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 .
Drawings
The drawings are objected to because Figures 13B-13D are distorted and therefore illegible. Additionally, the labels are not presented under each graph, therefore, it is unclear which graph is being labeled as 13B, 13C, or 13D. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1, 11, 17, and 27 are objected to because of the following informalities:
In claim 1, line 18, “the each” should read “each”
In claim 11, line 5, “their respective” should read “respective”
In claim 17, line 10, “the each” should read “each”
In claim 17, line 18, “the each” should read “each”
In claim 17, line 20, “connections” should read “connection”
In claim 27, line 2, “paired sets of first and second stimuli” should read “paired sets of the first and second stimuli”
Appropriate correction is required.
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 3, 5-6, 8, 11-13, 16-17, 20-21, and 25-27 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 claim 3, the phrase "preferably" renders the claim indefinite because it is unclear what this limitation imposes on the claim, and whether it’s required that the interstimulus interval be within the claimed range or not. For examination purposes, the claim will be read as if the interstimulus interval is between 1-2 milliseconds. See MPEP § 2173.05(c).
Claim 5 recites the limitation "the resultant pre-synaptic stimulus" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim. For examination purposes, claim 5 will be read as if “the resultant pre-synaptic stimulus” reads “a respective pre-synaptic stimulus”.
Claim 6 recites the limitation "the corticospinal pathway” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. For examination purposes, claim 6 will be interpreted as if the corticospinal pathway is a tract that the pre-synaptic and post-synaptic stimuli travel on.
Claim 6 further recites the limitation “the corticospinal neuron that terminates in a pre-synaptic cell” in line 5. Per the specification, a pre-synaptic cell is defined as a corticospinal neuron, therefore, it is unclear how the corticospinal neuron terminates in a corticospinal neuron. For examination purposes, the claim will be interpreted as if the action potential within the corticospinal neuron ceases once it reaches the corticospinal-motoneuronal neuronal pair.
Claim 8 recites the limitation "the resultant pre-synaptic stimulus" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim. For examination purposes, claim 8 will be read as if “the resultant pre-synaptic stimulus” reads “a respective pre-synaptic stimulus”.
Claim 11 recites the limitation "each in line. There is insufficient antecedent basis for this limitation in the claim. For examination purposes, claim 11 will be read as if “each resultant post-synaptic stimulus” reads “each post-synaptic stimulus”.
Claim 12 recites the limitation “the post-synaptic stimulus” in line 4. It is unclear which “post-synaptic stimulus” is being referenced with regard to the plurality of post-synaptic stimuli subsequently recited. For examination purposes, “the post-synaptic stimulus” is interpreted as “a respective post-synaptic stimulus”.
Claim 13 recites the limitation “the peripheral nerve that terminates in a post-synaptic cell” in lines 4-5. There is insufficient antecedent basis for this limitation in the claim. For examination purposes, “the peripheral nerve that terminates in a post-synaptic cell” is interpreted as “a respective peripheral nerve that terminates in a post-synaptic cell”.
Claim 16 recites the limitation “the post-synaptic stimulus” in line 7. It is unclear which “post-synaptic stimulus” is being referenced. For examination purposes, “the post-synaptic stimulus” is interpreted as “a respective post-synaptic stimulus”.
Claim 17 recites the limitation “a descending signal” in lines 13-14, then subsequently, recites “each descending signal” in line 19, and “the descending signal” in lines 20-21. It is unclear whether “the descending signal” refers to one of the previously recited, each descending signal, or a separate descending signal. For examination purposes, “the descending signal” is interpreted as “a respective descending signal”.
Claim 17 further recites the limitation “an ascending signal” in lines 17-18, then subsequently, recites “each ascending signal” in line 19, and “the ascending signal” in line 22. It is unclear whether “the ascending signal” refers to one of the previously recited, each ascending signal, or a separate ascending signal. For examination purposes, “the ascending signal” is interpreted as “a respective ascending signal”.
The dependent claims not specifically addressed above are rejected under 35 U.S.C. 112(b) as indefinite due to their dependence from indefinite claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 6, 9, and 13 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 6 recites “generates the pre-synaptic stimulus within the spinal cord of the body” in lines 1-2 and “by application of a magnetic field parallel to a skull of the body” in line 3; as a result, these limitations are directed to human subject matter. “Configured to” language is suggested to overcome these rejections.
Claim 9 recites “generates the pre-synaptic stimulus within a corticospinal neuron of the motor cortex pathway of the body” in lines 1-2, and “by application of the pre-synaptic stimulus to a thoracic spine of the body” in lines 2-3; as a result, these limitations are directed to human subject matter. “Configured to” language is suggested to overcome these rejections.
Claim 13 recites “by application of an electrical waveform to a peripheral limb of the body” in lines 3-4; as a result, this limitation is directed to human subject matter. “Configured to” language is suggested to overcome this rejection.
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) 1-9 and 11-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ahmed (US 9011310) in view of Bunday and Perez ("Motor Recovery after Spinal Cord Injury Enhanced by Strengthening Corticospinal Synaptic Transmission"), hereinafter referred to as "Bunday and Perez".
Regarding claim 1, Ahmed teaches a system (Abstract; Fig. 1, stimulation system 100), comprising:
a plurality of post-synaptic electrodes in communication with a waveform generator (Col. 6, lines 11-21; Fig. 1, peripheral stimulator 103 and leads +/-);
a processor in communication with a memory and the waveform generator, the memory including instructions, which, when executed, cause the processor to (Fig. 1, control center 105 and processor 120; Col. 6, lines 51-58; Col. 7, lines 1-7);
periodically apply a pre-synaptic stimulus having a pre-synaptic time of arrival to a motor cortex pathway of a body (Col. 3, lines 48-57, “providing pulsed motor cortex stimulation signal to a motor cortex area”; Fig. 1, coil 140 over the M1 region); and
periodically apply, by the waveform generator (Fig. 1, stimulator 103), a plurality of post-synaptic stimuli each having a respective post- synaptic time of arrival to a respective peripheral nerve of a plurality of peripheral nerves of the body (Col. 12, lines 42-52; Fig. 2b).
While Ahmed teaches a presynaptic and postsynaptic stimulus, Ahmed fails to teach a pre-synaptic time of arrival preceding the post-synaptic time of arrival, specifically wherein an interstimulus interval between the pre- synaptic time of arrival of the pre-synaptic stimulus at a synapse of a corticospinal-motoneuronal neuronal pair of the body and each post-synaptic time of arrival of each post-synaptic stimulus at the synapse is within a predetermined range.
Bunday and Perez teach an analogous paired associative stimulation protocol wherein an interstimulus interval between the pre-synaptic time of arrival of the pre-synaptic stimulus at a synapse of a corticospinal-motoneuronal neuronal pair of the body and each post-synaptic time of arrival of the each post-synaptic stimulus at the synapse is within a predetermined range (page 9, Fig. 1A, “The interstimulus interval between paired pulses was designed to allow descending volleys, elicited by TMS, to arrive at the presynaptic terminal of corticospinal neurons 1-2 ms before antidromic PNS volleys in the motoneurons reached the dendrites”).
Therefore, it would have been obvious to someone of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the system of Ahmed with the interstimulus interval between the pre-synaptic time of arrival of the pre-synaptic stimulus and the post-synaptic time of arrival of the post-synaptic stimulus of Bunday and Perez. Precisely timing the arrival of the presynaptic action potentials prior to the postsynaptic depolarizing action potentials may enhance voluntary motor output in humans with chronic incomplete SCI and increase the size of motor evoked potentials (MEPs) in resting muscles (Bunday and Perez, page 1, Results; page 2, Effects of Paired-Pulse Simulation Protocols on Electrophysiological Recordings).
Regarding claim 2, Ahmed, in view of Bunday and Perez, teaches the system according to claim 1 as stated above wherein each post-synaptic electrode of the plurality of post-synaptic electrodes is configured for electrical communication with a respective peripheral nerve of the plurality of peripheral nerves of the body and the waveform generator (Ahmed, Col. 8, lines 50-60; Col. 17, lines 7-17; Fig. 2a, distal nerves 114 and stimulator 103).
Regarding claim 3, Ahmed, in view of Bunday and Perez, teaches the system according to claim 1 as stated above wherein the predetermined range of the interstimulus interval is preferably between 1 millisecond and 2 milliseconds (Bunday and Perez, page 2, Paired-Pulse Stimulation Protocols, “the ISI between paired pulses allowed descending volleys to arrive at the presynaptic terminal of corticospinal neurons 1–2 ms before antidromic volleys in motoneurons reached the dendrites”).
Regarding claim 4, Ahmed, in view of Bunday and Perez, teaches the system according to claim 1 as stated above further comprising:
a transcranial magnetic stimulation (TMS) device in association with the processor (Ahmed, Fig. 1, stimulator 101, and coil 140), wherein the TMS device is operable to apply the pre- synaptic stimulus to the motor cortex pathway (Ahmed, Col. 8, lines 1-3; Col. 6, lines 44-50; Col. 12, lines 45-47).
Regarding claim 5, Ahmed, in view of Bunday and Perez, teaches the system according to claim 4 as stated above. Ahmed further teaches wherein the memory includes instructions, which, when executed, further cause the processor to: provide a control input to the TMS device (Ahmed, Col. 6, lines 51-61; Col. 10, 35-43; Fig. 1).
Ahmed fails to specifically teach wherein the control input causes the resultant pre- synaptic stimulus to arrive at the synapse at the pre-synaptic time of arrival.
Bunday and Perez teach an analogous paired associative stimulation protocol wherein the resultant pre- synaptic stimulus arrives at the synapse at the pre-synaptic time of arrival (Bunday and Perez, page 9, Fig. 1(A), TMS volley is 1st, red arrow).
Therefore, it would have been obvious to someone of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the system of Ahmed to include the reversed pre-synaptic and post-synaptic arrival times of the pre-synaptic and post-synaptic stimuli of Bunday and Perez. Precisely timing the arrival of the presynaptic action potentials prior to the postsynaptic depolarizing action potentials may enhance voluntary motor output in humans with chronic incomplete SCI and increase the size of motor evoked potentials (MEPs) in resting muscles (Bunday and Perez, page 1, Results; page 2, Effects of Paired-Pulse Simulation Protocols on Electrophysiological Recordings).
Regarding claim 6, Ahmed, in view of Bunday and Perez, teaches the system according to claim 1 as stated above wherein the system generates the pre-synaptic stimulus within the spinal cord of the body by stimulating the corticospinal pathway by application of a magnetic field parallel to a skull of the body (Ahmed, Col. 8, lines 1-8; Col. 2, lines 47-60; Fig. 2a depicts the coil 140 parallel to the skull stimulating the corticospinal pathway that runs from the motor cortex 111 does the spinal cord 112),
wherein the applied magnetic field is configured to induce an action potential within the corticospinal neuron that terminates in a pre-synaptic cell of the corticospinal- motoneuronal neuronal pair of the body (Ahmed, Col. 3, lines 22-33, the “spinal junction” is being construed as the corticospinal-motoneuronal neural pair).
Regarding claim 7, Ahmed, in view of Bunday and Perez, teaches the system according to claim 1 as stated above further comprising:
a pre-synaptic electrode in association with the waveform generator, wherein the pre-synaptic electrode is configured to apply the pre- synaptic stimulus to a descending motor pathway (Ahmed, Col. 2, lines 47-60; Col. 6, lines 44-46).
Regarding claim 8, Ahmed, in view of Bunday and Perez, teaches the system according to claim 7 as stated above. Ahmed further teaches wherein the memory includes instructions, which, when executed, further cause the processor to: provide a control input to the waveform generator (Ahmed, Fig. 1, trigger signal 127; Col. 6, lines 51-61; Col. 10, 35-43).
Ahmed fails to specifically teach wherein the waveform generator causes the resultant pre-synaptic stimulus to arrive at the synapse at the pre-synaptic time of arrival.
Bunday and Perez teach an analogous paired associative stimulation protocol wherein the resultant pre-synaptic stimulus arrives at the synapse at the pre-synaptic time of arrival (Bunday and Perez, page 11, Figure 2, TMS and/or Transcranial electrical stimulation (TES) were delivered to the motor cortex and preceded peripheral nerve stimulation; Fig. 1(A), first volley, red arrow).
Therefore, it would have been obvious to someone of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the system of Ahmed to include the reversed pre-synaptic and post-synaptic arrival times of the pre-synaptic and post-synaptic stimuli of Bunday and Perez. Precisely timing the arrival of the presynaptic action potentials prior to the postsynaptic depolarizing action potentials may enhance voluntary motor output in humans with chronic incomplete SCI and increase the size of motor evoked potentials (MEPs) in resting muscles (Bunday and Perez, page 1, Results; page 2, Effects of Paired-Pulse Simulation Protocols on Electrophysiological Recordings).
Regarding claim 9, Ahmed, in view of Bunday and Perez, teaches the system according to claim 1 as stated above wherein the system generates the pre-synaptic stimulus within a corticospinal neuron of the motor cortex pathway of the body by application of the pre-synaptic stimulus to a thoracic spine of the body to stimulate a descending motor pathway that terminates in a pre-synaptic cell of the corticospinal-motoneuronal neuronal pair of the body (Ahmed, Col. 2, lines 47-60; col. 12, lines 21-31).
Regarding claim 11, Ahmed, in view of Bunday and Perez, teaches the system according to claim 1 as stated above. Ahmed further teaches wherein the memory includes instructions, which, when executed, further cause the processor to: provide a plurality of control inputs to the waveform generator (Fig. 1, stimulator 103; Col. 10, lines 35-38; Fig. 2b, P1 and P2).
Ahmed fails to specifically teach wherein the waveform generator cause each resultant post-synaptic stimulus of the plurality of post- synaptic stimuli to arrive at the synapse at their respective post- synaptic times of arrival.
Bunday and Perez teach an analogous paired associative stimulation protocol wherein each resultant post-synaptic stimulus of the plurality of post- synaptic stimuli arrive at the synapse at their respective post- synaptic times of arrival (Bunday and Perez, page 9, Fig. 1(A), antidromic PNS volley is 2nd, black arrow).
Therefore, it would have been obvious to someone of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the system of Ahmed to include the reversed pre-synaptic and post-synaptic arrival times of the pre-synaptic and post-synaptic stimuli of Bunday and Perez. Precisely timing the arrival of the presynaptic action potentials prior to the postsynaptic depolarizing action potentials may enhance voluntary motor output in humans with chronic incomplete SCI and increase the size of motor evoked potentials (MEPs) in resting muscles (Bunday and Perez, page 1, Results; page 2, Effects of Paired-Pulse Simulation Protocols on Electrophysiological Recordings).
Regarding claim 12, Ahmed, in view of Bunday and Perez, teaches the system according to claim 11 as stated above. Ahmed further teaches wherein the memory further includes instructions, which, when executed, further cause the processor to:
provide a control input to the waveform generator (Fig. 1, stimulator 103; Col. 10, lines 35-38) that adjusts a post- synaptic pulse initiation time of the post-synaptic stimulus of the plurality of post-synaptic stimuli based on a length of an associated peripheral nerve of the plurality of peripheral nerves (Ahmed, Table 1, peripheral delay and F-wave delay based on stimulated site; Col. 13, lines 18-51).
Ahmed fails to teach wherein the interstimulus interval is within the predetermined range.
Bunday and Perez teach an analogous paired associative stimulation protocol wherein the interstimulus interval is within the predetermined range (Bunday and Perez, page 2, Paired-Pulse Stimulation Protocols, “the ISI between paired pulses allowed descending volleys to arrive at the presynaptic terminal of corticospinal neurons 1–2 ms before antidromic volleys in motoneurons reached the dendrites”).
Therefore, it would have been obvious to someone of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the system of Ahmed with the predetermined interstimulus interval of Bunday and Perez. Incorporating a predetermined interstimulus interval allows descending (TMS) volleys to arrive at the presynaptic terminal of the corticospinal neurons before the antidromic PNS volleys reach the dendrites (Bunday and Perez, page 9, Figure 1, “The interstimulus interval between paired pulses was designed to allow descending volleys, elicited by TMS, to arrive at the presynaptic terminal of corticospinal neurons (1st, red arrow) 1–2 ms before antidromic PNS volleys in the motoneurons reached the dendrites (2nd, black arrow)”).
Regarding claim 13, Ahmed, in view of Bunday and Perez, teaches the system according to claim 1 as stated above wherein the system generates a post-synaptic stimulus of the plurality of post-synaptic stimuli within a respective peripheral nerve of the plurality of peripheral nerves of the body by application of an electrical waveform to a peripheral limb of the body to stimulate the peripheral nerve that terminates in a post-synaptic cell of the corticospinal-motoneuronal pair of the body (Ahmed, Fig. 2a, peripheral stimulator 103 and distal nerves 114; Col. 6, lines 11-21; Col. 11, lines 53-55).
Regarding claim 14, Ahmed, in view of Bunday and Perez, teaches the system according to claim 1 as stated above wherein the system applies the post-synaptic stimuli such that the pre-synaptic stimulus from the motor cortex pathway arrives at the synapse 1-2 ms before each post-synaptic stimulus of the plurality of post- synaptic stimuli from the plurality of peripheral nerves (Bunday and Perez, page 9, Figure 1, “corticospinal neurons were activated at a cortical level by using transcranial magnetic stimulation (TMS volley) delivered over the motor cortex and spinal motoneurons were activated antidromically by peripheral nerve stimulation (PNS volley) delivered to the ulnar nerve at the wrist. The interstimulus interval between paired pulses was designed to allow descending volleys, elicited by TMS, to arrive at the presynaptic terminal of corticospinal neurons (1st, red arrow) 1–2 ms before antidromic PNS volleys in the motoneurons reached the dendrites (2nd, black arrow)”).
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ahmed in view of Bunday and Perez, further in view of Shulga et al. ("The use of F-response in defining interstimulus intervals appropriate for LTP-like plasticity induction in lower limb spinal paired associative stimulation"), hereinafter referred to as "Shulga et al."
Regarding claim 16, Ahmed, in view of Bunday and Perez, teaches the system according to claim 1 as stated above. Ahmed, in view of Bunday and Perez, further teaches wherein the memory includes instructions, which when executed, further cause the processor to: select a post-synaptic pulse initiation time of the post-synaptic stimulus such that the interstimulus interval between the pre-synaptic time of arrival and the post-synaptic time of arrival at a synapse is within the predetermined range interval (Bunday and Perez, page 3, para. 2, “using electrophysiological measurements by stimulating different levels of the corticospinal pathway in individual subjects, we could generate accurate estimates of the time of arrival of action potentials to the muscle”; page 2, entirety of Paired-Pulse Stimulation Protocols).
Ahmed, in view of Bunday and Perez, fails to specifically disclose wherein the memory includes instructions, which, when executed, further cause the processor to: measure a plurality of latency values associated with a plurality of targeted peripheral nerves and the motor pathway; determine a peripheral conduction time (PCT) and a central conduction time (CCT) based on the plurality of latency values.
Shulga et al. discloses an analogous paired associative stimulation system further comprising protocol steps that:
measure a plurality of latency values associated with a plurality of targeted peripheral nerves and the motor pathway (Table 1);
determine a peripheral conduction time (PCT) and a central conduction time (CCT) based on the plurality of latency values (Fig. 1b; page 114, para. 2.2.2., “The conduction times for lower motor neurons (ICT) and upper motor neurons (uCT) were calculated based on the basis of F-, M- and MEP latencies”).
Therefore, it would have been obvious to someone of ordinary skill in the art, before the effective filing date of the claimed invention, to have combined the system of Ahmed, in view of Bunday and Perez, with the measured latency values and determined peripheral and central conduction times of Shulga et al. Upper and lower motor neuron conduction times derived from measured latencies are useful in estimating and adjusting interstimulus intervals (ISIs), ISIs determine whether plasticity is induced at the motor cortex or the spinal cord (Shulga et al., page 113, para. Introduction; page 114, para. 2.2.2.).
Claim(s) 17, 20-21, and 25-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ahmed, in view of Shulga et al., further in view of Bunday and Perez.
Regarding claim 17, Ahmed teaches a method of treating a subject (Abstract), the method comprising:
(a) identifying two or more peripheral nerves innervating at least two different muscle sites in the subject and forming two or more peripheral nerve-muscle pairings (Col. 8, lines 50-60);
(b) identifying two or more corticospinal-motoneuronal connections each comprising a corticospinal neuron connected at a synapse with each peripheral nerve in each of the peripheral nerve-muscle pairings (Col. 8, lines 37-49);
Ahmed fails to disclose wherein the method comprises: (c) calculating a peripheral conduction time (PCT) and a central conduction time (CCT) for the each of the peripheral nerve-muscle pairings; (d) periodically applying a first stimulus to a location in the central nervous system (CNS) in the subject such that the first stimulus triggers a descending signal in at least one corticospinal neuron in the corticospinal-motoneuron connections; and (e) periodically applying a second stimulus to each of the two or more peripheral nerves such that the second stimulus triggers an ascending signal in the each of the two or more peripheral nerves, wherein, each ascending signal and each descending signal arrive at the synapse of each corticospinal-motoneuronal connections and the descending signal arrives at a pre-determined interstimulus interval (ISI) prior to the arrival of the ascending signal.
Shulga et al. discloses an analogous paired associative stimulation method further comprising: c) calculating a peripheral conduction time (PCT) and a central conduction time (CCT) for the each of the peripheral nerve-muscle pairings (Fig. 1b; page 114, para. 2.2.2., “The conduction times for lower motor neurons (ICT) and upper motor neurons (uCT) were calculated based on the basis of F-, M- and MEP latencies”).
Therefore, it would have been obvious to someone of ordinary skill in the art, before the effective filing date of the claimed invention, to have combined the method of Ahmed with the calculation of PCT and CCT of Shulga et al. Upper and lower motor neuron conduction times are useful in estimating and adjusting interstimulus intervals (ISIs), ISIs determine whether plasticity is induced at the motor cortex or the spinal cord (Shulga et al., page 113, Introduction; page 114, para. 2.2.2.).
While the combination of Ahmed and Shulga et al. discloses calculating the PCT and CCT for each of the peripheral nerve-muscle pairings, Ahmed and Shulga et al. fail to disclose wherein the method comprises: (d) periodically applying a first stimulus to a location in the central nervous system (CNS) in the subject such that the first stimulus triggers a descending signal in at least one corticospinal neuron in the corticospinal-motoneuron connections; and (e) periodically applying a second stimulus to each of the two or more peripheral nerves such that the second stimulus triggers an ascending signal in the each of the two or more peripheral nerves, wherein, each ascending signal and each descending signal arrive at the synapse of each corticospinal-motoneuronal connections and the descending signal arrives at a pre-determined interstimulus interval (ISI) prior to the arrival of the ascending signal.
Bunday and Perez teach an analogous paired associative stimulation protocol comprising: (d) periodically applying a first stimulus to a location in the central nervous system (CNS) in the subject such that the first stimulus triggers a descending signal in at least one corticospinal neuron in the corticospinal-motoneuron connections (Fig. 1(A); page 9, Figure 1, “paired pulses was designed to allow descending volleys, elicited by TMS, to arrive at the presynaptic terminal of corticospinal neurons (1st, red arrow)”; page 2, Paired-Pulse Stimulation Protocols, “100 pairs of TMS and PNS pulses”); and
(e) periodically applying a second stimulus to each of the two or more peripheral nerves such that the second stimulus triggers an ascending signal in the each of the two or more peripheral nerves (Fig. 1(a), page 9, Figure 1, “antidromic PNS volleys in the motoneurons reached the dendrites (2nd, black arrow)”),
wherein, each ascending signal and each descending signal arrive at the synapse of each corticospinal-motoneuronal connections and the descending signal arrives at a pre-determined interstimulus interval (ISI) prior to the arrival of the ascending signal (page 2, Paired-Pulse Stimulation Protocols, “the ISI between paired pulses allowed descending volleys to arrive at the presynaptic terminal of corticospinal neurons 1–2 ms before antidromic volleys in motoneurons reached the dendrites”).
Therefore, it would have been obvious to someone of ordinary skill in the art, before the effective filing date of the claimed invention, to have combined the method of Ahmed and Shulga et al. with the triggered descending signal of the first stimulus and ascending signal of the second stimulus of Bunday and Perez. Precisely timing the arrival of the presynaptic action potentials prior to the postsynaptic depolarizing action potentials may enhance voluntary motor output in humans with chronic incomplete SCI and increase the size of motor evoked potentials (MEPs) in resting muscles (Bunday and Perez, page 1, Results; page 2, Effects of Paired-Pulse Simulation Protocols on Electrophysiological Recordings).
Regarding claim 20, Ahmed, in view Shulga et al., further in view of Bunday and Perez, teaches the method according to claim 17 as stated above wherein the peripheral conduction time (PCT) for each peripheral nerve-muscle pairing is calculated using the following equation: PCT = (F-wave latency - M-max latency) x 0.5 (Shulga et al., page 114, Fig. 1(b), where the lower motoneuron conduction time (ICT) is analogous to “PCT”).
Regarding claim 21, Ahmed, in view Shulga et al., further in view of Bunday and Perez, teaches the method according to claim 17 as stated above wherein the central conduction time (CCT) for each peripheral nerve-muscle pairing is calculated using the following equation: CCT = MEP latency - (PCT + M-max latency) (Shulga et al., page 114, Fig. 1(b), where the upper motoneuron conduction time (uCT) is analogous to “CCT”).
Regarding claim 25, Ahmed, in view Shulga et al., further in view of Bunday and Perez, teaches the method according to claim 17 as stated above wherein the interstimulus interval (ISI) is about 0-5 milliseconds (Bunday and Perez, page 9, Figure 1, “The interstimulus interval between paired pulses was designed to allow descending volleys, elicited by TMS, to arrive at the presynaptic terminal of corticospinal neurons (1st, red arrow) 1–2 ms before antidromic PNS volleys in the motoneurons reached the dendrites (2nd, black arrow)”).
Regarding claim 26, Ahmed, in view Shulga et al., further in view of Bunday and Perez, teaches the method according to claim 25 as stated above wherein the ISI is about 1-2 milliseconds (Bunday and Perez, page 9, Figure 1, “The interstimulus interval between paired pulses was designed to allow descending volleys, elicited by TMS, to arrive at the presynaptic terminal of corticospinal neurons (1st, red arrow) 1–2 ms before antidromic PNS volleys in the motoneurons reached the dendrites (2nd, black arrow)”).
Claim(s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ahmed in view of the combination of Shulga et al. and Bunday and Perez, further in view of Stefan et al. (“Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation"), hereinafter referred to as "Stefan et al."
Regarding claim 27, Ahmed, in view of Shulga et al., further in view of Bunday and Perez, teaches the method according to claim 17 as stated above.
Bunday and Perez further teach wherein paired sets of the first and second stimuli are applied at a frequency of about 0.1 Hz (page 9, Figure 1, “100 pairs of TMS and PNS pulses were applied at 0.1 Hz for ~17 min”). However, Ahmed, in view of Shulga et al., further in view of Bunday and Perez, does not disclose wherein the paired sets are applied for about 30 minutes.
Stefan et al. discloses an analogous paired associative stimulation method wherein paired sets of first and second stimuli are applied for about 30 minutes (page 700, Experimental Procedures, “Ninety pairs were delivered at 0.05 Hz over 30 min”).
Therefore, it would have been obvious to someone of ordinary skill in the art, before the effective filing date of the claimed invention, to have combined the method of Ahmed, in view of Shulga et al., further in view of Bunday and Perez, with sets of stimuli applied for about 30 minutes of Stefan et al. A rapidly evolving protocol, designated by a stimulation duration of 30 minutes or less, may induced plasticity in the human motor cortex (page 699, Col. 2, “We have recently developed a protocol, shaped after models of associative LTP in experimental animals, to induce plasticity in the human motor cortex (Stefan et al. 2000). A rapidly evolving (< 30 min)”; page 705, Discussion).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Taylor and Martin (2009) disclose a paired associative stimulation protocol designed to produce STDP at the corticospinal-motoneuronal synapse to ultimately induced intensifications and reductions in corticospinal transmissions. Boveja et al. (US 2005/0154426) discloses a system that applies a repetitive transcranial magnetic stimulation to the brain via a TMS coil and a pulsed electrical stimulation to the vagus nerves via an implanted pulse generator and/or stimulus-receiver. Palazzolo et al. (US 2016/0058613) discloses a system that produces either a magnetic field near an individual’s skull or an electrical stimulation near a subject’s wrist in order to reduce the likelihood of shivering.
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/B.R.L./Examiner, Art Unit 3791
/CHRISTINE H MATTHEWS/Primary Examiner, Art Unit 3791