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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/4/2026 has been entered.
Response to Arguments
Claim Objections
The claim objections have been withdrawn as the applicant has amended to overcome said claim objections.
35 USC § 112 Rejection
The 35 USC § 112 rejection has been adapted in response to the latest claim amendment.
35 USC § 103 Rejection
Applicant's arguments filed 9/4/2026 with respect to the 35 USC § 103 rejection have been fully considered but they are not persuasive. The applicant argues many limitations not claimed. The examiner has underlined such arguments as follows:
“Independent claims 1 and 13 have been amended to further distinguish the invention from these references, now indicating that the control of the stimulation is to change the duty cycle or periodicity of the stimulation per paragraph [0014]. This control addresses the problem of habituation (paragraph [0088]) and proposes real-time adjustment of duty cycle ([0113]) in order to overcome acclamation and increase CSF flow (final sentence of paragraph [0090]).
As noted by the Examiner, Ludwig teaches an electrical stimulation intended to increase CSF/ISF flow. Ludwig selects a duty cycle based on an empirical study of patients intended to maximize CSF/ISF flow against habituation, but does not recognize the possibility of varying that duty cycle during treatment according to real-time feedback to further resist habituation.
It is believed that Zhu fails to remedy this deficiency. Zhu teaches electrical stimulation that can be varied based on measurements, but Zhu proposes electrical stimulation only for purposes such as spinal cord stimulation for the treatment of chronic pain, incontinence, or the like, not for controlling CSF flow. See generally paragraph [0003]. It is also submitted that Zhu also fails to teach variation of the signal's duty cycle according to measured signals or the measurement of CSF flow (rather, Zhu measures CSF pressure only to the extent that it relates to blood flow).
While Lewis teaches an electrical measurement of CSF flow, like Ludwig and Zhu, Lewis fails to teach using the signal to adjust the duty cycle of a waveform, allowing reduction in habituation during treatment. The use of an MRI machine in Lewis teaches away from the present invention, which has practicality only if it can be applied to the patient for an extended period of time, such as would preclude the use of MRI for the collection of the necessary signal.
It is submitted that a combination of the Ludwig, Zhu, and Lewis references, if recognized, would, per their teachings, lead to real-time control of the carrier wave and modulation wave qualities such as frequency and amplitude, as taught by Ludwig, for the purpose of controlling CSF flow, but not a change in duty cycle for the purpose of resisting acclimation.”
Thus, it is noted that the applicant claims adjusting periodicity, not adjusting duty cycle. Additionally, the phrases “resist habitation” and “resisting acclimation” are not in the claims. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “duty cycle”, “resist habitation” and “resisting acclimation”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to the most recent amendment, the examiner has adjusted the rejection as underlined:
“Regarding claims 1, 6, 13, and 19, Ludwig discloses an electrical stimulation device (e.g. see figure 2 element 58, [0058]) for modulating function of a glymphatic system or meningeal lymphatic system (e.g. see [0060]) of a human patient comprising: at least one electrode (e.g. see figure 1 element 50, [0055]-[0056]) configured to stimulate a cranial nerve (e.g. see [0008], [0010]) of the human patient; an electrical generator (e.g. see figure 2 element 60, [0058]-[0059]) configured to generate at least one carrier wave having a first carrier amplitude and a first carrier frequency (e.g. see [0059]); a modulator (e.g. see figure 2 element 64) receiving the at least one carrier wave and a modulation wave to modulate the at least one carrier wave (e.g. see [0060]) for application to the at least one electrode; an electrical modulation generator (e.g. see figure 2 element 70, [0060]) generating the modulation wave having a periodicity providing a first period of stimulation and a second period of a different or no stimulation (e.g. see [0060]), the periodicity selected to increase wall movement over continuous stimulation of the glymphatic system or meningeal system by the carrier frequency (e.g. see [0060]); a sensing device measuring cerebral spinal fluid (CSF)/interstitial fluid (ISF) flow in the brain of the human patient or a representative measure of CSF/ISF flow (e.g. see [0060]) and adjusting the periodicity in response to a measurement of the sensing device (e.g. see [0060]-[0061]. Note: “adjusting the stimulation time and relaxation time” in [0060], “modulating signal frequencies” in [0061], and “Similar comparisons may be done with respect to the spacing between stimulation provided by the relaxation period” in [0061] will read on the claim language “adjusting the periodicity”. Additionally, “monitoring a set of patients being scanned in a computed tomography (CT) scanner or magnetic resonance imaging (MRI) scanner with contrast media to detect CSF/ISF flow” in [0060], “the dilation/constriction of arterial vessels at various modulating signal frequencies may be compared to maximize the area 80 under the curve 82” in [0061], and “Similar comparisons may be done with respect to the spacing between stimulation provided by the relaxation period” in [0061] will read on the claim language “in response to a measurement of the sensing device”.
Ludwig discloses adjusting the periodicity in response to a measurement of the sensing device (e.g. see [0060]-[0061], see paragraph above) and discloses a controller (e.g. see [0058]-[0059], figure 5 element 102) but Ludwig does not explicitly disclose using a controller to perform electrical stimulation based on feedback from a CSF flow sensor. Zhu teaches it is known to use a controller to perform electrical stimulation based on feedback from a CSF flow sensor as disclosed in [0070], figure 5, [0005]-[0007] to provide electrical stimulation systems having leads capable of detecting pulsation of cerebrospinal fluid within a patient (e.g. see [0002]). It would have been obvious to one having ordinary skill in the art at the time the invention was made to use a controller to perform electrical stimulation based on feedback from a CSF flow sensor as taught by Zhu in the system/method of Ludwig, since said modification would provide the predictable results of electrical stimulation systems having leads capable of detecting pulsation of cerebrospinal fluid within a patient (e.g. see [0002]).”
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1 and 13, the applicant has removed the language “or a representative measure of CSF/ISF flow” and kept the language “measuring cerebral spinal fluid (CSF)/interstitial fluid (ISF) flow in the brain of the human patient”. However, the claims end with “the measurement of the sensing device is a measure of an electrical activity of the brain”. Electrical activity (EEG or MEG as disclosed by the applicant’s specification) would be “a representative measure of CSF/ISF flow” and not a direct measure of CSF/ISF flow as claimed by the phrase “measuring cerebral spinal fluid (CSF)/interstitial fluid (ISF) flow in the brain of the human patient”. Thus, the claims contradict themselves. It appears as if the representative measure should have remained and the direct measurement of flow should have been deleted in the most recent amendment.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1, 3-4, 6-8, 10-15, and 17-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ludwig et al. (Pub. No.: US 2021/0038884 A1); hereinafter referred to as “Ludwig”, in view of Zhu (Pub. No.: US 2015/0018634 A1) and Lewis et al. (WO 2020/210813 A1); hereinafter referred to as “Lewis”.
Regarding claims 1, 6, 13, and 19, Ludwig discloses an electrical stimulation device (e.g. see figure 2 element 58, [0058]) for modulating function of a glymphatic system or meningeal lymphatic system (e.g. see [0060]) of a human patient comprising: at least one electrode (e.g. see figure 1 element 50, [0055]-[0056]) configured to stimulate a cranial nerve (e.g. see [0008], [0010]) of the human patient; an electrical generator (e.g. see figure 2 element 60, [0058]-[0059]) configured to generate at least one carrier wave having a first carrier amplitude and a first carrier frequency (e.g. see [0059]); a modulator (e.g. see figure 2 element 64) receiving the at least one carrier wave and a modulation wave to modulate the at least one carrier wave (e.g. see [0060]) for application to the at least one electrode; an electrical modulation generator (e.g. see figure 2 element 70, [0060]) generating the modulation wave having a periodicity providing a first period of stimulation and a second period of a different or no stimulation (e.g. see [0060]), the periodicity selected to increase wall movement over continuous stimulation of the glymphatic system or meningeal system by the carrier frequency (e.g. see [0060]); a sensing device measuring cerebral spinal fluid (CSF)/interstitial fluid (ISF) flow in the brain of the human patient or a representative measure of CSF/ISF flow (e.g. see [0060]) and adjusting the periodicity in response to a measurement of the sensing device (e.g. see [0060]-[0061]. Note: “adjusting the stimulation time and relaxation time” in [0060], “modulating signal frequencies” in [0061], and “Similar comparisons may be done with respect to the spacing between stimulation provided by the relaxation period” in [0061] will read on the claim language “adjusting the periodicity”. Additionally, “monitoring a set of patients being scanned in a computed tomography (CT) scanner or magnetic resonance imaging (MRI) scanner with contrast media to detect CSF/ISF flow” in [0060], “the dilation/constriction of arterial vessels at various modulating signal frequencies may be compared to maximize the area 80 under the curve 82” in [0061], and “Similar comparisons may be done with respect to the spacing between stimulation provided by the relaxation period” in [0061] will read on the claim language “in response to a measurement of the sensing device”).
Ludwig discloses adjusting the periodicity in response to a measurement of the sensing device (e.g. see [0060]-[0061], see paragraph above) and discloses a controller (e.g. see [0058]-[0059], figure 5 element 102) but Ludwig does not explicitly disclose using a controller to perform electrical stimulation based on feedback from a CSF flow sensor. Zhu teaches it is known to use a controller to perform electrical stimulation based on feedback from a CSF flow sensor as disclosed in [0070], figure 5, [0005]-[0007] to provide electrical stimulation systems having leads capable of detecting pulsation of cerebrospinal fluid within a patient (e.g. see [0002]). It would have been obvious to one having ordinary skill in the art at the time the invention was made to use a controller to perform electrical stimulation based on feedback from a CSF flow sensor as taught by Zhu in the system/method of Ludwig, since said modification would provide the predictable results of electrical stimulation systems having leads capable of detecting pulsation of cerebrospinal fluid within a patient (e.g. see [0002]).
Ludwig and Zhu disclose measuring CSF/ISF flow (e.g. see [0060] and [0070], figure 5, [0005]-[0007] respectively) but are silent as to the measurement of the sensing device is a measure of an electrical activity of the brain. Lewis teaches an imaging-based biomarker that indicates a neurological state of a subject is generated from magnetic resonance imaging data acquired from the subject while the subject was sleeping, or during both a sleep state and wake state (Abstract). These magnetic resonance imaging data are acquired in such a way so that they simultaneously enable measurement of cerebrospinal fluid ("CSF") flow and blood-oxygenation-level dependent ("BOLD") signals. The imaging-based biomarker can be generated based on a correlation between CSF signals and BOLD signals extracted from these magnetic resonance imaging data (Abstract). Using electroencephalography ("EEG") data, CSF flow dynamics can also be estimated based on a physiological model in which coherent neural activity is modeled as entraining oscillations in blood volume and CSF (Abstract). It would have been obvious to one having ordinary skill in the art at the time the invention was filed to measure electrical activity of the brain in a CSF/ISF flow increasing device using EEG as taught by Lewis in the system/method of Ludwig and Zhu, since said modification would provide the predictable results of effective monitoring of CSF dynamics relate directly to the major changes in neural activity and important physiological states.
Regarding claim 3, Ludwig discloses adjusting the first carrier frequency in response to a measurement of the sensing device (e.g. see [0035]-[0038], [0059]-[0061]) but Ludwig does not disclose using a controller. Zhu teaches it is known to use a controller as disclosed in [0070], figure 5, [0005]-[0007] to provide electrical stimulation systems having leads capable of detecting pulsation of cerebrospinal fluid within a patient (e.g. see [0002]). It would have been obvious to one having ordinary skill in the art at the time the invention was made to use a controller as taught by Zhu in the system/method of Ludwig, since said modification would provide the predictable results of electrical stimulation systems having leads capable of detecting pulsation of cerebrospinal fluid within a patient (e.g. see [0002]).
Regarding claim 4, Ludwig discloses adjusting the first carrier amplitude in response to a measurement of the sensing device (e.g. see [0059]-[0061]) but Ludwig does not disclose using a controller. Zhu teaches it is known to use a controller as disclosed in [0070], figure 5, [0005]-[0007] to provide electrical stimulation systems having leads capable of detecting pulsation of cerebrospinal fluid within a patient (e.g. see [0002]). It would have been obvious to one having ordinary skill in the art at the time the invention was made to use a controller as taught by Zhu in the system/method of Ludwig, since said modification would provide the predictable results of electrical stimulation systems having leads capable of detecting pulsation of cerebrospinal fluid within a patient (e.g. see [0002]).
Regarding claims 7 and 17, Ludwig discloses the measurement of the sensing device is a measure of blood perfusion in the brain (e.g. see [0011], [0067], [0060]).
Regarding claim 8, Ludwig discloses the sensing device is at least one of a computerized topography (CT) scanner, magnetic resonance imaging (MRI) scanner, functional magnetic resonance imaging (fMRI) scanner, positron emission tomography (PET) scanner, transcranial ultrasound, and single-photon emission computed tomography (SPECT) scanner (e.g. see [0060]).
Regarding claim 10, Ludwig discloses at least one electrode is adapted to stimulate at least one of a trigeminal nerve, buccal branch nerve, mental branch nerve, facial branch nerve, vagus branch nerve (e.g., auricular vagus nerve), cervical nerve, sympathetic trunk/sympathetic ganglia, and sympathetic efferent branches (e.g. see [0052]-[0056]).
Regarding claims 11 and 14, Ludwig discloses the at last one carrier wave comprises first and second carrier waves having first and second distinct frequencies and delivered simultaneously to the at least one electrode (e.g. see [0038], [0060]).
Regarding claim 12, Ludwig discloses sensors detecting salivary biomarkers indicating a change to CSF flow selected from at least one of amyloid beta peptide, tau protein, lactoferrin, alpha-synuclein, DJ-1 protein, chromogranin A, huntingtin protein, DNA methylation disruptions, and micro-RNA (e.g. see [0030], [0094]).
Regarding claim 15, Ludwig discloses adjusting the second carrier frequency to increase CSF/ISF flow in response to the measurement of the CSF/ISF flow in the brain of the patient (e.g. see [0038], [0060]).
Regarding claim 18, Ludwig discloses adjusting a position of the at least one electrode in response to the measurement of the CSF/ISF flow in the brain of the patient (e.g. see [0052]-[0056]).
Regarding claim 20, Ludwig discloses the at least one electrode is positioned over at least one of an inferior alveolar nerve and a mental branch nerve (e.g. see [0052]-[0056]).
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ludwig and Zhu and Lewis as applied to claim 1 above, and further in view of Nakatomi et al. (Pub. No.: US 2010/0241203 A1); hereinafter referred to as “Nakatomi”.
Regarding claim 9, Ludwig and Zhu and Lewis disclose the claimed invention except for the sensing device is at least one of a pupilometer measuring a dilation of the pupil, functional near-infrared spectroscopy (fNIRS) measuring changes in hemoglobin in cerebral blood, a device measuring blood perfusion in the skin of the face or head, and a device measuring an evoked neural signal in the facial or trigeminal nerves. Nakatomi teaches that it is known to use such a modification as set forth in [0093] to provide real-time stimulation feedback from the evoked neural signal in the facial nerve. It would have been obvious to one having ordinary skill in the art at the time the invention was made to use evoked signal sensing in the facial nerves as taught by Nakatomi in the system/method of Ludwig and Zhu and Lewis, since said modification would provide the predictable results of real-time stimulation feedback from the evoked neural signal in the facial nerve.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ludwig et al. (US 20210038884 A1) teaches the following in [0076]:
The CSF/ISF flow may be monitored using known imaging modalities such as CT scan, MRI scan, and panoramic x-ray during electrical stimulation. It is understood that other physiological factors may also be monitored to determine the effectiveness of stimulation parameters, such as changes to heart rate, respiratory rate, or presence of certain biomarkers in the patient's blood or saliva as further described below. These physiological factors may be measured using, for example, neuroimaging techniques (e.g., panoramic x-ray, computerized topography (CT) scan, diffuse optical imaging (DOI), event-related optical signal (EROS), magnetic resonance imaging (MM), functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and cranial ultrasound), cognitive function testing (e.g., learning tests and memory tests), motor function testing, sensory function testing, biopsy, CSF testing, blood testing and/or genetic testing.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILIP C EDWARDS whose telephone number is (571)270-1804. The examiner can normally be reached Mon-Fri, 9:00-5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Unsu Jung can be reached at 571-272-8506. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.C.E/Examiner, Art Unit 3792
/AMANDA L STEINBERG/Examiner, Art Unit 3792
