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 .
Response to Arguments
Applicant’s amendments overcome the rejections under 35 U.S.C. § 112 and the rejections are therefore withdrawn.
Applicant's arguments filed 8/7/2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 102, Applicant alleges that Levine does not teach “a method of modulating gene expression of inflammatory cytokines in the CNS and/or neurotransmitter pathway genes”, stating that Levine only teaches “monitoring biomarkers” rather than “modulating gene expression.”
This is not persuasive, firstly because Applicant’s “modulating gene expression” is disclosed as an inherent result of the claimed steps of stimulation. Therefore, when the steps of stimulation are performed, the result is also performed. Applicant has disclosed no other steps required to achieve this result. Secondly, the teaching Levine includes the following:
[0064] Leakiness in the blood brain barrier may allow immune cells and inflammatory cytokines and chemokines to pass through and contribute to continued inflammation in the brain and/or spinal cord. Therefore, VNS may reduce vessel leakiness around the central nervous system (CNS), thereby reducing the recruitment of proinflammatory cells such as lymphocytes (e.g., T-cells) and macrophages to the brain and spinal cord, thereby reducing the inflammation in the CNS and reducing the amount demyelination that results from an inflammatory attack by the immune system.
T-cells are an inflammatory cytokine. Modulation of gene expression of inflammatory cytokines requires altering the number of cytokines. Reducing the recruitment of T-cells meets this claim requirement. Therefore the argument is unpersuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant alleges that Levine and John in combination does not teach “overlapping low-frequency and high-frequency stimulations having different durations” because Levine does not discuss overlapping stimulations, and John describes combines stimulation fields that Applicant does not consider overlapping treatment.
This is not found persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Additionally, John does teach overlapping stimulation in the form of partial signals, both concurrent and partially overlapping in ¶[0076], Fig. 4a-b and ¶¶[0059-0060]. Applicant’s claims do not require that the stimulations are not partial signals as taught by John, and John teaches an advantage of multiple stimulation signals provided in such a fashion: because partial signal in combination allow for charge balancing (John ¶[0059]) and limiting the stimulation to only signal that produce desired effects (John ¶[0059]), improving transmission of energy to tissue (John ¶[0059]) and avoiding unwanted side effects of treatment (John ¶[0060]). Therefore, Applicant’s arguments are not persuasive.
Applicant goes on to state that neither Levine nor John teach “a first stimulation at less than 20Hz, a second stimulation at greater than 20Hz, a second stimulation having a shorter duration than the first stimulation, or a second stimulation occurring during the first stimulation period.”
This is both a mischaracterization of the rejection, and not persuasive. Levine teaches all of the claimed stimulation parameters except for the stimulation provided in an overlapping fashion:
Levine teaching applying a first nerve stimulation at a first low frequency of less than 20 Hz (¶[0011] 1-20 Hz, ¶[0041] less than 20 Hz) for a first time period (¶[0041] proscribed duration) having a first duration of between 10 seconds and 2 minutes (¶[0041] less than 2 minutes) and applying a nerve stimulation at a frequency of greater than 20 Hz (¶[0041] greater than 20 Hz, ¶[0011]) for a second time period that is less than the first time period (¶[0041] smaller time periods).
Therefore, John modifies the stimulation of Levine to use overlapping periods because John, as noted above, teaches several advantages to overlapping stimulation periods. Applicant’s allegation that John teaches no benefit to PHOSITA is unpersuasive in light of the cited portions of John teaching specific benefits.
Applicant’s remaining remarks are directed to whether the Kilgard reference teaches claim limitations that are taught by Levine and/or John. Therefore these remarks are unpersuasive.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 17-22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Levine et al. (U.S. Patent Application Publication No. 2019/0111263) hereinafter referred to as Levine.
Regarding claim 17, Levine teaches a method of modulating gene expression of inflammatory cytokines in the CNS and/or neurotransmitter pathway genes (¶[0064]), the method comprising
applying vagus nerve stimulation to the patient (¶[0039]) of between 2.5 nC to 7.5 mC per day (¶[0041] 0.25mA-5ma for less than 2 minutes/120 seconds with a duty cycle of 10, 5, 4, 3, 2, 1, or 0.5% encompasses this range; Total Charge (C) = (Current (A) * Time (s)) * (Duty Cycle (%)/100), e.g. (0.00025 A * 120 s)*0.1 = 3mC).
Regarding claim 18, Levine teaches the method of claim 17.
Levine further teaches wherein applying comprises applying the vagus nerve stimulation at between 0.1 and 20 Hz to the vagus nerve (¶[0039]).
Regarding claim 19, Levine teaches the method of claim 17.
Levine further teaches wherein applying comprises applying the vagus nerve stimulation for less than 10 minute each day (¶[0041] stimulation is ceased for as much as an entire day after less than 2 minutes of stimulation).
Regarding claim 20, Levine teaches the method of claim 17.
Levine further teaches wherein applying comprises applying stimulation to the vagus nerve (¶[0039]) from an implanted neurostimulator attached or adjacent to the vagus nerve (¶[0041]).
Regarding claim 21, Levine teaches the method of claim 17.
Levine teaches further comprising adjusting the applied vagus nerve stimulation based on the level of a marker (¶¶[0008-0009], ¶[0054], ¶[0083]).
Regarding claim 22, Levine teaches the method of claim 21.
Levine teaches further comprising detecting a marker for demyelination in a blood, sputum, or cerebrospinal fluid sample (¶[0054]).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-3, 5, 7-10, and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Levine et al. (U.S. Patent Application Publication No. 2019/0111263) hereinafter referred to as Levine; in view of John (U.S. Patent Application Publication No. 2006/0149337) hereinafter referred to as John.
Regarding claim 1, Levine teaches a method of treating a neurodegenerative disorder (¶[0006]), the method comprising
applying a first nerve stimulation at a first low frequency of less than 20 Hz (¶[0011] 1-20 Hz, ¶[0041] less than 20 Hz) for a first time period (¶[0041] proscribed duration) having a first duration of between 10 seconds and 2 minutes (¶[0041] less than 2 minutes) and
applying a nerve stimulation at a frequency of greater than 20 Hz (¶[0041] greater than 20 Hz, ¶[0011]) for a second time period that is less than the first time period (¶[0041] smaller time periods).
Levine further teaches two stimulations (¶[0010] mechanical stimulation followed by additional electrical stimulation) and the stimulator configured for either or both of electrical and mechanical stimulation (¶[0046], ¶[0081]) where the stimulator can be implanted or non-invasive (¶¶[0045-0046]).
Levine does not teach applying a second nerve stimulation wherein the first nerve stimulation at least partially overlaps with the second nerve stimulation.
Attention is drawn to the John reference, which teaches creation and variation of stimulation parameters using sensed data in order to match, adjust, or avoid matching characteristics of the stimulation therapy relative to certain endogenous brain activities (Abstract), including two periods of stimulation that partially overlap (¶[0076], Fig. 4a-b and ¶¶[0059-0060]) applied to a vagus nerve (¶[0100]).
It would have been obvious to one of ordinary skill in the art at the time of filing to modify the known efficacious stimulation parameters of Levine to use overlapping electrical stimulation waveforms for treatment, as taught by John, because partial signal in combination allow for charge balancing (John ¶[0059]) and limiting the stimulation to only signal that produce desired effects (John ¶[0059]), improving transmission of energy to tissue (John ¶[0059]) and avoiding unwanted side effects of treatment (John ¶[0060]).
Regarding claim 2, Levine as modified teaches the method of claim 1.
Levine further teaches wherein the first nerve stimulation comprises vagus nerve stimulation (¶[0039]).
Regarding claim 3, Levine as modified teaches the method of claim 1,.
Levine further teaches wherein the total charge per day delivered by the first and second nerve stimulation is between 2.5 nC to 7.5 mC per day (¶[0041] 0.25mA-5ma for less than 2 minutes/120 seconds with a duty cycle of 10, 5, 4, 3, 2, 1, or 0.5% encompasses this range; Total Charge (C) = (Current (A) * Time (s)) * (Duty Cycle (%)/100), e.g. (0.00025 A * 120 s)*0.1 = 3mC).
Regarding claim 5, Levine as modified teaches the method of claim 1.
Levine further teaches wherein the first and second nerve stimulation comprises vagus and/or splenic nerve stimulation (¶[0039]).
Regarding claim 7, Levine as modified teaches the method of claim 1.
Levine further teaches wherein applying the first and second nerve stimulation comprises applying for less than 10 minute each day (¶[0041]).
Regarding claim 8, Levine as modified teaches the method of claim 1.
Levine further teaches wherein applying the first nerve stimulation comprises applying stimulation to the vagus nerve from an implanted neurostimulator (¶[0041]) attached or adjacent to the vagus nerve (¶[0039]).
Regarding claim 9, Levine as modified teaches the method of claim 1.
Levine teaches further comprising adjusting the applied nerve stimulation based on the level of a marker (¶¶[0008-0009], ¶[0054], ¶[0083]).
Regarding claim 10, Levine as modified teaches the method of claim 9.
Levine teaches further comprising detecting a marker for demyelination in a blood, sputum, or cerebrospinal fluid sample (¶[0054]).
Regarding claim 15, Levine teaches a system for treating a patient (Abstract), the system comprising:
one or more electrodes (¶[0045]);
a pulse generator (¶[0080]);
one or more processors (¶[0080] controller, ¶[0084] processors); and
a memory coupled to the one or more processors (¶[0084] memory), the memory storing computer-program instructions, that, when executed by the one or more processors, perform a computer-implemented method comprising:
applying a first nerve stimulation at a first low frequency of less than 20 Hz (¶[0011] 1-20 Hz, ¶[0041] less than 20 Hz) for a first time period (¶[0041] proscribed duration) having a first duration of between 10 seconds and 2 minutes (¶[0041] less than 2 minutes) and
applying a nerve stimulation at a frequency of greater than 20 Hz (¶[0041] greater than 20 Hz, ¶[0011]) for a second time period that is less than the first time period (¶[0041] smaller time periods).
Levine further teaches two stimulations (¶[0010] mechanical stimulation followed by additional electrical stimulation) and the stimulator configured for either or both of electrical and mechanical stimulation (¶[0046], ¶[0081]) where the stimulator can be implanted or non-invasive (¶¶[0045-0046]).
wherein the first and second nerve stimulation to the patient delivers between 2.5 nC to 7.5 mC per day (¶[0041] 0.25mA-5ma for less than 2 minutes/120 seconds with a duty cycle of 10, 5, 4, 3, 2, 1, or 0.5% encompasses this range; Total Charge (C) = (Current (A) * Time (s)) * (Duty Cycle (%)/100), e.g. (0.00025 A * 120 s)*0.1 = 3mC).
Levine does not teach applying a first and second electrical nerve stimulation in sequence.
Attention is drawn to the John reference, which teaches creation and variation of stimulation parameters using sensed data in order to match, adjust, or avoid matching characteristics of the stimulation therapy relative to certain endogenous brain activities (Abstract), including two periods of stimulation that in a sequence (¶[0076], Fig. 4a-b and ¶¶[0059-0060]) applied to a vagus nerve (¶[0100]).
It would have been obvious to one of ordinary skill in the art at the time of filing to modify the known efficacious stimulation parameters of Levine to use a sequence of electrical stimulation waveforms for treatment, as taught by John, because partial signal in combination allow for charge balancing (John ¶[0059]) and limiting the stimulation to only signal that produce desired effects (John ¶[0059]), improving transmission of energy to tissue (John ¶[0059]) and avoiding unwanted side effects of treatment (John ¶[0060]).
Claim(s) 4, 6, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Levine and John as applied to claims 1 and 15 above, and further in view of Kilgard et al. (U.S. Patent Application Publication No. 2015/0073493) hereinafter referred to as Kilgard.
Regarding claims 4 and 6/16, Levine as modified teaches the method of claim 1/15.
Levine as modified does not teach further comprising pairing the second nerve stimulation with performance of a motor task.
Attention is brought to the Kilgard reference, which teaches pairing a vagus nerve stimulation (¶[0019] delivered by implantable nerve stimulator (¶[0019]) with performance of a motor task (¶[0019], ¶[0047]) wherein the second time period is between 0.5 seconds and 10 seconds (¶[0047], 500 milliseconds is equivalent to 0.5 seconds).
It would have been obvious to one of ordinary skill in the art at the time of filing to modify the nerve stimulation of Levine as modified to include pairing with motor tasks, as taught by Kilgard, because Kilgard teaches enhancing recovery of motor function with increased neural plasticity from vagus nerve stimulus of 0.5 seconds in duration (Kilgard, ¶[0160] and ¶[0047]).
Claim(s) 11-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Levine et al. (U.S. Patent Application Publication No. 2019/0111263) hereinafter referred to as Levine; in view of John (U.S. Patent Application Publication No. 2006/0149337) hereinafter referred to as John; in view of Kilgard et al. (U.S. Patent Application Publication No. 2015/0073493) hereinafter referred to as Kilgard.
Regarding claims 11-12, Levine teaches a method of reducing demyelination and/or increasing remyelination (¶[0014]), the method comprising
applying a first nerve stimulation at a first low frequency of less than 20 Hz (¶[0011] 1-20 Hz, ¶[0041] less than 20 Hz) for a first time period (¶[0041] proscribed duration) having a first duration of between 10 seconds and 2 minutes (¶[0041] less than 2 minutes) and
applying a nerve stimulation at a frequency of greater than 20 Hz (¶[0041] greater than 20 Hz, ¶[0011]) for a second time period that is less than the first time period (¶[0041] smaller time periods).
Levine further teaches two stimulations (¶[0010] mechanical stimulation followed by additional electrical stimulation) and the stimulator configured for either or both of electrical and mechanical stimulation (¶[0046], ¶[0081]) where the stimulator can be implanted or non-invasive (¶¶[0045-0046]).
wherein the first and second nerve stimulation to the patient delivers between 2.5 nC to 7.5 mC per day (¶[0041] 0.25mA-5ma for less than 2 minutes/120 seconds with a duty cycle of 10, 5, 4, 3, 2, 1, or 0.5% encompasses this range; Total Charge (C) = (Current (A) * Time (s)) * (Duty Cycle (%)/100), e.g. (0.00025 A * 120 s)*0.1 = 3mC). .
Levine does not teach applying a second nerve stimulation wherein the first nerve stimulation at least partially overlaps with the second nerve stimulation, further comprising pairing the application of the second nerve stimulation with performance of a motor task.
Attention is drawn to the John reference, which teaches creation and variation of stimulation parameters using sensed data in order to match, adjust, or avoid matching characteristics of the stimulation therapy relative to certain endogenous brain activities (Abstract), including two periods of stimulation that partially overlap (¶[0076], Fig. 4a-b and ¶¶[0059-0060]) applied to a vagus nerve (¶[0100]).
It would have been obvious to one of ordinary skill in the art at the time of filing to modify the known efficacious stimulation parameters of Levine to use overlapping electrical stimulation waveforms for treatment, as taught by John, because partial signal in combination allow for charge balancing (John ¶[0059]) and limiting the stimulation to only signal that produce desired effects (John ¶[0059]), improving transmission of energy to tissue (John ¶[0059]) and avoiding unwanted side effects of treatment (John ¶[0060]).
Levine as modified does not teach pairing the application of the second nerve stimulation with performance of a motor task.
Attention is brought to the Kilgard reference, which teaches pairing a vagus nerve stimulation (¶[0019] delivered by implantable nerve stimulator (¶[0019]) with performance of a motor task (¶[0019], ¶[0047]).
It would have been obvious to one of ordinary skill in the art at the time of filing to modify the nerve stimulation of Levine as modified to include pairing with motor tasks, as taught by Kilgard, because Kilgard teaches enhancing recovery of motor function with increased neural plasticity from vagus nerve stimulus (Kilgard, ¶[0160] and ¶[0047]).
Regarding claim 13, Levine as modified teaches the method of claim 11.
Levine further teaches wherein the application of the nerve stimulation comprises applying stimulation to a vagus nerve and/or a splenic nerve (¶[0039]).
Regarding claim 14, Levine as modified teaches the method of claim 11.
Levine further teaches wherein the applying the second nerve stimulation comprises stimulation for between 1 and 15 seconds (¶[0010] mechanical simulation provided 1 ms-5 minutes, 10 ms-10 s, ¶[0041] less than 1 minute, ¶[0047] 0.1 sec-10 minutes, 1 sec-5 min, 1 sec-2 min, etc., encompasses this range as an effective stimulation parameter).
Claim(s) 23-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Levine et al. (U.S. Patent Application Publication No. 2019/0111263) hereinafter referred to as Levine; in view of Kilgard et al. (U.S. Patent Application Publication No. 2015/0073493) hereinafter referred to as Kilgard.
Regarding claim 23, Levine teaches a method of reducing demyelination and/or increasing remyelination, the method comprising
pairing the application of a nerve stimulation to the patient of between 2.5 nC to 7.5 mC per day (¶[0041] 0.25mA-5ma for less than 2 minutes/120 seconds with a duty cycle of 10, 5, 4, 3, 2, 1, or 0.5% encompasses this range; Total Charge (C) = (Current (A) * Time (s)) * (Duty Cycle (%)/100), e.g. (0.00025 A * 120 s)*0.1 = 3mC) while performing a motor task.
Attention is brought to the Kilgard reference, which teaches pairing a vagus nerve stimulation (¶[0019] delivered by implantable nerve stimulator (¶[0019]) with performance of a motor task (¶[0019], ¶[0047]).
It would have been obvious to one of ordinary skill in the art at the time of filing to modify the nerve stimulation of Levine as modified to include pairing with motor tasks, as taught by Kilgard, because Kilgard teaches enhancing recovery of motor function with increased neural plasticity from vagus nerve stimulus of at least 0.5 seconds in duration (Kilgard, ¶[0160] and ¶[0047]).
Regarding claim 24, Levine teaches the method of claim 23.
Levine further teaches wherein the application of the nerve stimulation comprises applying stimulation to a vagus nerve or a splenic nerve (¶[0039]).
Regarding claim 25, Levine teaches the method of claim 23.
Levine further teaches wherein the application of the nerve stimulation comprises applying stimulation at a frequency of greater than 20 Hz (¶[0010] mechanical stimulation provided at 1-2kHz, greater than 20Hz in addition to electrical stimulation).
Regarding claim 26, Levine teaches the method of claim 23.
Levine further teaches wherein the application of the nerve stimulation comprises applying stimulation at a frequency of greater than 30 Hz (¶[0010] mechanical stimulation provided at 1-2kHz, greater than 20Hz in addition to electrical stimulation).
Regarding claim 27, Levine teaches the method of claim 23.
Levine further teaches wherein the application of the nerve stimulation comprises stimulation for between 1 and 15 seconds (¶[0010] mechanical simulation provided 1 ms-5 minutes, 10 ms-10 s).
Conclusion
The prior art made of record and not relied upon remains pertinent to applicant's disclosure.
U.S. Patent Application Publication No. 2011/0106213 to Davis et al. teaches modifying electrical stimulation parameters based on desired charge limits.
U.S. Patent Application Publication No. 2011/0313488 to Ordonez et al. teaches limiting electrical stimulation dosage and total charge delivery calculations.
U.S. Patent Application Publication No. 2014/0243714 to Ward et al. teaches closed loop control of Vagus Nerve Stimulation based on biomarker level information.
THIS ACTION IS MADE FINAL. 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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/AMANDA L STEINBERG/ Examiner, Art Unit 3792
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