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 .
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 reads “between a anterior cingulate cortex” it should read “between an anterior cingulate cortex”.
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.
Claim 1 is 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. It is unclear what is meant by the phrase “functional connectivity” and it is not described in the applicant’s specification. Please provide a description or definition of the term.
Claim 11 is 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. It is unclear how the neuronavigator “generates” the target and is not described in the applicant’s specification. It is suggested the claim be amended to “the neuronavigator identifies the target”.
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.
Claims 11 - 12 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Pascual – Leone (US 2015/0119689).
Regarding claim 11, A hypnotherapy system, comprising:
a brain scanner configured to obtain a scan of a recipient's brain (paragraph [0007] “the method for selecting TMS target sites may be based on identification of functional connectivity between different regions of the brain using functional connectivity magnetic resonance imaging (fMRI).” The examiner is noting the fMRI as the brain scanner.);
a neuronavigator configured to generate at least one stimulation target based on the scan (paragraph [0087] “neuronavigation equipment may be used to apply TMS to the identified target site. Neuronavigation equipment may comprise a frameless stereotactic system, such as, for example, Brainsight.TM., which may allow targeting a specific coordinate in the patient's brain.”);
a brain stimulation device configured to deliver a neurostimulation to the at least one stimulation target (Figure 3, element 312, shows a TMS device. The examiner is interpreting the TMS device as the brain stimulation device. Paragraph [0081] “Any suitable TMS device may be used to administer TMS to the brain of the patient to induce a desired current density to the identified target site, as embodiments are not limited in this respect. For example, the TMS device may comprise a NeuroStar TMS Therapy System from Neuronetics, Inc.“ paragraph [0006] “One or more target stimulation sites may be identified in regions of the brain that may be suitable for TMS application”),
where the stimulation pattern increases hypnotizability (paragraph [0267] “but this connectivity-based targeting paradigm has the potential to improve therapeutic stimulation across a range of diseases with distributed network pathology” The examiner is interpreting “improve therapeutic stimulation” as hypnotizability.)
by increasing functional connectivity between an anterior cingulate cortex (ACC) and a dorsolateral prefrontal cortex (DLPFC) of the recipient's brain, and decreasing activity in the ACC (paragraph [0043] “Existing TMS-based techniques are used to induce stimulating electrical current in the underlying cortical surface, …. The left DLPFC, which has been shown to be functionally connected with the subgenual cingulate, is more accessible for application of TMS. Accordingly, TMS may be used to induce an antidepressant effect on the subgenual cingulate cortex by stimulating specific areas in the DLPFC.” And paragraph [0004] “The subgenual cingulate region has been shown to decrease its activity in response to multiple treatment modalities and has been used as a target of deep brain stimulation” The subgenual cingulate is a region of the anterior cingulate cortex. Since stimulating the DLPFC induces an effect on the subgenual cingulate cortex, the examiner is interpreting that as “increasing functional connectivity”.)
where the recipient is subsequently provided hypnotherapy in order to treat a condition (this is an intended use limitation which does not structurally limit the system claim).
Regarding claim 12, Pascual-Leone teaches the system of claim 11, wherein the condition is selected from the group consisting of: depression, anxiety, phobia, pain, stress, disordered eating, sleep disorders, posttraumatic stress, and addiction (paragraph [0002] “Applications for rTMS include, but are not limited to, psychiatric disorders, such as depression, hallucinations, obsessions, and drug craving, and different neurologic diseases.”).
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.
Claims 1, 6, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Pascual-Leone (US 2015/0119689) and Stubbeman (US 2014/0058189), herein referred to as Stubbeman (2014).
Regarding claim 1, A method of treating a recipient using hypnotherapy, comprising:
applying neurostimulation to a recipient's brain such that functional connectivity between a anterior cingulate cortex (ACC) and a dorsolateral prefrontal cortex (DLPFC) of the recipient's brain is increased, and activity in the ACC is decreased (paragraph [006] “One or more target stimulation sites may be identified in regions of the brain that may be suitable for TMS application….stimulation sites may be identified in the left dorsolateral prefrontal cortex (DLPFC) to remotely modulate the activity in a subgenual cingulate region.” And paragraph [0004] “The subgenual cingulate region has been shown to decrease its activity in response to multiple treatment modalities and has been used as a target of deep brain stimulation” The examiner is interpreting TMS (transcranial magnetic stimulation) as neurostimulation and the cingulate region as the anterior cingulate cortex. )
However, Pascual Leone does not teach applying hypnotherapy in order to treat a condition of the recipient.
Stubbeman (2014) teaches a TMS system and method with a sensory stimuli device that could provide sensory stimulation to the patient before, during or after brain stimulation (paragraph [0063] “Sensory stimuli may include trauma-related virtual-reality stimulation to treat PTSD… guided imagery; guided meditation to enhance psychological skills”. The examiner is interpreting the sensory stimuli (VR, guided imagery, and guided meditation) as hypnotherapy.)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the TMS system taught in Pascual-Leone to incorporate the hypnotherapy taught in Stubbeman. One of ordinary skill in the art would have been able to recognize this is a known technique in the art of applying hypnotherapy after TMS treatment to improve similar devices and methods as the claimed invention.
Regarding claims 2 and 12, Pascual-Leon teaches the method of claim 1 and claim 11 , but fails to teach wherein the condition is selected from the group consisting of: depression, anxiety, phobia, pain, stress, disordered eating, sleep disorders, posttraumatic stress, and addiction.
However, Stubbeman (2014) teaches wherein the condition is selected from the group consisting of: depression, anxiety, phobia, pain, stress, disordered eating, sleep disorders, posttraumatic stress, and addiction. (Figure 4A and 4B lists anxiety, addiction, phobia, PTSD, and chronic pain. Paragraph [0129] “Patients with severe depression may also be successfully treated according to the disclosed exemplary embodiments”
Regarding claims 6 and 16, Pascual-Leon teaches the method of claim 1, and multiple pulse stimulation (rTMS) to DLPFC (paragraph [0153] “Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is showing utility in the treatment of a variety of neurological and psychiatric disorders ….. Its most common use and only FDA approved therapeutic indication is excitatory stimulation to the left dorsal-lateral prefrontal cortex (DLPFC) for the treatment of medication-resistant depression) but fails to teach wherein the neurostimulation is quadrapulse transcranial magnetic stimulation to the DLPFC.
However, Stubbeman (2014) teaches wherein the neurostimulation is quadrapulse transcranial magnetic stimulation to the DLPFC. (paragraph [0151] “Quadripulse burst protocols have been successfully tested that contain four high frequency pulses in a cluster rather than three….Burst protocols may have an arbitrary number of high-frequency pulses in each cluster ranging from 2-100 pulses per cluster or more”, paragraph [0031] “One or more exemplary embodiments of the disclosed subject matter may further be understood to comprise direct or indirect TMS of the cingulate cortex ("CC")…. And in some cases preceded or followed by electromagnetic brain stimulation to the same brain area with different parameters or to another brain area. The paired sensory stimuli may include….TMS of the left dorsolateral prefrontal cortex ("LDLPFC")”).
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the treatment in Pascual-Leon to be an rTMS quadripulse treatment as in Stubbeman. One of ordinary skill in the art would have been able to recognize this is a known technique in the art for improving similar brain stimulation devices for treating depression as the claimed invention.
Regarding claims 7 and 17, Pascual-Leon fails to teach wherein the neurostimulation is quadrapulse transcranial magnetic stimulation to the ACC.
However, Stubbeman (2014) teaches wherein the neurostimulation is quadrapulse transcranial magnetic stimulation to the ACC . (paragraph [0151] “Quadripulse burst protocols have been successfully tested that contain four high frequency pulses in a cluster rather than three….Burst protocols may have an arbitrary number of high-frequency pulses in each cluster ranging from 2-100 pulses per cluster or more”, paragraph [0031] “One or more exemplary embodiments of the disclosed subject matter may further be understood to comprise direct or indirect TMS of the cingulate cortex ("CC")…. And in some cases preceded or followed by electromagnetic brain stimulation to the same brain area with different parameters or to another brain area. The paired sensory stimuli may include….TMS of the left dorsolateral prefrontal cortex ("LDLPFC")”).
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the treatment in Pascual-Leon to apply the treatment directly to the ACC instead of the DLPFC as taught in Stubbeman. One of ordinary skill in the art would have been able to recognize this is a known technique in the art for improving similar brain stimulation devices for treating depression as the claimed invention.
Claims 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Pascual – Leone, Stubbeman (2014) and further in view of Stubbeman (US 2016/0008620), herein referred to as Stubbeman (2016).
Regarding claim 3, Pascual-Leon teach the method of claim 1, but fail to teach wherein the neurostimulation is repetitive paired associative stimulation with the DLPFC and the ACC.
Stubbeman (2014) teaches stimulation of the ACC preceded or followed by stimulation to another brain area. (paragraph [0031] “One or more exemplary embodiments of the disclosed subject matter may further be understood to comprise direct or indirect TMS of the cingulate cortex ("CC") or area of the brain with strong connections to the CC while paired with one or more specific sensory stimuli and in some cases preceded or followed by electromagnetic brain stimulation to the same brain area with different parameters or to another brain area.“ The examiner is interpreting the cingulate cortex as the ACC.)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the device taught in Pascual-Leone to stimulate both the cingulate cortex and another area of the brain as taught in Stubbeman (2016). One of ordinary skill in the art would have been able to recognize TMS releases dopamine, dopamine mediates neuroplasticity, neuroplasticity is critically involved in the pathology of depression, depression is connected to activation changes in CC, and the CC is linked via frontocingulate neural circuits to the LDLPFC. See paragraph [0081] of Stubbeman (2014).
However, Stubbeman (2016) teaches a brain TMS stimulation device wherein the neurostimulation is repetitive paired associative stimulation (paragraph [0244] “The neurological stimulation device may comprise a transcranial magnetic stimulation (TMS) device configured to non-invasively stimulate the human subject’s brain by repetitively emitting the electronic pulses in the form of a transient electromagnetic field generated from one or more energized coils. The neurological stimulation device may also be selected from the group of: …. a paired associative stimulation device, or a combination of the aforementioned devices.” The examiner is interpreting that since the system and method apply a repetitive stimulation and can be a paired associative stimulation device then the neurostimulation applied is a repetitive paired associative stimulation.) with the DLPFC and the ACC (paragraph [0244] “The electromagnetic pulses may be applied to the left dorsolateral prefrontal cortex, right dorsolateral prefrontal cortex, or cingulate cortex of the human subject's brain” The examiner is interpreting the cingulate cortex as the ACC.)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the system taught in Pascual-Leone and Stubbeman (2014) to apply a repetitive paired associative stimulation as taught in Stubbeman (2016). One of ordinary skill in the art would have been able to recognize that this would be a simple substitution of the stimulation targets taught in Stubbeman (2014) for the stimulation targets in the device taught in Stubbeman (2016) (adding the repetitive paired associate stimulation device to a TMS system).
Regarding claim 4, Pascual – Leone teaches the method of claim 1, but fails to teach wherein the neurostimulation is sequential continuous theta burst stimulation (cTBS) to the DLPFC followed by sequential cTBS to the ACC.
Stubbeman (2014) teaches stimulation of the ACC preceded or followed by stimulation to another brain area. (paragraph [0031] “One or more exemplary embodiments of the disclosed subject matter may further be understood to comprise direct or indirect TMS of the cingulate cortex ("CC") or area of the brain with strong connections to the CC while paired with one or more specific sensory stimuli and in some cases preceded or followed by electromagnetic brain stimulation to the same brain area with different parameters or to another brain area.“ The examiner is interpreting the cingulate cortex as the ACC.)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the device taught in Pascual-Leone to stimulate both the cingulate cortex and another area of the brain as taught in Stubbeman (2016). One of ordinary skill in the art would have been able to recognize TMS releases dopamine, dopamine mediates neuroplasticity, neuroplasticity is critically involved in the pathology of depression, depression is connected to activation changes in CC, and the CC is linked via frontocingulate neural circuits to the LDLPFC. See paragraph [0081] of Stubbeman (2014).
However, Stubbeman (2016) teaches wherein the neurostimulation is sequential continuous theta burst stimulation (cTBS) (paragraph [0141] “FIG. 10D shows a pulse sequence 1045 involving a continuous train of pulses (cTBS), with a series of bursts”) to the DLPFC followed by sequential cTBS to the ACC (paragraph [0244] “The electromagnetic pulses may be applied to the left dorsolateral prefrontal cortex, right dorsolateral prefrontal cortex, or cingulate cortex of the human subject's brain”).
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the system taught in Pascual-Leone and Stubbeman (2014) to apply a cTBS pulse as taught in Stubbeman (2016). One of ordinary skill in the art would have been able to recognize that several studies of human motor-evoked potential have indicated that TBS yields longer lasting post-stimulation effects on cortical activity than conventional TMS. These post-stimulation effects which outlast the stimulation interval are frequently referred to as long-term potentiation and long-term depression. Researchers have also found that long-term potentiation and long-term depression are not limited to motor cortex but occur in multiple brain regions. See paragraph [0024] of Stubbeman (2016).
Regarding claim 5, Pascual – Leone and Stubbeman (2014) teach the method of claim 1, Pascual-Leon teaches TMS to DLPFC (paragraph [006] “One or more target stimulation sites may be identified in regions of the brain that may be suitable for TMS application….stimulation sites may be identified in the left dorsolateral prefrontal cortex (DLPFC)) but fails to teach wherein the neurostimulation is repetitive paired associative stimulation with transcranial magnetic stimulation to the DLPFC and Vagus nerve stimulation to the ACC.
Stubbeman (2016) teaches wherein the neurostimulation is repetitive paired associative stimulation with transcranial magnetic stimulation (paragraph [0226] “The neurological stimulation device may comprise a device selected from the group of: a vagus nerve stimulation device….a multi-coil transcranial magnetic stimulation device, a paired associative stimulation device, or a combination of the aforementioned devices.”) to the DLPFC and Vagus nerve stimulation to the ACC (paragraph [0244] “The electromagnetic pulses may be applied to the left dorsolateral prefrontal cortex, right dorsolateral prefrontal cortex, or cingulate cortex of the human subject's brain.” The examiner notes that this combination would allow for vagus nerve stimulation which would stimulate the ACC.).
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the method taught by Pascual-Leone and Stubbeman (2014) to be repetitive paired associative stimulation with TMS to the DLPFC and vagus nerve stimulation to the ACC as taught in Stubbeman (2016). One of ordinary skill in the art would have been able to recognize this is a combination of prior art elements according to known methods to yield predictable results of using a paired associative stimulation device to stimulate the vagus nerve.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Pascual – Leone and Stubbeman (2014) and further in view of Mishelevich (US 2017/0246481).
Regarding claims 8 and 9, Pascual-Leone and Stubbeman (2014) teach the method of claim 1, but fail to teach wherein the neurostimulation comprises inhibitory low intensity focused ultrasound to the ACC (of claim 8) and to the DLPFC (of claim 9).
However, Mishelevich teaches a system for neuromodulation wherein the neurostimulation comprises inhibitory (paragraph [0014] “Low frequencies (defined as typically below 400 Hz) are inhibitory.” and paragraph [0160] “The range of either of the two frequencies will be between approximately 10 Hz to 400 Hz for down regulation“) low intensity focused ultrasound to the ACC (of claim 8) and to the DLPFC (of claim 9). (pages 57 - 58, table 11, lists the Anterior Cingulate Cortex and the dorsal prefrontal cortex as target options. And paragraph [0496] “The power applied will determine whether the ultrasound is high intensity or low intensity (or medium intensity)” paragraph [0022] “It would be preferable to not only stimulate single or multiple targets synchronously,” The examiner would like to note that a low intensity ultrasound is an option that can be used in this prior art. Further, the art notes that it would be preferable to stimulate multiple targets in the brain so the examiner interprets that the art is capable of applying inhibitory low intensity focused ultrasound to the ACC and DLPFC.).
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the method taught in Pascual-Leon and Stubbeman (2014) to use low intensity ultrasound to the target sites taught in Mishelevich. One of ordinary skill in the art would have been able to recognize with respect to non-invasive neuromodulation, ultrasound neuromodulation has the benefit over Transcranial Magnetic Stimulation in that the equipment for performing the neuromodulation costs less and is smaller, could be used at home, work, school, and could be shared over time for tune-ups. Because it is noninvasive and relatively low cost, ultrasound neuromodulation appears to be the modality capable of reaching the deep brain that could potentially be cleared by the FDA or other organizations for over-the-counter purchase. See paragraph [0034] of Mishelevich.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Pascual – Leone and Stubbeman (2014) further in view of Mishelevich and Williams (US 2019/0217116).
Regarding claim 10, Pascual-Leone, Stubbeman, and Mishelevich teach the method of claim 8, and Mishelevich further teaches wherein the inhibitory low intensity ultrasound comprises
Ultrasound bursts delivered in 10-millisecond bursts repeated every 200 milliseconds (paragraph [0159] “Thus each of the on and off interval times may be selected from 1 (or a fraction thereof), 2, 3, 4, 5 seconds ranging up to 500 seconds and not necessarily integer time so 0.06, 1.05, 2.3, 5.0002 sec, etc. are permissible.” The examiner would like to note that the “on” times can be set to 10 ms and “off” times can be set to 200 ms which would deliver 10 ms burst repeated every 200 ms.) using:
a fundamental frequency between 300 and 700 kHz (paragraph [0073] “In some variations, the acoustic ultrasound frequency is in the range of 0.3 MHz to 0.8 MHz.”);
a pulse repetition frequency of 5Hz (paragraph [0279] “a repetition frequency of approximately 2 Hz or higher”)
and a duty cycle of between 1% and 5% (paragraph [0589] “The neuromodulation pulse duty cycle (the proportion of the inter-pulse interval that is with filled neuromodulation pulse) may be either fixed at different values or swept through a set of values ….The duty cycle is swept in the range of 1% to 100% of the inter-pulse interval with the controlling frequency sweeping occurring over approximately 1 Hz to approximately 20 kHz” The examiner is interpreting this is as the duty cycle can be set to values within the range of 1%-100%, therefore it can have a duty cycle of between 1% and 5%. Or this can be interpreted as the duty cycle can be varied between 1% and 100%, therefore can be varied between 1% and 5%.)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the method taught in Pascual – Leone to have the parameters taught in Mishelevich. One of ordinary skill in the art would have been able to recognize the parameters of claimed invention are the optimum or workable ranges discovered by routine experimentation. However, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Please see MPEP 2144.05.II.a, Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382, and In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
However, Mishelevich does not teach that between 600 – 1800 bursts were delivered.
Williams teaches a neuromodulation system where between 600 and 1800 bursts were delivered (paragraph [0068] “In numerous embodiments, aiTBS schedules involves applying iTBS pulses for multiple sessions per day, for several days. In a variety of embodiments, the iTBS pulse parameters involve 3-pulse, 50 Hz pulses at 5 Hz for 2 second trains, with trains every 10 seconds for 10 minute sessions (1,800 total pulses per session).” And paragraph [0070] “In a variety of embodiments, the cTBS pulse parameters involve 3-pulse trains with 50 Hz pulses at 5 Hz for 40 second sessions (600 total pulses per session).”)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the method taught in Pascual – Leone, Stubbeman (2014), and Mishelevish to have the parameters taught in Williams. One of ordinary skill in the art would have been able to recognize the parameters of claimed invention are the optimum or workable ranges discovered by routine experimentation. However, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Please see MPEP 2144.05.II.a, Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382, and In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claims 13 – 15 are rejected under 35 U.S.C. 103 as being unpatentable over Pascual – Leone, in view of Stubbeman (2014) and Stubbeman (2016).
Regarding claim 13, Pascual-Leon teaches the method of claim 11, but fails to teach wherein the neurostimulation is repetitive paired associative stimulation with the DLPFC and the ACC.
Stubbeman (2014) teaches stimulation of the ACC preceded or followed by stimulation to another brain area. (paragraph [0031] “One or more exemplary embodiments of the disclosed subject matter may further be understood to comprise direct or indirect TMS of the cingulate cortex ("CC") or area of the brain with strong connections to the CC while paired with one or more specific sensory stimuli and in some cases preceded or followed by electromagnetic brain stimulation to the same brain area with different parameters or to another brain area.“ The examiner is interpreting the cingulate cortex as the ACC.)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the device taught in Pascual-Leone to stimulate both the cingulate cortex and another area of the brain as taught in Stubbeman (2016). One of ordinary skill in the art would have been able to recognize TMS releases dopamine, dopamine mediates neuroplasticity, neuroplasticity is critically involved in the pathology of depression, depression is connected to activation changes in CC, and the CC is linked via frontocingulate neural circuits to the LDLPFC. See paragraph [0081] of Stubbeman (2014).
However, Stubbeman (2016) teaches a brain TMS stimulation device wherein the neurostimulation is repetitive paired associative stimulation (paragraph [0244] “The neurological stimulation device may comprise a transcranial magnetic stimulation (TMS) device configured to non-invasively stimulate the human subject’s brain by repetitively emitting the electronic pulses in the form of a transient electromagnetic field generated from one or more energized coils. The neurological stimulation device may also be selected from the group of: …. a paired associative stimulation device, or a combination of the aforementioned devices.” The examiner is interpreting that since the system and method apply a repetitive stimulation and can be a paired associative stimulation device then the neurostimulation applied is a repetitive paired associative stimulation.) with the DLPFC and the ACC (paragraph [0244] “The electromagnetic pulses may be applied to the left dorsolateral prefrontal cortex, right dorsolateral prefrontal cortex, or cingulate cortex of the human subject's brain” The examiner is interpreting the cingulate cortex as the ACC.)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the system taught in Pascual-Leone and Stubbeman (2014) to apply a repetitive paired associative stimulation as taught in Stubbeman (2016). One of ordinary skill in the art would have been able to recognize that this would be a simple substitution of the stimulation targets taught in Stubbeman (2014) for the stimulation targets in the device taught in Stubbeman (2016) (adding the repetitive paired associate stimulation device to a TMS system).
Regarding claim 14, Pascual – Leone teaches the method of claim 11, but fails to teach wherein the neurostimulation is sequential continuous theta burst stimulation (cTBS) to the DLPFC followed by sequential cTBS to the ACC.
Stubbeman (2014) teaches stimulation of the ACC preceded or followed by stimulation to another brain area. (paragraph [0031] “One or more exemplary embodiments of the disclosed subject matter may further be understood to comprise direct or indirect TMS of the cingulate cortex ("CC") or area of the brain with strong connections to the CC while paired with one or more specific sensory stimuli and in some cases preceded or followed by electromagnetic brain stimulation to the same brain area with different parameters or to another brain area.“ The examiner is interpreting the cingulate cortex as the ACC.)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the device taught in Pascual-Leone to stimulate both the cingulate cortex and another area of the brain as taught in Stubbeman (2016). One of ordinary skill in the art would have been able to recognize TMS releases dopamine, dopamine mediates neuroplasticity, neuroplasticity is critically involved in the pathology of depression, depression is connected to activation changes in CC, and the CC is linked via frontocingulate neural circuits to the LDLPFC. See paragraph [0081] of Stubbeman (2014).
However, Stubbeman (2016) teaches wherein the neurostimulation is sequential continuous theta burst stimulation (cTBS) (paragraph [0141] “FIG. 10D shows a pulse sequence 1045 involving a continuous train of pulses (cTBS), with a series of bursts”) to the DLPFC followed by sequential cTBS to the ACC (paragraph [0244] “The electromagnetic pulses may be applied to the left dorsolateral prefrontal cortex, right dorsolateral prefrontal cortex, or cingulate cortex of the human subject's brain”).
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the system taught in Pascual-Leone and Stubbeman (2014) to apply a cTBS pulse as taught in Stubbeman (2016). One of ordinary skill in the art would have been able to recognize that several studies of human motor-evoked potential have indicated that TBS yields longer lasting post-stimulation effects on cortical activity than conventional TMS. These post-stimulation effects which outlast the stimulation interval are frequently referred to as long-term potentiation and long-term depression. Researchers have also found that long-term potentiation and long-term depression are not limited to motor cortex but occur in multiple brain regions. See paragraph [0024] of Stubbeman (2016).
Regarding claim 15, Pascual – Leone and Stubbeman (2014) teach the method of claim 1, Pascual-Leon teaches TMS to DLPFC (paragraph [006] “One or more target stimulation sites may be identified in regions of the brain that may be suitable for TMS application….stimulation sites may be identified in the left dorsolateral prefrontal cortex (DLPFC)) but fails to teach wherein the neurostimulation is repetitive paired associative stimulation with transcranial magnetic stimulation to the DLPFC and Vagus nerve stimulation to the ACC.
Stubbeman (2016) teaches wherein the neurostimulation is repetitive paired associative stimulation with transcranial magnetic stimulation (paragraph [0226] “The neurological stimulation device may comprise a device selected from the group of: a vagus nerve stimulation device….a multi-coil transcranial magnetic stimulation device, a paired associative stimulation device, or a combination of the aforementioned devices.”) to the DLPFC and Vagus nerve stimulation to the ACC (paragraph [0244] “The electromagnetic pulses may be applied to the left dorsolateral prefrontal cortex, right dorsolateral prefrontal cortex, or cingulate cortex of the human subject's brain.” The examiner notes that this combination would allow for vagus nerve stimulation which would stimulate the ACC.).
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the method taught by Pascual-Leone and Stubbeman (2014) to be repetitive paired associative stimulation with TMS to the DLPFC and vagus nerve stimulation to the ACC as taught in Stubbeman (2016). One of ordinary skill in the art would have been able to recognize this is a combination of prior art elements according to known methods to yield predictable results of using a paired associative stimulation device to stimulate the vagus nerve.
Claims 18 – 19 are rejected under 35 U.S.C. 103 as being unpatentable over Pascual – Leone and Mishelevich.
Regarding claims 18 and 19, Pascual-Leone) teach the method of claim 11, but fails to teach wherein the neurostimulation comprises inhibitory low intensity focused ultrasound to the ACC (of claim 18) and to the DLPFC (of claim 19).
However, Mishelevich teaches a system for neuromodulation wherein the neurostimulation comprises inhibitory low intensity focused ultrasound to the ACC (of claim 8) and to the DLPFC (of claim 9). (pages 57 - 58, table 11, lists the Anterior Cingulate Cortex and the dorsal prefrontal cortex as target options. And paragraph [0496] “The power applied will determine whether the ultrasound is high intensity or low intensity (or medium intensity)” The examiner would like to note that a low intensity ultrasound is an option that can be used in this prior art.)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the method taught in Pascual-Leon and Stubbeman (2014) to use low intensity ultrasound to the target sites taught in Mishelevich. One of ordinary skill in the art would have been able to recognize with respect to non-invasive neuromodulation, ultrasound neuromodulation has the benefit over Transcranial Magnetic Stimulation in that the equipment for performing the neuromodulation costs less and is smaller, could be used at home, work, school, and could be shared over time for tune-ups. Because it is noninvasive and relatively low cost, ultrasound neuromodulation appears to be the modality capable of reaching the deep brain that could potentially be cleared by the FDA or other organizations for over-the-counter purchase. See paragraph [0034] of Mishelevich.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Pascual – Leone, Mishelevich, further in view of Williams (US 2019/0217116).
Regarding claim 20, Pascual – Leon and Mishelevich teach the method of claim 18, wherein the inhibitory low intensity ultrasound comprises
Ultrasound bursts delivered in 10-millisecond bursts repeated every 200 milliseconds (paragraph [0159] “Thus each of the on and off interval times may be selected from 1 (or a fraction thereof), 2, 3, 4, 5 seconds ranging up to 500 seconds and not necessarily integer time so 0.06, 1.05, 2.3, 5.0002 sec, etc. are permissible.” The examiner would like to note that the “on” times can be set to 10 ms and “off” times can be set to 200 ms which would deliver 10 ms burst repeated every 200 ms.) using:
a fundamental frequency between 300 and 700 kHz (paragraph [0073] “In some variations, the acoustic ultrasound frequency is in the range of 0.3 MHz to 0.8 MHz.”);
a pulse repetition frequency of 5Hz (paragraph [0279] “a repetition frequency of approximately 2 Hz or higher”)
and a duty cycle of between 1% and 5% (paragraph [0589] “The neuromodulation pulse duty cycle (the proportion of the inter-pulse interval that is with filled neuromodulation pulse) may be either fixed at different values or swept through a set of values ….The duty cycle is swept in the range of 1% to 100% of the inter-pulse interval with the controlling frequency sweeping occurring over approximately 1 Hz to approximately 20 kHz” The examiner is interpreting this is as the duty cycle can be set to values within the range of 1%-100%, therefore it can have a duty cycle of between 1% and 5%. Or this can be interpreted as the duty cycle can be varied between 1% and 100%, therefore can be varied between 1% and 5%.)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the method taught in Pascual – Leone to have the parameters taught in Mishelevich. One of ordinary skill in the art would have been able to recognize the parameters of claimed invention are the optimum or workable ranges discovered by routine experimentation. However, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Please see MPEP 2144.05.II.a, Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382, and In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
However, Mishelevich does not teach that between 600 – 1800 bursts were delivered.
Williams teaches a neuromodulation system where between 600 and 1800 bursts were delivered (paragraph [0068] “In numerous embodiments, aiTBS schedules involves applying iTBS pulses for multiple sessions per day, for several days. In a variety of embodiments, the iTBS pulse parameters involve 3-pulse, 50 Hz pulses at 5 Hz for 2 second trains, with trains every 10 seconds for 10 minute sessions (1,800 total pulses per session).” And paragraph [0070] “In a variety of embodiments, the cTBS pulse parameters involve 3-pulse trains with 50 Hz pulses at 5 Hz for 40 second sessions (600 total pulses per session).”)
It would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to modify the method taught in Pascual – Leone, Stubbeman (2014), and Mishelevish to have the parameters taught in Williams. One of ordinary skill in the art would have been able to recognize the parameters of claimed invention are the optimum or workable ranges discovered by routine experimentation. However, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Please see MPEP 2144.05.II.a, Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382, and In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Etkin (US 2019/0083805) discloses a neuromodulation system for treating PTSD that determines connectivity between different parts of the brain.
Park (KR 2021/0033926) discloses a theta burst ultrasound system to stimulate the brain for treating ADHD.
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/A.L.D./Examiner, Art Unit 3791
/JACQUELINE CHENG/Supervisory Patent Examiner, Art Unit 3791
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