hereinabove. Fitzgerald further discloses the sensing part is a brain wave measurement part that measures a brain wave of the brain induced corresponding to the stimulation ([0098-0099] – EEG signal containing both the native brain signal and artifact from stimulation), and the processor determines whether the gamma oscillation is derived or not ([0134-0135] – gamma frequency assessed for content in signals) by using a determination of whether a measured brain wave corresponds to an output ([0095-0098] – a continuous feedback loop assessing brain activity is used to assess whether stimulation parameters need to be adjusted) and a waveform of an entrained brain wave that appears only when entraining ([0109]) the gamma oscillation or not ([0134-0135] – gamma frequency assessed).
Therefore, Claim 7 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 8, the transcranial stimulation apparatus in Claim 7 is obvious over Fitzgerald in view of De Ridder and Thiele, as indicated hereinabove. Fitzgerald further discloses the processor calculates an average of power spectrum values of respective frequency bands and a standard deviation thereof (Figure 10, [0143-0147] – power spectrum for alpha, beta, gamma, delta, and theta waves), and a ratio of each average value according to at least one brain wave combination of gamma/ alpha/beta/delta/theta brain waves from the measured brain wave, thus extracting a property of the measured brain wave (Figure 10, [0143-0147] – determining the composition of measured brain waves as a composite of alpha, beta, gamma, delta, and theta waves).
Therefore, Claim 8 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 11, the transcranial stimulation apparatus in Claim 1 is obvious over Fitzgerald in view of De Ridder and Thiele, as indicated hereinabove. Fitzgerald further discloses a transcranial stimulator stimulates the prefrontal cortex ([0105]) through entrainment of the gamma oscillation through stimulation ([0134-0135]). Fitzgerald does not disclose a local field potential (LFP) of 40 Hz is induced in the prefrontal cortex and the hippocampus.
The transcranial stimulator using EEG feedback in Fitzgerald is placed to deliver transcranial stimulation ([0097] – tACS signal applied via a stimulation part to the brain). Based on MPEP 2114 (II) and MPEP 2115 (II), the results of stimulation for producing a specific effect in a tissue are related to how the apparatus is used (intended use) rather than the apparatus structure itself. Therefore, the apparatus of Fitzgerald modified with the stimulation waveform of De Ridder is inherently capable of being applied to brain stimulation to generate a local field potential (LFP) of 40 Hz in the prefrontal cortex and the hippocampus in the same manner as the transcranial apparatus in the instant application, consistent with guidelines in MPEP 2114 (II) and MPEP 2115 (II).
Therefore, Claim 11 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 12, the transcranial stimulation apparatus in Claim 11 is obvious over Fitzgerald in view of De Ridder and Thiele, as indicated hereinabove. Fitzgerald further discloses a transcranial stimulator stimulates the prefrontal cortex ([0105]) to regulate neuronal activity ([0118]) through entrainment of the gamma oscillation through stimulation ([0134-0135]). Fitzgerald does not disclose neuronal activity is regulated among the brain areas of the object including the hippocampus, and a balance of transmission between GABAergic and glutamatergic neurons that are secreted by excitatory and inhibitory activities of the neuron is induced.
The transcranial stimulator using EEG feedback in Fitzgerald is placed to deliver transcranial stimulation ([0097] – tACS signal applied via a stimulation part to the brain). Based on MPEP 2114 (II) and MPEP 2115 (II), the results of stimulation for producing a specific effect in a brain region are related to how the apparatus is used (intended use) rather than the apparatus structure itself. Therefore, the apparatus of Fitzgerald modified with the stimulation waveform of De Ridder is inherently capable of being applied to brain stimulation to regulate electrochemical reactions in brain neurons in the same manner as the transcranial apparatus in the instant application, consistent with guidelines in MPEP 2114 (II) and MPEP 2115 (II).
Therefore, Claim 12 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 13, the transcranial stimulation apparatus in Claim 12 is obvious over Fitzgerald in view of De Ridder and Thiele, as indicated hereinabove. Fitzgerald further discloses a transcranial stimulator stimulates the prefrontal cortex ([0105]) through entrainment of the gamma oscillation through stimulation ([0134-0135]). Fitzgerald does not disclose amyloid plaques are reduced in the brain areas of the object including the prefrontal cortex and the hippocampus, and hyperphosphorylation of tau is reduced in the brain areas of the object including the prefrontal cortex and the hippocampus.
The transcranial stimulator using EEG feedback in Fitzgerald is placed to deliver transcranial stimulation ([0097] – tACS signal applied via a stimulation part to the brain). Based on MPEP 2114 (II) and MPEP 2115 (II), the results of stimulation for producing a specific effect in a brain region are related to how the apparatus is used (intended use) rather than the apparatus structure itself. Therefore, the apparatus of Fitzgerald modified with the stimulation waveform of De Ridder is inherently capable of being applied to brain stimulation to regulate electrochemical reactions in brain neurons in the same manner as the transcranial apparatus in the instant application, consistent with guidelines in MPEP 2114 (II) and MPEP 2115 (II).
Therefore, Claim 13 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 14, the transcranial stimulation apparatus in Claim 13 is obvious over Fitzgerald in view of De Ridder and Thiele, as indicated hereinabove. Fitzgerald further discloses a transcranial stimulator stimulates the prefrontal cortex ([0105]) through entrainment of the gamma oscillation through stimulation ([0134-0135]). Fitzgerald does not disclose losses of neurons and synapses are reduced in the brain areas of the object including the prefrontal cortex and the hippocampus, brain atrophy is reduced in the brain areas of the object including the prefrontal cortex and the hippocampus, atrophy is reduced in the brain areas of the object including the prefrontal cortex and the hippocampus, bulging of a ventricle in the brain is reduced in the brain areas of the object including the prefrontal cortex and the hippocampus, and neuroinflammation is reduced in the brain areas of the object including the prefrontal cortex and the hippocampus.
The transcranial stimulator using EEG feedback in Fitzgerald is placed to deliver transcranial stimulation ([0097] – tACS signal applied via a stimulation part to the brain). Based on MPEP 2114 (II) and MPEP 2115 (II), the results of stimulation for producing a specific effect in a brain region are related to how the apparatus is used (intended use) rather than the apparatus structure itself. Therefore, the apparatus of Fitzgerald modified with the stimulation waveform of De Ridder is inherently capable of being applied to brain stimulation to regulate electrochemical reactions in brain neurons in the same manner as the transcranial apparatus in the instant application, consistent with guidelines in MPEP 2114 (II) and MPEP 2115 (II).
Therefore, Claim 14 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 15, the transcranial stimulation apparatus in Claim 14 is obvious over Fitzgerald in view of De Ridder and Thiele, as indicated hereinabove. Fitzgerald further discloses a transcranial stimulator stimulates the prefrontal cortex ([0105]) through entrainment of the gamma oscillation through stimulation ([0134-0135]). Fitzgerald does not disclose an immune response of at least a part of microglia is reduced in the brain areas of the object including the prefrontal cortex and the hippocampus, the microglia is deformed morphologically in the brain areas of the object including the prefrontal cortex and the hippocampus, and proteolysis in at least a part of the microglia is increased in the brain areas of the object including prefrontal cortex and hippocampus.
The transcranial stimulator using EEG feedback in Fitzgerald is placed to deliver transcranial stimulation ([0097] – tACS signal applied via a stimulation part to the brain). Based on MPEP 2114 (II) and MPEP 2115 (II), the results of stimulation for producing a specific effect in a brain region are related to how the apparatus is used (intended use) rather than the apparatus structure itself. Therefore, the apparatus of Fitzgerald modified with the stimulation waveform of De Ridder is inherently capable of being applied to brain stimulation to regulate electrochemical reactions in brain neurons in the same manner as the transcranial apparatus in the instant application, consistent with guidelines in MPEP 2114 (II) and MPEP 2115 (II).
Therefore, Claim 15 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 16, Fitzgerald discloses a system comprising:
• an apparatus ([0002]); and
• a server forming a network with the apparatus ([0103]), wherein the apparatus comprises:
an electrical stimulation part configured to transfer a transcranial alternating current stimulation (tACS) ([0097] – tACS signal applied via a stimulation part) to brain of an object ([0080] – stimulation signal applied transcranially to the brain), wherein the tACS is a first stimulation in which a signal is repeatedly turned on and off at a pulse repetition frequency (PRF) ([0113]) between 30 Hz to 50 Hz ([0114]), (According to MPEP 2144.05: “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” There is no evidence of an “unexpected result or criticality” on the analysis from the discussed range interpretations for frequency);
a sensing part comprising an electroencephalogram (EEG) sensor ([0047] – EEG device/sensor) configured to measure an EEG signal as a response of the brain ([0095] – receiving brain signal activity 240 after stimulation signal 220, which would constitute a response to the stimulation in the brain); and
a communication part that transmits ([0103] – “The processor can comprise a digital signal processor (DSP) and/or other components and/or software modules to carry out signal processing in accordance with the methods described herein … The modules and storage elements can be implemented using one or more processing devices and one or more data storage units, which processing devices and/or storage devices may be at one location or distributed across multiple locations and interconnected by one or more communication links”) a measured response of the brain to the server ([0101] – “receive the brain activity signal, generate the feedback signal based on the monitored properties of the stimulation signal”), the server transmits a first information for the EEG signal to a predetermined external apparatus, receives, from the external apparatus, a second information for determination of whether a gamma oscillation is derived or not based on the signal, and transmits the second information to the communication part of the apparatus ([0101] – “determine one or more second oscillation parameters of the modified activity signal and adjust the set of first oscillation parameters of the stimulation signal based on the one or more second oscillation parameters of the modified activity signal”);
the external apparatus is configured to:
filter out a noise signal from the EEG signal ([0047] – “Where an EEG device is employed to receive a brain activity signal/monitor brain activity, the EEG device can collect EEG signals via bio-amplifiers, which signals are conditioned and optionally filtered, in real-time, into the frequency bands of interest”) to obtain a first response signal ([0028] – the brain activity measured by EEG is considered a response to the stimulation);
determine whether the gamma oscillation synchronized in a plurality of brain areas of the object is derived or not, based on the first response signal ([0134] – “Various characteristics of the brain activity signal may be the focus of analysis, including the peak frequencies in specific frequency bands such as the alpha, theta and gamma frequency bands. The brain activity signal may also be analyzed to determine information about the involvement of multiple brain regions in generating the relevant activity and/or to determine information about the anatomical sites of the generation of oscillations in specific frequency bands”), based on the first response signal ([0095] – an artifact-free signal is calculated as the modified activity signal 260. If a difference is detected between the modified activity signal and external stimulation, the stimulation parameters are adjusted: “Thus an adjusted stimulation signal can then be generated at 210 that is based on features of the modified activity signal, which in turn correspond to features of the endogenous brain activity”);
based on the gamma oscillation not being derived, control the electrical stimulation part to transfer a second stimulation ([0095] – “At 280, the set of first oscillation parameters of the stimulation signal are adjusted based on the one or more second oscillation parameters of the modified activity signal. Thus an adjusted stimulation signal can then be generated at 210 that is based on features of the modified activity signal, which in turn correspond to features of the endogenous brain activity”), according to a 1-1 frequency that is lower than the PRF of the first stimulation ([0048] – “up-chirp” and “down-chirp” allows for frequency adjustment during subsequent sets of stimulation; [0116] – “Within one or more frequency bands of interest, the generation and adjusting of the stimulation signal may be matched and optimized for a best fit with the endogenous brain activity of the patient, e.g., by having a corresponding frequency and/or phase to the modified activity signal. The generation of a stimulation signal with an appropriate fit may be carried out over a period of time, e.g. iteratively”), to induce the gamma oscillation ([0134] – gamma frequency bands are included in this process), and
based on the gamma oscillation ([0134-0135] – gamma frequency assessed for content in signals) not derived according to the second stimulation, control the electrical stimulation part to transfer to a third stimulation according to a 1-2 frequency that is lower than the 1-1 frequency to be transferred to the brain of the object ([0048] – “up-chirp” and “down-chirp” allows for frequency adjustment during subsequent sets of stimulation).
Fitzgerald discloses: “Stimulation with tACS in the EEG range (conventionally: 0.1-80 Hz) is believed to directly modulate cortical oscillations, with a growing number of studies showing entrainment of endogenous oscillations at the frequency of stimulation. The ability of tACS to entrain endogenous oscillations at the frequency of stimulation is significant as it allows for more direct enhancement of processes underlying cognition” ([0004]). Entraining is interpreted as the phenomenon of brain signals naturally synchronizing with externally applied stimulation. Fitzgerald also discloses “By determining a frequency of the modified activity signal, for example, a frequency of the stimulation signal can be adjusted, e.g., at 280 of FIG. 2, to have the same frequency as the modified activity signal (and generally, therefore, the endogenous brain activity). This can provide for entrainment of the endogenous oscillations at the frequency of stimulation” ([0109]). This process is in line with the limitations in Claim 16 where an analysis of entrainment between endogenous brain activity and the stimulation signal is used to modify the stimulation signal to promote entrainment.
However, Fitzgerald does not disclose:
a combined stimulation in which a burst signal is repeatedly turned on and off at a pulse repetition frequency between 30 Hz to 50 Hz, and during an on state of the burst signal, the burst signal is applied to the brain at a burst frequency higher than the PRF
a second and third combined signal in the same fashion as the first combined signal
filter out a noise signal by ignoring a sensed combined stimulation from the EEG signal to obtain a first response signal
De Ridder, in the same field of endeavor of applying neurostimulation to the brain ([0006]), teaches a nested signal composed of multiple frequency components ([0052] – “more than one level of coupling or nesting may be achieved such as through a nesting hierarchy in which one or more high frequency ranges nest with one or more low frequency ranges. For example, combinations of the following frequency ranges may couple/nest with one another: infraslow (0.01-1 Hz), delta (1-3 Hz), theta (4-7 Hz), alpha (8-12 Hz), beta (13-30 Hz), gamma (31-100 Hz) to ultrafast waves (>100 Hz-1200 Hz)”). In this case the higher frequencies are contained within the lower frequencies, which become carrier waves ([0052]). De Ridder teaches: “As used herein, the term ‘burst firing’ or ‘burst mode’ refers to an action potential that is a burst of high frequency spikes/pulses (e.g. 400-1000 Hz)” ([0042]) and the use of nested stimulation to provide a pulse burst within a carrier waveform (Fig. 8A, [0067], Fig. 9, [0089-0092]). It has been established in [0052] that the gamma range 31-100 Hz can serve as a carrier wave for the higher burst frequency.
De Ridder further teaches the use of high frequency burst signals to address particular frequency-dependent features of neurological conditions:
Recently, new stimulation configurations such as burst stimulation and high frequency stimulation, have been developed, in which closely spaced high frequency pulses are delivered. In general, conventional neurostimulation systems seek to manage pain and other pathologic or physiologic disorders through stimulation of select nerve fibers that carry pain related signals. However, nerve fibers and brain tissue carry other types of signals, not simply pain related signals. A need remains for methods and systems that deliver therapies that stimulate brain tissue, in order to override or alter pathological neural oscillations to treat a neurological condition. [0004-0005]
De Ridder notes burst firing is a natural mechanism in some portions of the brain ([0047-0048]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to alter Fitzgerald’s stimulator for entraining endogenous brain oscillations by incorporating the nested stimulation signal in De Ridder. This would have been obvious because both Fitzgerald and De Ridder discuss applying neurostimulation to the brain and De Ridder provides a solution/improvement to provide high frequency burst signals nested in lower frequency signals to modulate neuronal pathways which communicate using burst signals. Therefore, a person of ordinary skill in the art would be motivated to improve the system of Fitzgerald by incorporating the nested stimulation signal in De Ridder.
Thiele, in the same field of endeavor of transcranial stimulation (Abstract, page 1), teaches the use of amplitude modulated tACS where a stimulation waveform contains a high frequency component and low frequency envelope (Page 2 – “A different approach to circumvent the artefact problem was proposed by Witkowski et al who used amplitude modulated tACS (AM-tACS). This method uses a stimulation waveform that consists of two components: a high-frequency (> 150 Hz) sinusoidal carrier and a low-frequency (e.g., 10 Hz) amplitude modulation. When combined, the modulation signal leads to a sinusoidally rising and falling amplitude of the carrier signal, often referred to as the envelope, generating an amplitude modulated waveform”). This method is discussed as being useful for minimizing the spectral power magnitude (noise) at the lower amplitude modulated frequency which overlaps with the EEG frequency (Page 2 – “AM-tACS aims to allow for the analysis of online stimulation effects, by theoretically avoiding the contamination of the recorded brain oscillations at the frequency of interest with a stimulation artefact. When using AM-TACS, the recorded signal should only be contaminated by the carrier frequency, which is way beyond the frequency of interest. The frequency of the amplitude modulation on the other hand exhibits no spectral power, thus not introducing an artefact into the signal”).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to alter Fitzgerald’s stimulator for entraining endogenous brain oscillations by incorporating the amplitude modulated tACS stimulation waveform and noise filter in Thiele. This would have been obvious because both Fitzgerald and Thiele discuss applying transcranial stimulation to the brain and Thiele provides a solution/improvement to minimize stimulation artifact noise from an EEG signal by reducing the spectral power of the stimulation artifact at EEG frequencies. Therefore, a person of ordinary skill in the art would be motivated to improve the system of Fitzgerald by incorporating the amplitude modulated tACS stimulation waveform and noise filter in Thiele.
Therefore, Claim 16 is obvious over Fitzgerald in view of De Ridder and Thiele.
Regarding Claim 17, Fitzgerald discloses a system comprising:
• an apparatus ([0002]); and
• a server forming a network with the apparatus ([0103]), wherein the apparatus comprises:
an electrical stimulation part configured to transfer a transcranial alternating current stimulation (tACS) ([0097] – tACS signal applied via a stimulation part) to a brain of an object ([0080] – stimulation signal applied transcranially to the brain), wherein the tACS is a first stimulation in which a signal is repeatedly turned on and off at a pulse repetition frequency (PRF) ([0113]) between 30 Hz to 50 Hz ([0114]) (According to MPEP 2144.05: “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” There is no evidence of an “unexpected result or criticality” on the analysis from the discussed range interpretations for frequency);
a sensing part comprising an electroencephalogram (EEG) sensor ([0047] – EEG device/sensor) configured to measure an EEG signal as a response of the brain ([0095] – receiving brain signal activity 240 after stimulation signal 220, which would constitute a response to the stimulation in the brain);
a processor configured to determine whether a gamma oscillation is derived or not, based on the EEG signal ([0101] – “subtract the feedback signal from the brain activity signal, determine one or more second oscillation parameters of the modified activity signal”); and
a communication part ([0103] – “The processor can comprise a digital signal processor (DSP) and/or other components and/or software modules to carry out signal processing in accordance with the methods described herein … The modules and storage elements can be implemented using one or more processing devices and one or more data storage units, which processing devices and/or storage devices may be at one location or distributed across multiple locations and interconnected by one or more communication links”) that transmits the EEG signal to the server ([0101] – “receive the brain activity signal, generate the feedback signal based on the monitored properties of the stimulation signal”)
the server transmits a first information for the EEG signal to a predetermined external apparatus, receives, from the external apparatus, a second information for determination of whether the gamma oscillation is derived or not based on the EEG signal, and transmits the second information to the communication part of the apparatus ([0101] – “determine one or more second oscillation parameters of the modified activity signal and adjust the set of first oscillation parameters of the stimulation signal based on the one or more second oscillation parameters of the modified activity signal”);
the external apparatus is configured to:
filter out a noise signal from the EEG signal ([0047] – “Where an EEG device is employed to receive a brain activity signal/monitor brain activity, the EEG device can collect EEG signals via bio-amplifiers, which signals are conditioned and optionally filtered, in real-time, into the frequency bands of interest”) to obtain a first response signa ([0028] – the brain activity measured by EEG is considered a response to the stimulation);
determine whether the gamma oscillation synchronized in a plurality of brain areas of the object is derived or not ([0134] – “Various characteristics of the brain activity signal may be the focus of analysis, including the peak frequencies in specific frequency bands such as the alpha, theta and gamma frequency bands. The brain activity signal may also be analyzed to determine information about the involvement of multiple brain regions in generating the relevant activity and/or to determine information about the anatomical sites of the generation of oscillations in specific frequency bands”), based on the first response signal ([0095] – an artifact-free signal is calculated as the modified activity signal 260. If a difference is detected between the modified activity signal and external stimulation, the stimulation parameters are adjusted: “Thus an adjusted stimulation signal can then be generated at 210 that is based on features of the modified activity signal, which in turn correspond to features of the endogenous brain activity”);
based on the gamma oscillation not being derived, control the electrical stimulation part to transfer a second stimulation ([0095] – “At 280, the set of first oscillation parameters of the stimulation signal are adjusted based on the one or more second oscillation parameters of the modified activity signal. Thus an adjusted stimulation signal can then be generated at 210 that is based on features of the modified activity signal, which in turn correspond to features of the endogenous brain activity”), according to a 1-1 frequency that is lower than the PRF of the first stimulation ([0048] – “up-chirp” and “down-chirp” allows for frequency adjustment during subsequent sets of stimulation; [0116] – “Within one or more frequency bands of interest, the generation and adjusting of the stimulation signal may be matched and optimized for a best fit with the endogenous brain activity of the patient, e.g., by having a corresponding frequency and/or phase to the modified activity signal. The generation of a stimulation signal with an appropriate fit may be carried out over a period of time, e.g. iteratively”), to induce the gamma oscillation ([0134] – gamma frequency bands are included in this process), and
based on the gamma oscillation ([0134-0135] – gamma frequency assessed for content in signals) not derived according to the second stimulation, control the electrical stimulation part to transfer to a third stimulation according to a 1-2 frequency that is lower than the 1-1 frequency to be transferred to the brain of the object ([0048] – “up-chirp” and “down-chirp” allows for frequency adjustment during subsequent sets of stimulation).
Fitzgerald discloses: “Stimulation with tACS in the EEG range (conventionally: 0.1-80 Hz) is believed to directly modulate cortical oscillations, with a growing number of studies showing entrainment of endogenous oscillations at the frequency of stimulation. The ability of tACS to entrain endogenous oscillations at the frequency of stimulation is significant as it allows for more direct enhancement of processes underlying cognition” ([0004]). Entraining is interpreted as the phenomenon of brain signals naturally synchronizing with externally applied stimulation. Fitzgerald also discloses “By determining a frequency of the modified activity signal, for example, a frequency of the stimulation signal can be adjusted, e.g., at 280 of FIG. 2, to have the same frequency as the modified activity signal (and generally, therefore, the endogenous brain activity). This can provide for entrainment of the endogenous oscillations at the frequency of stimulation” ([0109]). This process is in line with the limitations in Claim 17 where an analysis of entrainment between endogenous brain activity and the stimulation signal is used to modify the stimulation signal to promote entrainment.
However, Fitzgerald does not disclose:
a combined stimulation in which a burst signal is repeatedly turned on and off at a pulse repetition frequency between 30 Hz to 50 Hz, and during an on state of the burst signal, the burst signal is applied to the brain at a burst frequency higher than the PRF
a second and third combined signal in the same fashion as the first combined signal
filter out a noise signal by ignoring a sensed combined stimulation from the EEG signal to obtain a first response signal
De Ridder, in the same field of endeavor of applying neurostimulation to the brain ([0006]), teaches a nested signal composed of multiple frequency components ([0052] – “more than one level of coupling or nesting may be achieved such as through a nesting hierarchy in which one or more high frequency ranges nest with one or more low frequency ranges. For example, combinations of the following frequency ranges may couple/nest with one another: infraslow (0.01-1 Hz), delta (1-3 Hz), theta (4-7 Hz), alpha (8-12 Hz), beta (13-30 Hz), gamma (31-100 Hz) to ultrafast waves (>100 Hz-1200 Hz)”). In this case the higher frequencies are contained within the lower frequencies, which become carrier waves ([0052]). De Ridder teaches: “As used herein, the term ‘burst firing’ or ‘burst mode’ refers to an action potential that is a burst of high frequency spikes/pulses (e.g. 400-1000 Hz)” ([0042]) and the use of nested stimulation to provide a pulse burst within a carrier waveform (Fig. 8A, [0067], Fig. 9, [0089-0092]). It has been established in [0052] that the gamma range 31-100 Hz can serve as a carrier wave for the higher burst frequency.
De Ridder further teaches the use of high frequency burst signals to address particular frequency-dependent features of neurological conditions:
Recently, new stimulation configurations such as burst stimulation and high frequency stimulation, have been developed, in which closely spaced high frequency pulses are delivered. In general, conventional neurostimulation systems seek to manage pain and other pathologic or physiologic disorders through stimulation of select nerve fibers that carry pain related signals. However, nerve fibers and brain tissue carry other types of signals, not simply pain related signals. A need remains for methods and systems that deliver therapies that stimulate brain tissue, in order to override or alter pathological neural oscillations to treat a neurological condition. [0004-0005]
De Ridder notes burst firing is a natural mechanism in some portions of the brain ([0047-0048]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to alter Fitzgerald’s stimulator for entraining endogenous brain oscillations by incorporating the nested stimulation signal in De Ridder. This would have been obvious because both Fitzgerald and De Ridder discuss applying neurostimulation to the brain and De Ridder provides a solution/improvement to provide high frequency burst signals nested in lower frequency signals to modulate neuronal pathways which communicate using burst signals. Therefore, a person of ordinary skill in the art would be motivated to improve the system of Fitzgerald by incorporating the nested stimulation signal in De Ridder.
Thiele, in the same field of endeavor of transcranial stimulation (Abstract, page 1), teaches the use of amplitude modulated tACS where a stimulation waveform contains a high frequency component and low frequency envelope (Page 2 – “A different approach to circumvent the artefact problem was proposed by Witkowski et al who used amplitude modulated tACS (AM-tACS). This method uses a stimulation waveform that consists of two components: a high-frequency (> 150 Hz) sinusoidal carrier and a low-frequency (e.g., 10 Hz) amplitude modulation. When combined, the modulation signal leads to a sinusoidally rising and falling amplitude of the carrier signal, often referred to as the envelope, generating an amplitude modulated waveform”). This method is discussed as being useful for minimizing the spectral power magnitude (noise) at the lower amplitude modulated frequency which overlaps with the EEG frequency (Page 2 – “AM-tACS aims to allow for the analysis of online stimulation effects, by theoretically avoiding the contamination of the recorded brain oscillations at the frequency of interest with a stimulation artefact. When using AM-TACS, the recorded signal should only be contaminated by the carrier frequency, which is way beyond the frequency of interest. The frequency of the amplitude modulation on the other hand exhibits no spectral power, thus not introducing an artefact into the signal”).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to alter Fitzgerald’s stimulator for entraining endogenous brain oscillations by incorporating the amplitude modulated tACS stimulation waveform and noise filter in Thiele. This would have been obvious because both Fitzgerald and Thiele discuss applying transcranial stimulation to the brain and Thiele provides a solution/improvement to minimize stimulation artifact noise from an EEG signal by reducing the spectral power of the stimulation artifact at EEG frequencies. Therefore, a person of ordinary skill in the art would be motivated to improve the system of Fitzgerald by incorporating the amplitude modulated tACS stimulation waveform and noise filter in Thiele.
Therefore, Claim 17 is obvious over Fitzgerald in view of De Ridder and Thiele.
Conclusions
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Benjamin A. Schmitt/
Examiner
Art Unit 3796
/ALLEN PORTER/Primary Examiner, Art Unit 3796
Prosecution Insights