DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of invention I (claims 1-15) in the reply filed on 07/31/2026 is acknowledged.
Claims 16-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/31/2026.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/07/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 3 is objected to because of the following informalities: the phrase “the current level and the current level is selected from a range of 20-100 mA” is repetitive and should be amended to recite “wherein the stimulation settings include the current level . Appropriate correction is required.
Claim 4 is objected to because of the following informalities: the phrase “the frequency and the frequency is selected from a range of 10-100 Hz” is repetitive and should be amended to recite “the frequency . Appropriate correction is required.
Claim 5 is objected to because of the following informalities: the phrase “the pulse width and the pulse width is selected from a range of 0.5-2.0 ms” is repetitive and should be amended to recite “the pulse width . Appropriate correction is required.
Claim 6 is objected to because of the following informalities: the phrase “the duration of the electrical stimulation and the duration of the electrical stimulation is selected from a range of 0.5-2.0” is repetitive and should be amended to recite “the duration of the electrical stimulation . Appropriate correction is required.
Claim 10 is objected to because of the following informalities: the phrase “induces modulating” is grammatically incoherent and should be amended to recite “induces modulation”. Appropriate correction is required.
Claim Interpretation
Regarding claim 1, the phrase “modulating one or more genes” will be interpreted broadly, as any gene may be upregulated or downregulated as a result of stimulation. This can include any of the 1900 genes associated with the GBM pathway. It is also inherent that genes will be modulated regardless of any sort of stimulation or external effect. Furthermore, the phrase “wherein the electrical stimulation provides a therapeutic effect in the subject by modulating the one or more genes” will also be interpreted broadly as the breadth of the claim allows for any and all types of therapeutic effects, which can encompass treating migraines, seizures, strokes, depression, tremors, epilepsy, and many more effects. The phrase “modulating one or more genes” will not be interpreted as a stimulation, but rather the up- and down-regulation of genes. Examiner does note that an effect of a gene upstream can affect gene expression downstream.
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 1-15 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.
Regrading claim 1, it is unclear if the “electrical stimulation” of line 4 is the same or different than the “electrical stimulation” of line 1.
Claims 2-15 are rejected due to their dependency on independent claim 1.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-2, 4, 7-10, and 15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. (US 20200384266)(Hereinafter Wang).
Regarding claim 1, Wang teaches A method for electrical stimulation of a glioblastoma (GBM) in a subject ([0082] “a subject having the tumor, comprising electrically stimulating at least a portion of the tumor or a portion of the subject containing the tumor. In some cases, the cancer can be, e.g., breast cancer, kidney cancer, or glioblastoma.”), the method comprising:
receiving, by a neuromodulation device, stimulation settings determined to generate an electrical stimulation that modulates one or more genes associated with a GBM signaling pathway ([0114] “The electrical stimulation system can be a bench top device (that uses electrical stimulation to optimally tune EV cargo for therapeutic applications.” [0071] “ the miRNA content of an EV can be modulated by increasing or decreasing the amount of one or more miRNAs present in or on the surface of an EV released from a target cell by adjusting the electrical stimulation parameters.” Examiner notes that GBM signaling pathway includes 3 core pathways- receptor tyrosine kinase (RTK) activation, PI3K/AKT/mTOR signaling, and tumor suppressor inactivation. Examiner notes that Wang uses the PI3K/AKT/mTOR signaling pathway (implicitly) for reducing PD-L1 (upstream) used in apoptosis, see [0104]-[0107] referring to PD-L1s suppression in EVs based on stimulation and a marker for early cancer. Examiner further notes that miRNA (an oncogenic driver) is also regulated by the PI3K/AKT/mTOR signaling pathway.); and
delivering, via one or more electrodes connected to the neuromodulation device, the electrical stimulation to the subject using the stimulation settings, wherein the electrical stimulation provides a therapeutic effect in the subject by modulating the one or more genes associated with the GBM signaling pathway ([0071] “the miRNA content of an EV can be modulated by increasing or decreasing the amount of one or more miRNAs present in or on the surface of an EV released from a target cell by adjusting the electrical stimulation parameters. MicroRNAs (miRNAs) have therapeutic potential for regenerative medicine.sup.1. These small, non-coding RNAs direct post-transcriptional regulation of gene networks by targeting protein-coding mRNAs that are pivotal in the pathogenesis of neurological disorders such as epilepsy. For example, evidence for dysregulation of numerous specific miRNAs in epilepsy supports the hypothesis that miRNAs, as gene expression regulators, are pertinent to both the cause and treatment of epilepsy.” [0114] “The electrical stimulation system can be a bench top device (that uses electrical stimulation to optimally tune EV cargo for therapeutic applications.” [0040] “Such ES treatment can be invasive, such as electrodes in the organ (e.g. brain), on the organ (e.g. brain), in the organ blood vessels, or non-invasive and complementary to other treatments.”).
Regrading claim 2, Wang teaches wherein the stimulation settings include at least one of a voltage, a current level, a frequency, a pulse width, or a duration of the electrical stimulation ([0070] “It has been discovered surprisingly that electrical stimulation parameters, including the frequency of electrical signal and pulse width and the electrical field strength” [0104] “ES parameters (e.g., frequency, current amplitude, pulse width, wave-form morphology) can be adjusted and tuned by one skilled in the art to minimize the release of exosomal PD-L1, and thus optimize the cancer therapy and individualize the therapy for each patient and tumor type.”).
Regarding claim 4, Wang teaches wherein the stimulation settings include the frequency and the frequency is selected from a range of 10-100 Hz ([0065] “from about 10 Hz to about 30 Hz at from about 1 mV/mm to about 5 mV/mm for about 1 to about 5 minutes”).
Regarding claims 7-8, Wang teaches further comprising providing at least one additional treatment before, during, or after the electrical stimulation, wherein the at least one additional treatment is at least one of radiation therapy, immunotherapy, or chemotherapy ([0024] “the method can further include administering to the subject one or more additional therapies before, during, or after the electrical stimulation. In some cases, the one or more additional therapies can be selected from the group consisting of chemotherapy, radiation therapy, and immunotherapy. In some cases, the chemotherapy can include administering a chemotherapeutic agent selected from the group consisting of doxorubicin, paclitaxel, cyclophosphamide, and combinations thereof.”).
Regarding claim 9, Wang teaches wherein the stimulation settings are predetermined to induce a therapeutic seizure in the subject having a duration of between 10 and 120 seconds, such that the therapeutic seizure induces modulating the one or more genes associated with the GBM signaling pathway ([0120] “Both of these miRNAs have been reported elevated in brain tissue of children with mesial temporal lobe epilepsy.sup.13 and in regional brain homogenates of rats subjected to tetanic stimulation-induced seizures.sup.14. miR-21 is documented as a strong anti-apoptotic factor4 and miR-146 is a critical factor in immune responses” [0071] “the miRNA content of an EV can be modulated by increasing or decreasing the amount of one or more miRNAs present in or on the surface of an EV released from a target cell by adjusting the electrical stimulation parameters.” [0046] “FIG. 1(A-F) is a sequence of images showing EVs released during 2 Hz electrical stimulation from primary mouse astrocytes loaded with Calcein dye at 0 seconds (A), 16 seconds (B), 20 seconds (C), 60 seconds (D), 72 seconds (E), and 120 seconds (F) as described in Example 1.”).
Regarding claim 10, Wang teaches wherein the GBM signaling pathway comprises one or more GBM-associated electrical network signaling pathways ([0071] “ the miRNA content of an EV can be modulated by increasing or decreasing the amount of one or more miRNAs present in or on the surface of an EV released from a target cell by adjusting the electrical stimulation parameters.” Examiner notes that GBM signaling pathway includes 3 core pathways- receptor tyrosine kinase (RTK) activation, PI3K/AKT/mTOR signaling, and tumor suppressor inactivation. Examiner notes that Wang uses the PI3K/AKT/mTOR signaling pathway (implicitly) for reducing PD-L1 (upstream) used in apoptosis, see [0104]-[0107] referring to PD-L1s suppression in EVs based on stimulation and a marker for early cancer. Examiner further notes that miRNA (an oncogenic driver) is also regulated by the PI3K/AKT/mTOR signaling pathway.).
Regarding claim 15, Wang teaches wherein modulating the one or more genes comprises downregulating the one or more genes ([0095] “ES modulation of EV content may provide a generic mechanism of suppressing PD-L1 in EVs and/or PD-L1 carrying EVs, and may be useful as a therapeutic targeting cancer spread.” [0104] “Different cancer cells and cell types may have different responses to ES (e.g., suppression of PD-L1 EVs and/or PD-L1 content of EVs may occur at different applied field frequencies in for different cells).”).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 3 and 5-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 20200384266)(Hereinafter Wang).
Regarding claim 3, Wang teaches wherein the stimulation settings include the current level and the current level is selected from a range of 20-100 mA ([0104] “ES parameters (e.g., frequency, current amplitude, pulse width, wave-form morphology) can be adjusted and tuned by one skilled in the art to minimize the release of exosomal PD-L1, and thus optimize the cancer therapy and individualize the therapy for each patient and tumor type.”).
Although Wang teaches a current level that are optimized for cancer therapy, Wang does not teach selected from a range of 20-100 mA. Since the current level can be changed based on the individual, each of the current level values can be altered to optimize the cancer therapy. It would have been obvious to one having ordinary skill in the art at the time the invention was made to have selected from a range of 20-100 mA, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
Regarding claim 5, Wang teaches wherein the stimulation settings include the pulse width and the pulse width is selected from a range of 0.5-2.0 ms ([0104] “ES parameters (e.g., frequency, current amplitude, pulse width, wave-form morphology) can be adjusted and tuned by one skilled in the art to minimize the release of exosomal PD-L1, and thus optimize the cancer therapy and individualize the therapy for each patient and tumor type.”).
Although Wang teaches a pulse width that are optimized for cancer therapy, Wang does not teach pulse width is selected from a range of 0.5-2.0 ms. Since the pulse width can be changed based on the individual, each of the pulse width values can be altered to optimize the cancer therapy. It would have been obvious to one having ordinary skill in the art at the time the invention was made to have pulse width is selected from a range of 0.5-2.0 ms, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
Regarding claim 6, Wang teaches wherein the stimulation settings include the duration of the electrical stimulation and the duration of the electrical stimulation is selected from a range of 0.5-2.0 s ([0064] “electrically stimulating the target cell includes applying patterned pulses, such as by varying the duration and number of pulses in a single train, varying the quiet period between two pulse trains, and the like.”).
Although Wang teaches a duration that are optimized for cancer therapy, Wang does not teach a duration selected from a range of 0.5-2.0 s. Since the pulse width can be changed based on the individual, each of the duration values can be altered to optimize the cancer therapy. It would have been obvious to one having ordinary skill in the art at the time the invention was made to a duration selected from a range of 0.5-2.0 s, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
Claim(s) 12-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 20200384266)(Hereinafter Wang) in view of Winkler et al. (“Brain tumour cells interconnect to a functional and resistant network”, Nature volume 528, pages 93–98 (2015))(Hereinafter Winkler).
Regarding claim 12, Wang teaches the invention of claim 1. However, Wang does not teach GBM signaling pathway comprises one or more GBM network-associated signaling proteins. Winkler, in the same field of endeavor, teaches glioblastomas tumor growth and proliferation through microtube formation via neuronal networks (Abstract), and further teaches wherein the GBM signaling pathway comprises one or more GBM network-associated signaling proteins (Pg. 96 right col. lines 32-35 and Pg. 97 left col. lines 1-2 “GAP-43 is highly expressed in axonal growth cones34,35, induced by neurotrophin receptor signalling36,37, and drives neuronal progenitor cell migration38. Remarkably, GAP-43 overexpression is sufficient for the outgrowth of membrane tubes in neuronal39 and even in non-neuronal40 cells.”) to identify molecular pathways associated with GBM for progression and resistance (Pg. 96 right col. lines 10-15). It would have been obvious to one skilled in the art, prior to the effective filing date of the invention, to modify the method of Wang, with the GBM signaling pathway comprises one or more GBM network-associated signaling proteins of Winkler, because such a modification would allow to identify molecular pathways associated with GBM for progression and resistance.
Regarding claim 13, Wang teaches the invention of claim 1. However, Wang does not teach the one or more GBM network-associated signaling proteins comprise a neuronal growth associated protein 43 (GAP43). Winkler, in the same field of endeavor, teaches glioblastomas tumor growth and proliferation through microtube formation via neuronal networks (Abstract), and further teaches wherein the one or more GBM network-associated signaling proteins comprise a neuronal growth associated protein 43 (GAP43) (Pg. 96 right col. lines 32-35 and Pg. 97 left col. lines 1-2 “GAP-43 is highly expressed in axonal growth cones34,35, induced by neurotrophin receptor signalling36,37, and drives neuronal progenitor cell migration38. Remarkably, GAP-43 overexpression is sufficient for the outgrowth of membrane tubes in neuronal39 and even in non-neuronal40 cells.”) to identify molecular pathways associated with GBM for progression and resistance (Pg. 96 right col. lines 10-15). It would have been obvious to one skilled in the art, prior to the effective filing date of the invention, to modify the method of Wang, with the one or more GBM network-associated signaling proteins comprise a neuronal growth associated protein 43 (GAP43) of Winkler, because such a modification would allow to identify molecular pathways associated with GBM for progression and resistance.
Claim(s) 11 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 20200384266)(Hereinafter Wang) in view of Monje et al. (“Electrical and synaptic integration of glioma into neural circuits”, Nature volume 573, pages 539–545 (2019))(Hereinafter Monje).
Regarding claim 11, Wang teaches the invention of claim 1. However, Wang does not teach GBM signaling pathway comprises one or more GBM neuronal activity drivers. Monje, in the same field of endeavor, teaches glioma lethal brain cancer (Abstract) that uses electrical stimulation on xenografts (Fig. 2), and further teaches wherein the GBM signaling pathway comprises one or more GBM neuronal activity drivers (Fig. 2 the use of AMPA is a neuronal driver.) to suggest that AMPA production has a direct correlation with the formation of bona fide synapses of glioma cells (Page 540 right col. lines 8-15). It would have been obvious to one skilled in the art, prior to the effective filing date of the invention, to modify the method of Wang, with the GBM signaling pathway comprises one or more GBM neuronal activity drivers of Monje, because such a modification would allow to suggest that AMPA production has a direct correlation with the formation of bona fide synapses of glioma cells.
Regarding claim 14, Wang teaches the invention of claim 1. However, Wang does not teach one or more genes comprise at least one of GRIA4, GRIK1, GRIN1, or GRM4. Monje, in the same field of endeavor, teaches glioma lethal brain cancer (Abstract) that uses electrical stimulation on xenografts (Fig. 2), and further teaches wherein the one or more genes comprise at least one of GRIA4, GRIK1, GRIN1, or GRM4 (Page 540 right col. lines 3-7 “in response to paired stimuli (Fig. 2g), both of which are electrophysiological characteristics that suggest that synaptic communication occurs through AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs; a type of ionotropic glutamate receptor).” GRIA4 is part of the GRIA family that produces AMPA.) to suggest that AMPA production has a direct correlation with the formation of bona fide synapses of glioma cells (Page 540 right col. lines 8-15). It would have been obvious to one skilled in the art, prior to the effective filing date of the invention, to modify the method of Wang, with the one or more genes comprise at least one of GRIA4, GRIK1, GRIN1, or GRM4 of Monje, because such a modification would allow to suggest that AMPA production has a direct correlation with the formation of bona fide synapses of glioma cells.
Claim(s) 1-6, 10, and 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sita et al. (“Characterizing Seizure-Induced Changes in the Glioma Microenvironment”, International Journal of Radiation Oncology*Biology*Physics Volume 111, Issue 3, Supplement, 1 November 2021, Pages e599-e600)(Hereinafter Sita) in view of Hebb et al. (US 11167133)(Hereinafter Hebb).
Regarding claim 1, Sita teaches A method for electrical stimulation of a glioblastoma (GBM) in a subject (Materials/Methods “Mice were randomized to receive ECT via ear-clip electrodes or sham treatment daily up to five times per week until survival endpoints were reached.”), the method comprising:
… determined to generate an electrical stimulation that modulates one or more genes associated with a GBM signaling pathway (Purpose/Objective “ECT has been shown to decrease extracellular glutamate and glutamate receptor expression in vivo and increase blood-brain barrier (BBB) permeability.”); and
delivering, via one or more electrodes connected to the neuromodulation device, the electrical stimulation to the subject using the stimulation settings, wherein the electrical stimulation provides a therapeutic effect in the subject by modulating the one or more genes associated with the GBM signaling pathway (Material/Methods “Mice were randomized to receive ECT via ear-clip electrodes or sham treatment daily up to five times per week until survival endpoints were reached.” Purpose/Objective “ECT has been shown to decrease extracellular glutamate and glutamate receptor expression in vivo and increase blood-brain barrier (BBB) permeability. ECT, then, may have previously unexplored oncologic value. We hypothesized that seizure-induced changes in the glioma microenvironment occur with ECT, increasing permeability of the BBB, slowing tumor progression, and prolonging overall survival in glioma-bearing mice.”).
However, Sita does not teach receiving, by a neuromodulation device, stimulation settings determined to generate an electrical stimulation. Hebb, in the same field of endeavor, teaches a method for electrical stimulation for treating glioblastoma cancer cells (Abstract), and further teaches receiving, by a neuromodulation device, stimulation settings determined to generate an electrical stimulation (Col. 4 lines 1-37 and Col. 7 line 7 “implantable device”) to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors (col. 3 lines 52-45). It would have been obvious to one skilled in the art, prior to the effective filing date of the invention, to modify the method of Sita, with the receiving, by a neuromodulation device, stimulation settings determined to generate an electrical stimulation of Hebb, because such a modification would allow to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors.
Regrading claim 2, claim 1 is obvious over Sita and Hebb. However, Sita does not teach the stimulation settings include at least one of a voltage, a current level, a frequency, a pulse width, or a duration of the electrical stimulation. Hebb, in the same field of endeavor, teaches a method for electrical stimulation for treating glioblastoma cancer cells (Abstract), and further teaches wherein the stimulation settings include at least one of a voltage, a current level, a frequency, a pulse width, or a duration of the electrical stimulation (Col. 13 lines 21-25 “the PG generates pulsed current, which may be applied at about 0.1 milli-amps (mA) to about 4 amps (A), including any mA or A there in between, such as 2 mA.”) to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors (col. 3 lines 52-45). It would have been obvious to one skilled in the art, prior to the effective filing date of the invention, to modify the method of Sita, with the stimulation settings include at least one of a voltage, a current level, a frequency, a pulse width, or a duration of the electrical stimulation of Hebb, because such a modification would allow to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors.
Regarding claim 3, claim 1 is obvious over Sita and Hebb. However, Sita does not teach the stimulation settings include the current level and the current level is selected from a range of 20-100 mA. Hebb, in the same field of endeavor, teaches a method for electrical stimulation for treating glioblastoma cancer cells (Abstract), and further teaches wherein the stimulation settings include the current level and the current level is selected from a range of 20-100 mA (Col. 13 lines 21-25 “the PG generates pulsed current, which may be applied at about 0.1 milli-amps (mA) to about 4 amps (A), including any mA or A there in between, such as 2 mA.”) to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors (col. 3 lines 52-45). It would have been obvious to one skilled in the art, prior to the effective filing date of the invention, to modify the method of Sita, with the stimulation settings include the current level and the current level is selected from a range of 20-100 mA of Hebb, because such a modification would allow to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors.
Although Hebb teaches a current level that are optimized for cancer therapy, Hebb does not teach selected from a range of 20-100 mA. Since the current level can be changed based on the individual, each of the current level values can be altered to optimize the cancer therapy. It would have been obvious to one having ordinary skill in the art at the time the invention was made to have selected from a range of 20-100 mA, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
Regarding claim 4, claim 1 is obvious over Sita and Hebb. However, Sita does not teach the stimulation settings include the frequency and the frequency is selected from a range of 10-100 Hz. Hebb, in the same field of endeavor, teaches a method for electrical stimulation for treating glioblastoma cancer cells (Abstract), and further teaches wherein the stimulation settings include the frequency and the frequency is selected from a range of 10-100 Hz (Col. 14 lines 17-22 “Direct or pulsed current may be applied at about 1-10 V at a frequency of 50 Hz to 200 kHz or any combination thereof. For example, the current may be 1-2 V at a frequency of 200 kHz or it may be 4 V at a frequency of 130 Hz square wave. Another example may be the application of 1-10 V at 50-200 Hz.”) to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors (col. 3 lines 52-45). It would have been obvious to one skilled in the art, prior to the effective filing date of the invention, to modify the method of Sita, with the stimulation settings include the frequency and the frequency is selected from a range of 10-100 Hz of Hebb, because such a modification would allow to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors.
Regarding claim 5, claim 1 is obvious over Sita and Hebb. However, Sita does not teach the stimulation settings include the pulse width and the pulse width is selected from a range of 0.5-2.0 ms. Hebb, in the same field of endeavor, teaches a method for electrical stimulation for treating glioblastoma cancer cells (Abstract), and further teaches wherein the stimulation settings include the pulse width and the pulse width is selected from a range of 0.5-2.0 ms (Col. 13 lines 33-38 “the application of voltages pulses with a pulse width of less than 100 μs. The period (interval between pulses or pulse spacing) may be less than 1 second. In another embodiment, the period may be less than 500 msec. In another embodiment, the period may be less than 20 msec.”) to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors (col. 3 lines 52-45). It would have been obvious to one skilled in the art, prior to the effective filing date of the invention, to modify the method of Sita, with the stimulation settings include the pulse width and the pulse width is selected from a range of 0.5-2.0 ms of Hebb, because such a modification would allow to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors.
Regarding claim 6, claim 1 is obvious over Sita and Hebb. However, Sita does not teach the stimulation settings include the duration of the electrical stimulation and the duration of the electrical stimulation is selected from a range of 0.5-2.0 s. Hebb, in the same field of endeavor, teaches a method for electrical stimulation for treating glioblastoma cancer cells (Abstract), and further teaches wherein the stimulation settings include the duration of the electrical stimulation and the duration of the electrical stimulation is selected from a range of 0.5-2.0 s (Col. 13 lines 34-37 “The period (interval between pulses or pulse spacing) may be less than 1 second. In another embodiment, the period may be less than 500 msec.”) to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors (col. 3 lines 52-45). It would have been obvious to one skilled in the art, prior to the effective filing date of the invention, to modify the method of Sita, with the stimulation settings include the duration of the electrical stimulation and the duration of the electrical stimulation is selected from a range of 0.5-2.0 s of Hebb, because such a modification would allow to enable development of personalized gene therapies and enhance the effect of existing treatments to improve outcomes for patients with GBM and other systemic and nervous system tumors.
Regarding claim 10, Sita teaches wherein the GBM signaling pathway comprises one or more GBM-associated electrical network signaling pathways (Purposes/Objectives “Analogously, GBM cells are dependent on bountiful neuronal glutamate, utilize elevated dopamine receptor expression to activate the hypoxic response and augment progression, and catabolize serotonin to drive proliferation. The clinical induction of seizure, known as electroconvulsive therapy (ECT), has been used by psychiatrists since the 1930s to treat severe cases of depression, mania, psychosis, and catatonia. ECT has been shown to decrease extracellular glutamate and glutamate receptor expression in vivo and increase blood-brain barrier (BBB) permeability.”).
Regarding claim 14, Sita teaches wherein the one or more genes comprise at least one of GRIA4, GRIK1, GRIN1, or GRM4 (Purposes/Objectives “Analogously, GBM cells are dependent on bountiful neuronal glutamate, utilize elevated dopamine receptor expression to activate the hypoxic response and augment progression, and catabolize serotonin to drive proliferation. The clinical induction of seizure, known as electroconvulsive therapy (ECT), has been used by psychiatrists since the 1930s to treat severe cases of depression, mania, psychosis, and catatonia. ECT has been shown to decrease extracellular glutamate and glutamate receptor expression in vivo and increase blood-brain barrier (BBB) permeability.”).
Regarding claim 15, Sita teaches wherein modulating the one or more genes comprises downregulating the one or more genes (Purposes/Objectives “Analogously, GBM cells are dependent on bountiful neuronal glutamate, utilize elevated dopamine receptor expression to activate the hypoxic response and augment progression, and catabolize serotonin to drive proliferation. The clinical induction of seizure, known as electroconvulsive therapy (ECT), has been used by psychiatrists since the 1930s to treat severe cases of depression, mania, psychosis, and catatonia. ECT has been shown to decrease extracellular glutamate and glutamate receptor expression in vivo and increase blood-brain barrier (BBB) permeability.”).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Wong et al. (“Differential effects of kindled and electrically induced seizures on a glutamate receptor (GluR1) gene expression” Epilepsy Research, Volume 14, Issue 3, pages 2241-227, 1993), Xiong et al. (US 20080242588) ([0027] seizure induced inhibition of proteins.), and Hanada (“Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors”, Biomolecules. 2020 Mar 18;10(3):464.)(Glutamate receptor effects on seizure.)
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