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 .
The current application has an effective filing date of 10/27/2023.
Claim Status
As per Applicant’s response received on 08/21/2026, claims 1-30 are pending; and claims 1, 8-9, 11-12, 21, 25 and 27-30 have been amended.
Response to Amendment/Arguments
Regarding the 35 USC 112(b) rejection to claims 3 and 9 are withdrawn.
Regarding the 35 USC 102 rejection, the Applicant’s response has been fully considered, but the arguments are not entirely persuasive, in view of the following rationale.
The Applicant argued that applied references Covalin (US 11,351,370 B2), at a minimum recognizes that medical intervention such as surgery causes pain, which can be alleviated by applying transcutaneous auricular vagal nerve stimulation; this is shown in col.26, ll.6-19:
In an aspect, the stimulation targets specific neural targets in a local manner using bipolar stimulation. In an aspect, the system can be programmed for optimal therapy according to the needs of individual users including custom stimulation frequency, custom pulse width, custom stim intensity (amplitude), independently controlled stimulation channels. In some implementations, the treatment is configured to abate withdrawal symptoms including acute and/or chronic pain. In an aspect, pain control is due to modulation of endorphin, enkephalins, and/or dynorphins output in opioid related systems. In an example, the therapy can be provided during surgery, and/or post-surgery to reduce dependency of pain killer medications, including opioids, up to not needing medication at all.
Another prior art reference in the analogous art, Errico et al US 2022/0062622 A1 discloses system and methods for treating post-operative symptoms following major surgery by applying transcutaneous stimulation protocol to specialized nerve groups, including to the auricular vagal nerve (see Abstract and [0210]). Post-operative pain is often treated with opioid pain relievers, leading to post-operative inflammatory response/dysfunction; and treating with electrical impulses to bodily tissues for therapeutic purposes would alleviate and/or reduce opioid-induced and/or inflammatory-induced dysfunction of intestinal transit to improve motility ([0014, 0027, 0039, 0092-0093]). Since Covalin correlates auricular stimulation to post-operative pain, and Errico correlates post-operative pain to post-operative inflammation, and both treatable by auricular nerve stimulation. It would have been obvious to a person of ordinary skill in the art at the time of invention to apply Covalin’s auricular device to treat pain associated with post-operative pain treatment, in view of Errico; for the benefit of reducing inflammation and reducing post-operative pain. (Errico: Abstract).
To claim 1- method claim, see new grounds of rejection below.
As for claims 27 and 29, the 102 rejections based on Cov are maintained as these claims are apparatus claims, and the disclosed device are sufficient to meet the intended use recited in the claims.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier.
Such claim limitation(s) is/are:
“stimulation elements” in claims 1-2, 27 and 29.
“first/second extending structure” in claim 2
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Interpretation
To claims 1, 27 and 29, regarding the limitation “…applying transcutaneous auricular vagal nerve stimulation to the patient after the medical intervention…” Under the broadest reasonable interpretation, there is no specific time frame defining ‘after’; as such, this is taken to encompass any time relative to “medical intervention,” Furthermore, the crux of the current invention (according to Summary of Invention and claim preamble) lies in recognizing “medical intervention” causing inflammatory complications, and thus “applying transcutaneous auricular vagal nerve stimulation” with respect to said “medical intervention” to cause anti-inflammatory effects. Accordingly, it is the Examiner’s understanding and position in this office action, that, applying transcutaneous auricular vagal nerve stimulation to a patient for mitigating inflammation is sufficient to encompass the “applying” limitation in the claim.
Regarding the limitation “medical intervention” in the claims (unless specifically defined) are taken to encompass any medical intervention/treatment associated with any health condition.
Regarding the limitation “wherein the transcutaneous auricular vagal nerve stimulation activates one or more neuroimmune anti-inflammatory pathways to reduce inflammatory complications triggered by the administration or performance of the medical intervention” is interpreted as intended use/result of the “applying transcutaneous auricular vagal nerve stimulation” step since there is no recitation of specific stimulation parameters.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Regarding claim 27, Cov discloses a transcutaneous auricular vagal nerve stimulation device (device 200/300/400) configured for post-intervention inflammatory modulation after administering or performing a medical intervention on a patient (col.11, ll.40-col.12, ll.22 reduce inflammation caused by viral or bacterial infections, e.g. COVID treatment- taken to encompass “medical intervention” in the claim. Alternatively, see col.26, ll.14-19, post-surgery to reduce dependency of pain kill medication), comprising:
a housing (see Figs. 2A-4C and col.17, ll.35-42) adapted for placement relative to an ear of the patient (as shown in Figs. 2A-4C);
one or more stimulation elements (Fig. 2A-2B: auricular component 201 comprising electrodes) positioned to contact auricular tissue when the housing is placed relative to the ear (see col.12, ll.46-col.13, ll.27));
a controller (pulse generator 210/controller) coupled to a memory storing instructions (col.14, ll.56-61 controller having management software); and
output circuitry (I/O interface) coupled to the controller (col.17, ll.61-65) and the one or more stimulation elements (e.g. electrodes); wherein the instructions, when executed by the controller,
cause the output circuitry to deliver stimulation via the one or more stimulation elements (e.g. electrodes) according to a post-intervention inflammatory modulation protocol (This limitation “post-intervention inflammatory modulation protocol” is generic and is not tied to detecting inflammation or medical intervention, as such, it is met by selecting a generic protocol taught in Cov, see col.17, ll.61-col.18, ll.25 interface allowing for customizable treatment protocol including mode selection) after the administration or performance of the medical intervention to reduce inflammation triggered by the administration or performance of the medical intervention (Cov col.12, ll.34 teaches activation of anti-inflammation pathway, col.26, ll.14-19 stimulation applied post-surgery to reduce dependency of pain kill medication and Fig:14 reduce inflammation; since Cov teaches a device that aims at reducing inflammation, it is sufficient to meet the intended use for “post-intervention inflammatory modulation protocol” in this claim).
Regarding claim 28, Cov discloses the device of claim 27, wherein the instructions further cause the controller to adaptively adjust at least one stimulation parameter based on a measured physiologic parameter selected from heart rate variability, blood pressure variability, and/or temperature (col.10, ll.26-34, col.25, ll.45-51 automatically adjusting operational parameters of the stimulation therapy based on detected physiological parameter, e.g. heart rate variability; the adjusted stimulation operation parameter including: pulse width, intensity/amplitude, see col.26, ll.9-12 and col.35, ll.53-56) during a post-intervention period following the administration or performance of the medical intervention (regarding “post-intervention period”, this is a non-specific time period, it is interpreted as any time period/duration after surgery, see rejection to claim 27), wherein the measured physiological parameter is indicative of an inflammatory state of the patient (col.10, ll.23-34, col.11, ll.40-52, biomarkers indicative of inflammatory state e.g. cytokine, HRV).
Regarding claim 29, Cov discloses a non-transitory computer-readable medium storing instructions (col.14, ll.57-61 VNS device comprises pulse generator 210/controller and memory having software instructions) that, when executed by a controller (pulse generator 210/controller) of a transcutaneous auricular vagal nerve stimulation device (device 200/300/400), cause the device to:
receive at least one input selected from: (i) a medical intervention type (col.17, ll.61-col.18, ll.25 I/O interface allowing for customizable treatment protocol including mode selection), (ii) a patient risk stratification parameter, or (iii) both the medical intervention type and the patient risk stratification parameter (limitations (ii) and (iii) are not required based on “or”);
select a post-intervention inflammatory modulation protocol based on the at least one input (This limitation “post-intervention inflammatory modulation protocol” is generic and is not tied to detecting inflammation or medical intervention, as such, it is met by selecting a generic protocol taught in Cov, see col.17, ll.61-col.18, ll.25 interface allowing for customizable treatment protocol including mode selection); and
deliver stimulation via one or more stimulation elements positioned on an auricle of a patient according to the selected post-intervention inflammatory modulation protocol after administration or completion of the medical intervention by medical personnel to mitigate inflammatory complications triggered by the administration or completion of the medical intervention on the patient (Cov col.12, ll.34 teaches activation of anti-inflammation pathway, col.26, ll.14-19 stimulation applied post-surgery to reduce dependency of pain kill medication and Fig:14 reduce inflammation; since Cov teaches a device that aims at reducing inflammation, it is sufficient to meet the intended use for “post-intervention inflammatory modulation protocol” in this claim)
Regarding claim 30, Cov discloses the non-transitory computer-readable medium of claim 29, wherein the instructions further cause the device to:
monitor a physiologic parameter selected from heart rate variability or blood pressure variability during delivery of the stimulation (after the administration or performance of the medical intervention on the patient col.10, ll.26-34, col.25, ll.45-51 automatically adjusting operational parameters of the stimulation therapy based on detected physiological parameter, e.g. heart rate variability; the adjusted stimulation operation parameter including: pulse width, intensity/amplitude, see col.26, ll.9-12 and col.35, ll.53-56), wherein the physiologic parameter is indicative of an inflammatory state of the patient (col.10, ll.23-34, col.11, ll.40-52, biomarkers indicative of inflammatory state e.g. cytokine, HRV); and
adaptively adjust at least one stimulation parameter selected from current amplitude, pulse width, frequency, and/or duty cycle based on the monitored physiologic parameter. (col.10, ll.26-34, col.25, ll.45-51 automatically adjusting operational parameters of the stimulation therapy based on detected physiological parameter, e.g. heart rate variability; the adjusted stimulation operation parameter including: pulse width, intensity/amplitude, see col.26, ll.9-12 and col.35, ll.53-56)
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, 3, 6-8, 10-11, 17-19 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Covalin et al. US 11,351,370 B2 (hereinafter “Cov”, previously cited) in view of Errico et al. US 2022/0062622 A1 (hereinafter “Errico”).
Regarding claim 1, Cov discloses a method (see Abstract) of mitigating inflammatory complications associated with a medical intervention in a patient (col.11, ll.40-col.12, ll.22 reduce inflammation caused by viral or bacterial infections, e.g. COVID treatment- taken to encompass “medical intervention” in the claim. Alternatively, see col.26, ll.14-19, post-surgery to reduce dependency of pain killer medication), the method comprising:
applying transcutaneous auricular vagal nerve stimulation (col.5, ll.20-58, col.11, ll.2-22, col.12, ll.34-59 vagus nerve stimulation (VNS) through auricle; also see Fig. 2B anti-inflammatory pathway stimulation) to the patient after the medical intervention is administered to or performed on the patient (This is taken to encompass medical interventions discussed in col. 11, ll.40-col.12, ll.33; also see col.26, ll.14-19, post-surgery), wherein the transcutaneous auricular vagal nerve stimulation is delivered via one or more stimulation elements (Fig. 2A-2B: auricular component 201) positioned on an auricle of the patient (see col.12, ll.46-col.13, ll.27); and
wherein the transcutaneous auricular vagal nerve stimulation activates one or more neuroimmune anti-inflammatory pathways to reduce inflammatory complications (see col.12, ll.34 activation of anti-inflammation pathway).
Cov’s auricular treatment is aimed to reduce opioid intake and to reduce pain by decreasing pro-inflammatory processes (col.25, ll.52-col.26, ll.61); Cov does not explicitly disclose wherein the inflammatory complications are triggered by the administration or performance of the medical intervention on the patient.
Errico, another prior art reference in analogous art, discloses a system and methods for treating post-operative symptoms following major surgery by applying transcutaneous stimulation protocol to specialized nerve groups, including to the auricular vagal nerve (see Abstract and [0210]). Errico teaches that post-operative/surgery pain is often treated with opioid pain relievers, leading to post-operative inflammatory response/dysfunction; and treating with electrical impulses to bodily tissues for therapeutic purposes would alleviate and/or reduce opioid-induced and/or inflammatory-induced dysfunction of intestinal transit to improve motility ([0014, 0027, 0039, 0092-0093]). Since Covalin correlates auricular stimulation to post-operative pain, and Errico correlates post-operative pain to post-operative inflammation, and both treatable by auricular nerve stimulation. It would have been obvious to a person of ordinary skill in the art at the time of invention to apply Covalin’s auricular device to treat pain associated with post-operative pain treatment, in view of Errico; for the benefit of reducing inflammation and reducing post-operative pain. (Errico: Abstract, [0014, 0027]).
Regarding claim 3, Cov modified discloses the method of claim 1, wherein the transcutaneous auricular vagal nerve stimulation is delivered periodically in sessions having a duration in a range of 30 seconds to 24 hours. (Cov: col.25, ll.53-col.26, ll.5 stimulation duration is adjustable; also see col.12, ll.63-65 “In an illustrative example, stimulation therapy may be provided for at least one hour each session and at least two daily sessions for a minimum of two hours total stimulation time,”)
Regarding claim 6, Cov modified discloses the method of claim 1, further comprising: monitoring at least one physiologic parameter selected from heart rate variability, blood pressure variability, and/or body temperature during applying the transcutaneous auricular vagal nerve stimulation; and adjusting at least one stimulation parameter selected from current amplitude, pulse width, frequency, and/or duty cycle based on the monitored physiologic parameter. (Cov: col.10, ll.26-34, col.25, ll.45-51 automatically adjusting operational parameters of the stimulation therapy based on detected physiological parameter, e.g. heart rate variability; the adjusted stimulation operation parameter including: pulse width, intensity/amplitude, see col.26, ll.9-12 and col.35, ll.53-56)
Regarding claim 7, Cov modified discloses the method of claim 6, wherein the adjusting at least one stimulation parameter comprises titrating the current amplitude to achieve at least a threshold increase in heart rate variability relative to a pre-stimulation baseline measurement. (See rejection to claim 6 above, and further Cov: see col.31, ll.66-col.32, ll.13 monitoring HRV for optimizing/adjusting therapy parameters, e.g. current/amplitude; see specifically col.35, ll.53-56 “Therapy may be optimized according to the needs of individual patients including custom stimulation frequency, custom pulse width, custom stimulation intensity (amplitude), and/or independently controlled stimulation channels.”)
Regarding claim 8, Cov discloses the method of claim 1 for detecting inflammatory biomarkers or parameters, e.g. HRV and cytokine (col.10, ll.23-34, col.11, ll.40-52), but Cov does not disclose further comprising: measuring at least one inflammatory biomarker selected from interleukin-6, tumor necrosis factor-α, C-reactive protein, and/or ferritin after applying the transcutaneous auricular vagal nerve stimulation; and comparing the measured inflammatory biomarker to a baseline measurement to assess reduction in inflammatory complications. However, this is taught in Errico, see [0230] which discloses detecting inflammatory biomarkers, including interleukin-6, TGF-β, cytokine, etc. Accordingly, it would have been obvious to a person of ordinary skill in the art at the time of invention to modify Cov to further include detecting the various inflammatory biomarkers in view of Errico, the motivation for doing so is to provide a broader spectrum of monitored parameters to determine inflammatory state.
Regarding claim 10, Cov modified discloses the method of claim 1, wherein the transcutaneous auricular vagal nerve stimulation is applied prior to the medical intervention as a preconditioning treatment for a duration in a range of hours to days before the medical intervention. (Cov: col.26, ll.53-57 an exemplary application-applying stimulation prior to medical intervention, e.g. surgery; also see col.27, ll.10-45, applying stimulation prior to medical intervention, e.g. MEDD)
Regarding claim 11, Cov modified discloses the method of claim 1, wherein the medical intervention comprises a tissue-disruptive medical intervention selected from the group consisting of: cranial surgery, spinal surgery, cardiothoracic surgery, cardiopulmonary bypass, radiation therapy, radiofrequency ablation, ischemia-reperfusion procedures, and organ transplantation. (see Cov: col.26, ll.53-57 surgery and also see Errico: [0007-0008])
Regarding claim 17, Cov modified discloses the method of claim 1, wherein the inflammatory complication is selected from the group consisting of: cytokine release syndrome, cerebral edema, systemic inflammatory response syndrome, acute kidney injury, immune effector cell-associated neurotoxicity syndrome, capillary leak syndrome, and ischemia-reperfusion injury. (Cov: col.10, ll.23-25 and col.11, ll.40-col.12, ll.22 cytokine)
Regarding claim 18, Cov modified discloses the method of claim 1, wherein the one or more neuroimmune anti-inflammatory pathways are selected from the group consisting of: cholinergic anti-inflammatory pathway activation, central network suppression, reduced cerebral metabolism, autonomic stabilization, sympathetic withdrawal, endothelial stabilization, thromboinflammation modulation, HPA-axis modulation, microglial phenotype shifting, gut-immune axis modulation, and/or pain-inflammation feedback loop interruption. (Cov: col.12, ll.34-46 activation of the Anti-inflammatory Pathway (a.k.a. the cholinergic anti-inflammatory pathway); col.26, ll.6-38 pain-inflammation feedback loop interruption)
Regarding claim 19, Cov modified discloses the method of claim 18, wherein the cholinergic anti-inflammatory pathway activation comprises binding of acetylcholine to alpha-7 nicotinic acetylcholine receptors (α7 nAChR) on macrophages, microglia, or both, thereby suppressing nuclear factor-κB (NF-κB) activation through JAK2-STAT3 intracellular signaling and reducing production of pro-inflammatory cytokines. (see rejection to claim 18 and col.12, ll.34-46)
Regarding claim 21, Cov modified discloses the method of claim 1, wherein the transcutaneous auricular vagal nerve stimulation is adaptively modulated during a post-intervention period following the administration or performance of the medical intervention based on real-time physiologic feedback selected from heart rate variability, blood pressure variability, and/or measured cytokine levels. (Cov: col.22, ll.59-67, col.29, ll.6-21, col.31, ll.7-39 real time biofeedback for adjusting stimulation parameters. Regarding “post-intervention period”, this is a non-specific time period, it is interpreted as any time period/duration after surgery, see rejection to claim 1.)
Regarding claim 22, Cov modified discloses the method of claim 1, wherein the transcutaneous auricular vagal nerve stimulation is delivered at a sub-perceptive current amplitude that suppresses high-gamma neural activity in the insular cortex, the orbitofrontal cortex, or both, to reduce centrally-mediated inflammatory drive through a central autonomic/limbic gateway mechanism that operates independently of conscious sensory perception and is active during general anesthesia or sedation. (See Cov: Fig. 14D and col.23, ll.1-15 and also see Figs. 16A-16D and col.33, ll.21-col.36, ll.56 modulation of neural activity and various parts of the brain, e.g. increase prefrontal cortex activity)
Regarding claim 23, Cov modified discloses the method of claim 1, wherein the stimulation is delivered via electrodes (electrodes 220-226) positioned within the external auditory canal, or via one or more percutaneous electrodes introduced through the skin of the auricle to a depth sufficient to reduce impedance and increase selectivity for activation of auricular branch of vagus nerve fibers relative to surface electrode delivery. (Cov: col.19, ll.25-35 “In an illustrative example, the treatment device 1000 may monitor impedance measurements allowing closed-loop neurostimulation. The notifications regarding removal or malfunction, for example, may be issued upon determining that the impedance measurements are indicative of lack of a proper contact between one or more electrodes of the treatment device 1000 and tissue on or surrounding the patient's ear. The notifications, for example, may be delivered to the patient and/or one or more third parties via an application executing on one of the peripheral devices 1010.”)
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Cov and Errico, as applied to claim 1, and further in view of Bouton et al. US 2021/0085974 A1 (hereinafter “Bouton”).
Regarding claim 2, Cov and Errico discloses the method of claim 1, further comprising: applying a wearable device (device 200/300/400) to an ear of the patient (Figs. 2A-4C), the wearable device comprising a housing containing electronics and a power source (see Figs. 2A-4C and col.17, ll.35-42). Cov does not disclose the wearable device having the specific claim structure recited in claim 2. Bouton, another prior art reference in analogous art of auricular stimulation device, as illustrated below:
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Bouton discloses a wearable device (see annotated Fig. 1A: auricular stimulation device 10) adapted for placement relative to an ear of a user (see Abstract and Fig. 5), comprising:
a housing (housing 12; [0051]) containing electronics (circuit board 50) and a power source (rechargeable power source 52);
a first extending structure (inner arm/probe 20) having a first end at the housing and a second end apart from the housing (12, see Fig. 1A), the first extending structure (20) having a first length (see Fig. 1A, probe 20 has a length);
a second extending structure (outer arm/probe 30) comprising a first end at the housing and a second end apart from the housing (12, see Fig. 1A), wherein the first (20) and second extending structures (30) are separated by an adjustable distance (the “adjustable distance” in this claim is interpreted as ‘clamped’ and ‘unclamped’ position between probes 20 and 30 described in [0049, 0055] , such as the distance “b” in annotated Fig. 1A), wherein the second extending structure (30) is configured to abut a first inner portion of an ear to create an opposing force to the first extending structure (20) which is configured to abut a second inner portion of the ear ([0046, 0049] “ The biasing member 42 of pivot 40 urges the inner and outer probes 20, 30 towards one another…into the tissue clamping configuration to secure the stimulation device 10 to tissue ….”);
an anchor arm (inner electrode 22) extending laterally from the first extending structure (20; inner electrode 22 extends laterally from probe 20, this is shown in Fig. 3); and
an adjustment mechanism (rigid foot 30c; [0048]) configured to impart a force to adjust the adjustable distance ([0048: last sentence] “The foot 30c is actuatable a user's finger, as indicated by arrows “D,” to facilitate pivotal movement of outer probe 30 relative to inner probe 20 about pivot axis “P.”” When a user’s finger actuates 30c, the force adjusts the adjustable distance between structures 20 and 30, the distance is indicated by “B”)
With regard to claim 2, it would have been obvious to a person of ordinary skill in the art at the time of invention to apply Cov’s method for applying auricular stimulation device using the wearable device disclosed in Bouton (Fig.1A); the motivation would have been to apply auricular stimulation using a device that has adjustable tension aspect to fit/adapt to different size ears.
Claims 4-5, 9 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Cov and Errico as applied to claims 1 and 8, and in view of Libbus et al. US 2020/0254259 A1 (hereinafter “Libbus”).
Regarding claims 4 and 5, Cov and Errico discloses method of claim 1 for providing stimulation to activate anti-inflammatory pathway to decrease systemic and target organs pro-inflammatory processes (such as shown in Cov: Fig. 14F and col.24, ll.35-47 and col.25, ll.45-51). With respect to adjusting stimulation, Cov discloses monitoring baseline measurements including cytokine and HRV (col.10, ll.23-34, col.11, ll.40-52 and see col. 35, ll.58-col.36, ll.13, regarding adjusting baseline parameters ), Cov does not disclose measuring at least one baseline inflammatory biomarker selected from C-reactive protein, interleukin-6, tumor necrosis factor-α, and/or ferritin prior to applying the transcutaneous auricular vagal nerve stimulation. Cov also does not disclose wherein the at least one baseline inflammatory biomarker further comprises at least one selected from high mobility group box 1 protein (HMGB1), glial fibrillary acidic protein (GFAP), S100B, neutrophil gelatinase-associated lipocalin (NGAL), von Willebrand factor, D-dimer, neurofilament light chain, calprotectin, C3a, C5a, angiopoietin-2, high-sensitivity C-reactive protein, neutrophil-to-lymphocyte ratio, interleukin-8, interleukin-2, donor-specific antibodies (DSA), lipopolysaccharide-binding protein (LBP), intercellular adhesion molecule-1 (ICAM-1), and/or vascular cell adhesion molecule-1 (VCAM-1). However, Libbus, another prior art reference in the analogous art, discloses delivering VNS to a patient using an auricula VNS stimulation device ([0046: last sentence]). Libbus further discloses determining a patient’s suitability for VNS treatment by measuring biomarkers, e.g. C-reactive protein (CRP), interleukin (IL)-1, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases (MMPs), etc. ([0068, 0127]). It would have been obvious to a person of ordinary skill in the art at the time of inventio to modify Cov to include measuring inflammatory biomarker to quantify amount as inflammation in the patient, in view of Libbus, the motivation for doing so is to quantify efficacy of stimulation treatment. (Libbus: [0068])
Regarding claim 9, Cov modified discloses the method of claim 6 including automatically adjusting stimulation parameters to optimize treatment based on detected physiological parameter, e.g. heart rate variability (col.10, ll.26-34, col.25, ll.45-51, col.26, ll.9-12 and col.35, ll.53-56). Cov does not disclose wherein the at least one stimulation parameter is adjusted to achieve at least a threshold amount of reduction in a measured inflammatory biomarker level relative to a pre-treatment peak measurement. However, Libbus, another prior art reference in the analogous art, discloses delivering VNS to a patient using an auricula VNS stimulation device ([0046: last sentence]). Libbus further discloses determining a patient’s suitability for VNS treatment by measuring biomarkers, e.g. C-reactive protein (CRP), interleukin (IL)-1, IL-6, IL-8 to quantify an amount of inflammation prior to treatment, and to then determine the efficacy of treatment as compared to an inflammation threshold. Libbus discloses adjusting stimulation parameters based on the biomarker thresholds and inflammation thresholds ([0069, 0078]). It would have been an obvious modification to a person of ordinary skill in the art at the time of invention to modify Cov’s to optimize stimulation based on achieving a threshold amount of reduction in inflammatory biomarker level, the motivation for doing so is to quantify success/efficacy of treatment. (Libbus: [0069, 0078])
Regarding claim 24, Cov modified discloses the method of claim 1, wherein the stimulation comprises a transcutaneous auricular vagal nerve stimulation (see rejection to claim 1), but Cov does not disclose at least one additional modality selected from transcutaneous cervical vagal nerve stimulation, intranasal vagal nerve stimulation delivered via electrodes positioned within the nasal cavity to access trigeminal-vagal convergent pathways, transcranial direct current stimulation, transcranial magnetic stimulation, pulsed electromagnetic field stimulation delivered via a micro-coil positioned over a cervical vagus nerve location, and/or low-intensity focused ultrasound.
However, Libbus, another prior art reference in the analogous art, discloses a system for delivering combined cervical and auricular vagus nerve stimulation a patient (as shown in Fig. 3C: and [0038]). Libbus discloses a first auricular VNS stimulation device ([0046: last sentence]), and one additional modality: transcutaneous cervical vagal nerve stimulation ([0038-0039]). It would have been obvious to a person of ordinary skill in the art at the time of invention to modify Cov to include the combined auricular and cervical vagus nerve stimulation, in view of Libbus; the motivation for doing so is because providing stimulation both internally and externally has the advantage of enabling physician to determining efficacy of stimulation without unnecessary invasive implantation surgery (Libbus: [0028])
Claim 12-16 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Cov and Errico as applied to claims 1 or 11.
Regarding claim 12, Cov modified discloses the method of claim 11, wherein the medical intervention includes surgery (see col.26, ll.53-57); but Cov does not disclose wherein the ischemia-reperfusion procedure comprises a reperfusion phase, and wherein the transcutaneous auricular vagal nerve stimulation includes transcutaneous auricular vagal nerve stimulation that is synchronized with the reperfusion phase. However, it would have been obvious to provide vagus nerve stimulation to a patient undergoing a ischemia-reperfusion procedure comprising a reperfusion phase, and wherein the transcutaneous auricular vagal nerve stimulation is synchronized with the reperfusion phase; the motivation for doing so is to because Cov discloses synchronizing stimulation to one or more organs for the purpose of blood flow (col.24, ll.28-35).
Regarding claims 13 and 14, Cov modified discloses providing auricular vagus nerve stimulation therapy before, during and post-surgery to reduce dependency of pain killer medication and decrease inflammatory processes in one or more target organs (col.26, ll.16-19, col.25, ll.52-col.26, ll.5), but does not disclose wherein the medical intervention comprises an immune-activating intervention selected from the group consisting of: CAR-T cell therapy, immune checkpoint inhibitor therapy, stem cell infusion, viral vector gene therapy, and organ transplantation. Cov also does not explicitly disclose wherein immune-activating intervention comprises hematopoietic stem cell transplantation or organ transplantation, and the inflammatory complication comprises graft-versus-host disease or acute rejection, and wherein at least one of interleukin-6, tumor necrosis factor-α, graft-versus-host disease severity score, and/or donor-specific antibodies (DSA) is monitored to assess the reduction in inflammatory complications and to guide post-transplant protocol duration and intensity. However, a person of ordinary skill in the art, e.g. a physician of the patient, would have recognize that surgical preparation would include the various recited medical intervention, e.g. immune-activating intervention, organ transplantation etc. would have associated inflammation complications either before, and/or post-surgery. Accordingly, it would have been obvious to a person of ordinary skill in the art at the time of invention for apply auricular vagus nerve stimulation to a patient in before, during and/or post the recited medical interventions, the motivation is taught in Cov: to target specific organs to reduce inflammation. (Cov: col.12, ll.34-46 “…local anti-inflammatory effect occurs at organs reached by the efferent pathways; for example at the lungs, gut, and heart”; and col.24, ll.35-47 decrease inflammatory processes in target organs spleen, lungs, gut and heart)
Regarding claim 15 and 16, Cov modified discloses the method of claim 1, discloses providing auricular vagus nerve stimulation therapy before, during and post-surgery to reduce dependency of pain killer medication and decrease inflammatory processes in one or more target organs (col.26, ll.16-19, col.25, ll.52-col.26, ll.5). Cov does not disclose wherein the medical intervention comprises a foreign-material-introducing intervention selected from the group consisting of: neurostimulator implantation, cardiac device implantation, orthopedic hardware placement, vascular stent placement, contrast agent administration, and blood transfusion. Cov also does not disclose wherein the foreign-material-introducing intervention comprises implantation of a scaffold, bioengineered tissue construct, or synthetic matrix, and the inflammatory complication comprises fibrotic encapsulation or impaired tissue integration, and wherein TGF-β and/or matrix metalloproteinases are monitored as biomarkers of fibrotic remodeling. However, a person of ordinary skill in the art, e.g. a physician of the patient, would have recognize that surgical preparation would include the various recited medical intervention, e.g. immune-activating intervention, organ transplantation etc. would have associated inflammation complications either before, and/or post-surgery. Accordingly, it would have been obvious to a person of ordinary skill in the art at the time of invention for apply auricular vagus nerve stimulation to a patient in before, during and/or post the recited medical interventions, the motivation is taught in Cov: to target specific organs to reduce inflammation. (Cov: col.12, ll.34-46 “…local anti-inflammatory effect occurs at organs reached by the efferent pathways; for example at the lungs, gut, and heart”; and col.24, ll.35-47 decrease inflammatory processes in target organs spleen, lungs, gut and heart.)
Regarding claim 20, Cov modified discloses the method of claim 1, wherein the transcutaneous auricular vagal nerve stimulation is delivered via electrodes as electrical stimulation, wherein the current, pulse width, frequency are manually and/or automatically adjustable based on sensor detected data (col.26, ll.6-14, col.29, ll.6-13). Cov’s discussed operational ranges overlaps and/or encompasses the claimed ranges: see col.4, ll.24-31, col.29, ll.13-20 and col.29, ll.35-50 for exemplary frequency range in 1-150 Hertz, see col.29, ll.40-23 for exemplary pulse width in the range of 10-1000 microseconds, and see col.21, ll.5-12 for high current up to 90V. It would have been a mere design choice to a person of ordinary skill to modify Cov to adjust the operational parameters to the recited ranges: a current amplitude in a range of 0.05 milliamps (mA) to 10 mA; a pulse width in a range of 50 microseconds to 2000 microseconds; and a frequency in a range of 0.1 Hertz (Hz) to 100 Hz; the motivation is because Cov explicitly discloses stimulation parameters current, pulse width, frequency are adjusted and customed to each individual patient to optimize treatment (Cov: col.26, ll.6-14).
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Cov and Errico as applied to claim 1 and in view of Lim et al. US 2022/0080197 A1 (hereinafter “Lim”).
Regarding claim 25, Cov modified discloses the method of claim 1, Cov does not disclose wherein the transcutaneous auricular vagal nerve stimulation comprises a combination of electrical stimulation and at least one additional modality selected from vibratory stimulation at a frequency in a range of 1 Hertz (Hz) to 1000 Hz, thermal stimulation to a target tissue temperature in a range of 10 degrees Celsius (°C) to about 45 °C, and/or low-intensity focused ultrasound at a frequency in a range of 200 kilohertz (kHz) to 5 megahertz (MHz), delivered simultaneously or in a time-staggered sequence. However Lim, another prior art reference in the analogous art, discloses a combined ultrasound and electrical stimulation for treating inflammation (Abstract). Lim discloses electrical stimulation for non-invasive treatment inflammation applied to the ear ([0006, 0030]) and also applying low-intensity focused ultrasound at a frequency in a range of about 200 kilohertz (kHz) to about 5 megahertz (MHz), delivered simultaneously or in a time-staggered sequence ([0032], Table 1 and Fig. 1). It would have been obvious to a person of ordinary skill in the art at the time of invention to modify Cov to provide combined electrical and ultrasound stimulation therapy to a patient in view of Lim, the motivation for doing so is because of the advantages provided for treating a wide range of disorders associated with inflammation (Lim: [0004-0006]).
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Cov and Errico as applied to claim 1 and in view of Chu et al. US 2019/0232047 A1 (hereinafter “Chu”).
Regarding claim 26, Cov modified discloses the method of claim 1, Cov does not disclose wherein the transcutaneous auricular vagal nerve stimulation is delivered using a stochastically modulated waveform in which at least one stimulation parameter selected from current amplitude, pulse width, frequency, and/or inter-pulse interval is varied in a pseudo-random or noise-modulated manner within a therapeutically effective range, to reduce neural habituation and accommodation to repetitive stimulation during extended-duration protocols. Chu, another prior art reference in analogous art discloses a device that promotes stimulation to the greater auricular nerve ([0045]); Chu further discloses providing mechanical stimulation, wherein “[w]aveforms applied comprised stochastic resonance signals including random noise of various frequencies, standard and modified sine waves, incidentally transformed waves, and multi-scalar modulation of carrier waves.” ([0618]) It would have been obvious to a person of ordinary skill in the art at the time of invention to modify Cov in view of Chu, so as to deliver stochastically modulated waveform; the motivation for doing so is for testing the stimulation device and stimulation waveforms as to whether it is safe for both episodic or daily use. (Chu: [0617])
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Taca, JR. US 2018/0200522 A1 discloses an auricular stimulation device adapted for pain management.
Alataris et al. US 2020/0261722 A1 teaches an auricular stimulation device (abstract) adapted to provide anti-inflammatory effects (see background and [0026])
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/SHIRLEY X JIAN/ Primary Examiner, Art Unit 3792
September 8, 2026
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