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 .
Information Disclosure Statement
Applicant should note that the large number of references in the attached IDS have been considered by the examiner in the same manner as other documents in Office search files are considered by the examiner while conducting a search of the prior art in a proper field of search. See MPEP 609.05(b). Applicant is requested to point out any particular references in the IDS which they believe may be of particular relevance to the instant claimed invention in response to this Office action.
Restriction/Election
Claims 9-10, 19-21, 28, 36-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/22/2025.
Applicant's election with traverse of Group I and redox system biomarker Species A in the reply filed on 12/22/2025 is acknowledged. The traversal of Group restriction is on the grounds that claim 27 is rewritten/amended to depend on claim 1. Based on claim 27 amendments, this arguments were found persuasive and the restriction between Group I and Group II is being withdrawn.
The traversal of biomarker species restriction is on the grounds that it would not be unduly burdensome to perform a search on all of the species claims together in the present application. This is not found persuasive because the different species recite mutually exclusive characteristics of the species for example species A is drawn to redox system biomarkers, species B is drawn to metabolic system biomarkers, species C is drawn to immune system biomarkers while species D is drawn to electrical biomarkers of the tissue. In addition, these species are not obvious variants of each other based on the current record. Species restriction for examination purposes as indicated in Office Action dated 10/22/2025 is proper because at least the following reason(s) apply: the species or groupings of patentably indistinct species have acquired a separate status in the art in view of their different classification; the species or groupings of patentably indistinct species have acquired a separate status in the art due to their recognized divergent subject matter; and/or the species or groupings of patentably indistinct species require a different field of search (e.g., searching different classes/subclasses or electronic resources, or employing different search strategies or search queries).
The traversal of biomarker species restriction is additionally on the grounds that the specification at [0233-0240] discloses the use of biomarker combination types which was not found persuasive as the claims do not explicitly, positively and specifically recite the biomarker combination types. Examiner notes that the features upon which applicant relies (i.e., specification at [0233-0240] discloses the use of biomarker combination types) are not recited in the restricted species claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Furthermore, the reply dated 12/22/2025 does not sufficiently distinctly and specifically point out supposed errors in the species restriction requirement in Office Action dated 10/22/2025 nor provide details as to why the species are not patentably distinct, or submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case.
For the foregoing reasons, the requirement is still deemed proper and is therefore made FINAL.
Currently, claims 1-8, 11-18, 22-27 and 29-35 are being examined on the merits as drawn to the elected species.
Specification
The disclosure is objected to because of the following informalities:
“An example may deliver…” in abstract needs to be corrected. A suggested correction is -- An example system may deliver --.
“Existing therapies for chronic diseases, such as but not limited diabetes, cancer” in [0004] needs to be corrected. A suggested correction is -- Existing therapies for chronic diseases, such as but not limited to diabetes, cancer--.
“Similarly, an electric field produced by an alternating current is a changing electric field as its direction and magnitude changes with time, whereas an electric field produced a direct current is constant both in magnitude and direction” in [0057] needs to be corrected. A suggested correction is -- Similarly, an electric field produced by an alternating current is a changing electric field as its direction and magnitude changes with time, whereas an electric field produced by a direct current is constant both in magnitude and direction--.
Similar issues were noted in [0059], [0092]
Appropriate correction is required.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Following claims are objected to because of the following informalities:
Claim 14 “glutamate-cysteine ligase regulatory subunit (GCLM) (see Kansanen et al.)” needs to be corrected to -- glutamate-cysteine ligase regulatory subunit (GCLM)
Claim 23 “wherein changing the dose includes changing a duty cycle or a duration the therapy during a period of time” needs tot be corrected. A suggested correction is -- wherein changing the dose includes changing a duty cycle or a duration of the therapy during a period of time--.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-8, 11-18, 22-27 and 29-35 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 recites “monitoring efficacy of the therapy” which renders the claim unclear. More specifically, in the context used it is unclear as to what is meant by efficacy of the therapy i.e. what does efficacy of the therapy mean, how is efficacy of the therapy measured, what is efficacy of the therapy being in comparison to- control group/sample, population metrics, patient history, same subject before therapy, reference value/threshold, measured/quantitative redox and/or metabolic system imbalance or something else. It is unclear as to how therapy or therapy efficacy is related to or has a nexus to one or more biomarkers within at least one of a redox system and a metabolic system. The nexus between monitoring efficacy of the therapy and detecting one or more biomarkers within at least one of a redox system and a metabolic system is missing and thus unclear/vague.
Claim 1 recites “calibrating or adjusting the therapy” which renders this claim unclear. More specifically, in the context used, it is unclear as to what standard or reference is therapy calibrated, fine-tuned, adjusted or checked against i.e. some industry standard, based on healthy state of a control group/sample, population metrics, patient history, same subject before therapy, reference value/threshold, measured/quantitative redox and/or metabolic system imbalances or something else. It is unclear as to how calibrating or adjusting the therapy is related to or has any nexus to one or more biomarkers within at least one of a redox system and a metabolic system. The nexus between calibrating or adjusting the therapy and detecting one or more biomarkers within at least one of a redox system and a metabolic system is missing and thus unclear/vague.
Claim 14 recites “long-chain fatty acids (LCFAs) (e.g. myristate, … poly unsaturated fatty acids (PUFAs) (e.g. heneicosapentaenoate, ,,, medium chain fatty acids (MCFAs) (e.g. heptanoate, cis-4-decenoate, 10-undecenoate, … fatty acids dicarboxylate (e.g. glutarate, 2… amino fatty acids (e.g. 2-aminoheptanoate, … acyl glycine (e.g. isocaproylglycine, … and carnitines (e.g. acetylcarnitine,” which renders this claim unclear. More specifically, the abbreviation “e.g.” is being interpreted as "for example" which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 14 recites “long-chain fatty acids (LCFAs) …myristate, myristoleate, … etc.), … medium chain fatty acids (MCFAs) … heptanoate, … etc.), fatty acids dicarboxylate … 3-carboxy-4-methyl-5-pentyl-2-furanpropionate etc.), amino fatty acids … 2-aminoheptanoate, 2-aminooctanoate, n-acetyl-2-aminooctanoate etc.), acyl glycine … isocaproylglycine, … etc.) and carnitines … acetylcarnitine, … carnitine etc.)” which renders this claim unclear. More specifically, the abbreviation “etc.” is being interpreted as the Latin phrase "et cetera" which renders the claim indefinite the metes and bounds of the claim are unclear.
Dependent claims 2-8, 11-18, 22-27 and 29-35 when analyzed as a whole are held to be patent ineligible under 35 U.S.C. 112(b) because the additional recited limitations fail to cure the 35 U.S.C. 112(b) issue in their respective base claims. Consequently, dependent claims 2-8, 11-18, 22-27 and 29-35 are also rejected under 35 U.S.C. 112(b) based on their direct/indirect dependency on their respective base claims.
Claim Interpretation
Claims terms where relevant are being interpreted in light of definitions enumerated in instant application specification as-filed [0049], [0053-0056].
Please note that USPTO personnel are to give claims their broadest reasonable interpretation in light of the supporting disclosure. In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997). Limitations appearing in the specification but not recited in the claim should not be read into the claim. E-Pass Techs., Inc. v. 3Com Corp., 343 F.3d 1364, 1369, 67 USPQ2d 1947, 1950 (Fed. Cir. 2003) (claims must be interpreted "in view of the specification" without importing limitations from the specification into the claims unnecessarily). In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550-551 (CCPA 1969). See also In re Zletz, 893 F.2d 319, 321-22, 13 USPQ2d 1320, 1322 (Fed. Cir. 1989) ("During patent examination the pending claims must be interpreted as broadly as their terms reasonably allow.... The reason is simply that during patent prosecution when claims can be amended, ambiguities should be recognized, scope and breadth of language explored, and clarification imposed.... An essential purpose of patent examination is to fashion claims that are precise, clear, correct, and unambiguous. Only in this way can uncertainties of claim scope be removed, as much as possible, during the administrative process.").
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 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 of this title, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 6, 8, 11-18, 22-27 and 29-31, 33, 35 are rejected under 35 U.S.C. 103 as being unpatentable over Hershey et al. (Pub. No.: US 20170143972 A1, hereinafter referred to as "Hershey") in view of Maurer (Pat. No.: US 4556051 A, hereinafter referred to as “Maurer”).
As per independent Claim 1, Hershey discloses a method (Hershey in at least abstract, fig. 1-5, fig. 9, [0002], [0005-0030], [0045-0051], [0056-0058], [0061-0063], [0067], [0069-0070], [0083-0089] for example discloses relevant subject-matter. More specifically, Hershey in fig. 9, [0002], [0020], [0045], [0083] for example disclose a method. See at least Hershey [0002] “methods for delivering neuromodulation to treat neuroinflammation and controlling the delivery of the neuromodulation using sensed biomarkers”), comprising:
delivering a therapy by delivering energy to tissue (Hershey in at least [0018], [0047], [0058] for example discloses delivering a therapy by delivering energy to tissue. See at least Hershey [0058] “neuromodulation energy can be delivered in the form of electrical stimulation, magnetic stimulation… or a combination of two or more of such stimulations. Stimulation delivery device 314 can include one or more of lead and/or electrodes such as lead system 214 to deliver electrical stimuli such as electrical pulses, one or more electromagnets to deliver magnetic stimuli”), wherein delivering energy to the tissue includes:
providing a magnetic field in a first direction to the tissue using a magnetic field system including a magnetic field source to produce the magnetic field, wherein the magnetic field produced by the magnetic field source includes a magnetic field produced by at least one of a permanent magnet, a temporary magnet or electric current flow through a conductor (Hershey in at least [0018], [0047], [0058] for example discloses providing a magnetic field in a first direction to the tissue using a magnetic field system including a magnetic field source to produce the magnetic field, wherein the magnetic field produced by the magnetic field source includes a magnetic field produced by at least one of a permanent magnet, a temporary magnet or electric current flow through a conductor. See at least Hershey [0058] “neuromodulation energy can be delivered in the form of electrical stimulation, magnetic stimulation… or a combination of two or more of such stimulations. Stimulation delivery device 314 can include one or more of lead and/or electrodes such as lead system 214 to deliver electrical stimuli such as electrical pulses, one or more electromagnets to deliver magnetic stimuli”);
providing an electric field in a second direction to the tissue using an electric field system including an electric field source to produce the electric field (Hershey in at least [0018], [0047], [0058] for example discloses providing an electric field in a second direction to the tissue using an electric field system including an electric field source to produce the electric field. See at least Hershey [0058] “neuromodulation energy can be delivered in the form of electrical stimulation, magnetic stimulation… or a combination of two or more of such stimulations. Stimulation delivery device 314 can include one or more of lead and/or electrodes such as lead system 214 to deliver electrical stimuli such as electrical pulses, one or more electromagnets to deliver magnetic stimuli” ); and
detecting one or more biomarkers within at least one of a redox system and a metabolic system to perform at least one of: monitoring efficacy of the therapy; or calibrating or adjusting the therapy (Hershey in at least fig. 9, [0005], [0020], [0045-0046], [0061-0062], [0086-0088] for example discloses detecting one or more biomarkers within at least one of a redox system and a metabolic system to perform at least one of: monitoring efficacy of the therapy; or calibrating or adjusting the therapy. See at least [0020] “a method for delivering neuromodulation to a patient … delivering the neuromodulation; controlling the delivery of the neuromodulation using a neuromodulation parameter set selected to modulate neural activity at a tissue site; sensing a biomarker parameter, and adjusting the neuromodulation parameter set using the biomarker parameter. The biomarker parameter may be a measure of a biomarker or a measure of a derivative of the biomarker. The biomarker may be indicative of neuroinflammation at the tissue site.”; [0061] “biomarker can be a metabolic biomarker… the biomarker parameter can be a measure of metabolism of the patient at a particular tissue site … using the biomarker parameter to optimize neuromodulation targeting.” [0062] “using the biomarker parameter to inform a treatment for the patient, such as an intervention that alleviates oxidative stress conditions … the treatment can be delivering neuromodulation to the inflamed tissue site”).
Hershey does not explicitly disclose the electric field second direction is non-parallel to the magnetic field first direction.
However, in an analogous therapy delivering via combined electrical and magnetic energy to treat tissue field of endeavor, Maurer discloses a method (Maurer in abstract, fig. 1-10, col. 1 lines 61-col.10 line 26 for example discloses relevant subject-matter. More specifically, Maurer in abstract, fig. 1, fig. 13, col. 1 line 61- col. 2 line 10, col. 9 lines 60-68 for example discloses a method. See at least Maurer col. 1 line 61- col. 2 line 10 “method is a non-intrusive treatment utilizing electrode means attached to the skin of the patient adjacent the fracture of a bone and coil means located adjacent the skin and the fracture. The electrode means and coil means are used to establish interacting electric and magnetic fields to enhance tissue healing. The coil means is angularly spaced from the electrode means. The electric generator means is electrically connected to the electrode means and the coil means to provide current pulses to the electrode means and coil means. The energized coil means establishes a pulsed magnetic field. The current pulses and the pulsed magnetic field are in a phase relationship with each other so as to produce a unidirectional net current along the length of the bone and through the region of the injured tissue.”), comprising:
delivering a therapy by delivering energy to tissue (Maurer in abstract, fig. 1, fig. 13, col. 1 line 61- col. 2 line 10, col. 9 lines 60-68 for example discloses delivering a therapy by delivering energy to tissue. See at least Maurer col. 1 line 61- col. 2 line 10 “method is a non-intrusive treatment utilizing electrode means attached to the skin of the patient adjacent the fracture of a bone and coil means located adjacent the skin and the fracture. The electrode means and coil means are used to establish interacting electric and magnetic fields to enhance tissue healing”), wherein delivering energy to the tissue includes:
providing a magnetic field in a first direction to the tissue using a magnetic field system including a magnetic field source to produce the magnetic field, wherein the magnetic field produced by the magnetic field source includes a magnetic field produced by at least one of a permanent magnet, a temporary magnet or electric current flow through a conductor (Maurer in at least fig. 1, fig. 13, fig. 10, abstract, col. 1 line 61- col. 2 line 10, col. 9 lines 60-68 for example discloses providing a magnetic field in a first direction to the tissue using a magnetic field system including a magnetic field source/coil means to produce the magnetic field, wherein the magnetic field produced by the magnetic field source includes a magnetic field produced by at least one of a permanent magnet, a temporary magnet or electric current flow through a conductor. See at least Maurer col. 1 line 61- col. 2 line 10 “method is a non-intrusive treatment utilizing … coil means located adjacent the skin and the fracture”);
providing an electric field in a second direction to the tissue using an electric field system including an electric field source to produce the electric field, wherein the second direction is non-parallel to the first direction (Maurer in at least abstract, fig. 1, fig. 13, fig. 10, col. 1 line 61- col. 2 line 16, col. 9 lines 60-68 for example discloses providing an electric field in a second direction to the tissue using an electric field system including an electric field source/electrodes to produce the electric field, wherein the second direction is non-parallel to the first direction. See at least Maurer abstract “apparatus and method for promoting healing of injured tissue, such as fractured bone, with interacting electric current and a magnetic flux field. Electrodes are adhesively attached to the skin adjacent the injured tissue. One or more coil assemblies normally spaced from the electrodes are located adjacent the tissue in alignment with the fractured bone. A current generator electrically connected to the electrodes operates to provide electric current pulses to the electrodes. A field generator electrically connected to the coil assemblies is operable to energize the coil assemblies to produce magnetic field pulses. The pulse generator and field generator are electrically coupled to maintain the electrode current pulses and magnetic field pulses in fixed phase relationship to produce a net current in the region of the fractured bone and generally perpendicular to the plane of the fracture.”; col. 1 line 61- col. 2 line 16 “method is a non-intrusive treatment utilizing electrode means attached to the skin of the patient adjacent the fracture of a bone … The electrode means and coil means are used to establish interacting electric and magnetic fields to enhance tissue healing. The coil means is angularly spaced from the electrode means. The electric generator means is electrically connected to the electrode means and the coil means to provide current pulses to the electrode means and coil means. The energized coil means establishes a pulsed magnetic field. The current pulses and the pulsed magnetic field are in a phase relationship with each other so as to produce a unidirectional net current along the length of the bone and through the region of the injured tissue. The unidirectional current flows generally perpendicular to the surface of the fracture and is of a magnitude and duration appropriate to the specific ion or cellular charge and mobility. ”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the directions of electric field and magnetic fields used in the method as taught by Hershey, such that the electric field direction is non-parallel to the magnetic field direction, as taught by Maurer. A person of ordinary skill would have been motivated to do so, with a reasonable expectation of success, for the advantage of establishing interacting electric and magnetic fields in a manner as to enhance tissue healing (Maurer, abstract, col. 2 lines 1-15).
As per dependent Claim 2, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include at least one of glutathione (GSH) or glutathione disulfide (GSSG) (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0233] “antioxidants such as the glutathione (GSH), glutathione disulfide (GSSG), cysteine (Cys), cystine (CysS)…which participate in neutralizing oxidants by supporting or directly donating reducing equivalents to reduce and neutralize oxidants (see Jones, D. P. Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 295, C849-C868 (2008); Jones, D. P. & Sies, H. The Redox Code. Antioxidants & redox signaling 23, 734-746 (2015); Harris, I. S., et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer cell 27, 211-222 (2015);”).
As per dependent Claim 3, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include at least one cysteine (Cys) or cystine (CysS) (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0233] “antioxidants such as the glutathione (GSH), glutathione disulfide (GSSG), cysteine (Cys), cystine (CysS)…which participate in neutralizing oxidants by supporting or directly donating reducing equivalents to reduce and neutralize oxidants (see Jones, D. P. Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 295, C849-C868 (2008); Jones, D. P. & Sies, H. The Redox Code. Antioxidants & redox signaling 23, 734-746 (2015); Harris, I. S., et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer cell 27, 211-222 (2015);”).
As per dependent Claim 4, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include protein S-glutathionylation (PrSSG) (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0238] “see Dalie-Donne, I., Rossi, R., Colombo, G., Giustarini, D. and Milzani, A., Protein S-glutathionylation: a regulatory device from bacteria to humans. Trends in Biochemical Sciences 34, 86-96 (2008)”).
As per dependent Claim 6, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include at least one of a redox potential of glutathione (GSH) or a redox potential of glutathione disulfide (GSSG) (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0233] “Schafer, F. Q. & Buettner, G. R. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radical Biology and Medicine 30, 1191-1212 (2001).”).
As per dependent Claim 8, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include F2-isoprostane (Applicant in at least instant application specification as-filed [0233] discloses and admits use of F2-isoprostane as an oxidative stress biomarker as well-known prior art. See instant specification as-filed [0233] “F2-isoprostanes … a product of free radical mediated oxidation of arachidonic acid (see Sampson, M. J., Gopaul, N., Davies, I. R., Hughes, D. A. & Carrier, M. J. Plasma. F2 Isoprostanes. Diabetes Care 25, 537 (2002); Milne, G. L., Sanchez, S. C., Musick, E. S. & Morrow, J. D. Quantification of F2-isoprostanes as a biomarker of oxidative stress. Nature protocols 2, 221-226 (2007); Il, et al. Urinary F2-Isoprostanes as a Biomarker of Reduced Risk of Type 2 Diabetes. Diabetes Care 35, 173 (2012)),”).
As per dependent Claim 11, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include a product of free radical mediated oxidation of arachidonic acid (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See Schmidlin instant specification as-filed [0233] “F2-isoprostanes … a product of free radical mediated oxidation of arachidonic acid (see Sampson, M. J., Gopaul, N., Davies, I. R., Hughes, D. A. & Carrier, M. J. Plasma. F2 Isoprostanes. Diabetes Care 25, 537 (2002); Milne, G. L., Sanchez, S. C., Musick, E. S. & Morrow, J. D. Quantification of F2-isoprostanes as a biomarker of oxidative stress. Nature protocols 2, 221-226 (2007); Il, et al. Urinary F2-Isoprostanes as a Biomarker of Reduced Risk of Type 2 Diabetes. Diabetes Care 35, 173 (2012)),”).
As per dependent Claim 12, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include at least one antioxidant from thioredoxin (Trx), peroxiredoxin (Prdx), glutathione-S-transferase (GST), or glutathione peroxidase 3 (GPX3) (Applicant in at least instant application specification as-filed [0148], [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0148] “There is a growing body of evidence showing that the activation of hormesis can be therapeutic in a wide range of diseases or adverse conditions, including diabetes mellitus, obesity, cancer, neurodegenerative disease, inflammation and aging.sup.2-7. (Radak, Z., Chung, H. Y. & Coto, S. Exercise and hormesis: oxidative stress-related adaptation for successful aging. Biogerontology 6, 71-75 (2005); De Haes, W., et al. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proceedings of the National Academy of Sciences 111, E2501 (2014)”; [0233] “antioxidants such as the glutathione (GSH), glutathione disulfide (GSSG), cysteine (Cys), cystine (CysS), thioredoxin (Trx), peroxiredoxin (Prdx), glutathione-S-transferase (GST), glutathione peroxidase 3 (GPX3) which participate in neutralizing oxidants by supporting or directly donating reducing equivalents to reduce and neutralize oxidants (see Jones, D. P. Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 295, C849-C868 (2008); Jones, D. P. & Sies, H. The Redox Code. Antioxidants & redox signaling 23, 734-746 (2015); Harris, I. S., et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer cell 27, 211-222 (2015)”).
As per dependent Claim 13, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include an expression of genes that induce the antioxidant response, including NRF2 (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0233] “NRF2, which translocates to the nucleus upon activation by oxidative stimuli where they induce expression of genes that mediate an antioxidant response (see Kansanen, E., Kuosmanen, S. M., Leinonen, H. & Levonen, A.-L. The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biol 1, 45-49 (2013); Schmidlin, C. J., Dodson, M. B., Madhavan, L. & Zhang, D. D. Redox regulation by NRF2 in aging and disease. Free Radical Biology and Medicine 134, 702-707 (2019), expression of genes that are activated by NRF2 to mediate the antioxidant response: NAD(P)H dehydrogenase [quinone] 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase regulatory subunit (GCLM) (see Kansanen et al.)”).
As per dependent Claim 14, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include an expression of genes that are activated by NRF2 to mediate the antioxidant response, including at least one of: NAD(P)H dehydrogenase [quinone] 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase regulatory subunit (GCLM) (see Kansanen et al.), the redox couples, NADP+, NADPH, NAD+, NADH, redox post-translational modifications, long-chain fatty acids (LCFAs) (e.g. myristate, myristoleate, pentadeconoate, palmitate, palmitoleate, margarate, 10-heptadecenoate, stearate, oleate, vaccinate, nonadecanoate, 10-nonadecenoate, arachidate, eicosenoate, erucate etc.), poly unsaturated fatty acids (PUFAs) (e.g. heneicosapentaenoate, tetradecadienoate, hexadecadienoate, hexadecatrienoate, stearidonate, eicosapentaenoate, docasapentaenoate, docosahexaenoate, docosatrienoate, nisinate, linoleate, linolenate, dihomo-linolenate, arachidonate, adrenate, docosapentaenoate, docosadienoate, dihomo-linoleate, mead acid, docosatrienoate), medium chain fatty acids (MCFAs) (e.g. heptanoate, cis-4-decenoate, 10-undecenoate, 5-dodecenoate etc.), fatty acids dicarboxylate (e.g. glutarate, 2-hydroxyglutarate, 2-hydroxyadipate, 3-hydroxyadipate, suberate, azelate, sebacate, dodecadienoate, dodecanedioate, tetradecanedioate, hexadecanedioate, octadecenedioate, tetradecadienedioate, 3-carbodyy-4-methyl-5-propyl-2-furanpropanoate, 3-carboxy-4-methyl-5-pentyl-2-furanpropionate etc.), amino fatty acids (e.g. 2-aminoheptanoate, 2-aminooctanoate, n-acetyl-2-aminooctanoate etc.), acyl glycine (e.g. isocaproylglycine, valeryiglycine, hexanoylglycine, 4-methylhexanoyiglycine, trans-2-hexenoylglycine, n-octanoylglycine, 2-butenoyiglycine, 3-hydroxybutyroylglycine etc.) and carnitines (e.g. acetylcarnitine, (R)-3-hydroxybutyrylcarnitine, hexanoylcarnitine, octanoylcarnitine, decanoyicarnitine, 5-dodecenoylcarnitine, cis-4-decenoylcarnitine, laurylcarnitine, myristoylcarnitine, palmitoylcarnitine palmitoleoylcarnitine, stearoylcarnitine, linoleoylcarnitine, linolenoylcarnitine, 3-hydroxyoleoylcarnitine, oleoylcarnitine, myristoleoyicarnitine, adipoylcarnitine, octadecenedioylcarnitine, arachidoylcarnitine, arachidonoylcarnitine, behenoylcarnitine, dihomo-linolenoylcarnitine, dihomo-linoleoylcarnitine, eicosenoylcarnitine, docosahexaenoylcarnitine, lignoceroylcarnitine, nervonoylcarnitine, margaroylcarnitine, pentadecanoylcarnitine, 3-hydroxypalrnitoylcarnitine, deoxycarnitine, carnitine etc.) or beta-hydroxybutyrate (Applicant within the claim admits as prior art see Kansanen et al. as disclosing the biomarkers enumerated in this claim. Also, Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0233] “NRF2, which translocates to the nucleus upon activation by oxidative stimuli where they induce expression of genes that mediate an antioxidant response (see Kansanen, E., Kuosmanen, S. M., Leinonen, H. & Levonen, A.-L. The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biol 1, 45-49 (2013); Schmidlin, C. J., Dodson, M. B., Madhavan, L. & Zhang, D. D. Redox regulation by NRF2 in aging and disease. Free Radical Biology and Medicine 134, 702-707 (2019), expression of genes that are activated by NRF2 to mediate the antioxidant response: NAD(P)H dehydrogenase [quinone] 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase regulatory subunit (GCLM) (see Kansanen et al.)”).
As per dependent Claim 15, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include a redox potential (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0233] “Schafer, F. Q. & Buettner, G. R. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radical Biology and Medicine 30, 1191-1212 (2001).”).
As per dependent Claim 16, the combination of Hershey and Maurer as a whole further discloses method wherein detecting the one or more biomarkers includes detecting at least one biomarker in whole blood, plasma, serum, red blood cells, tears, urine, stool, cerebrospinal fluid, lymphatic fluid, breath or sweat (Hershey in at least [0044] for example discloses wherein detecting the one or more biomarkers includes detecting at least one biomarker in whole blood, plasma, serum, red blood cells, tears, urine, stool, cerebrospinal fluid, lymphatic fluid, breath or sweat. See at least Hershey [0044] “Cerebrospinal fluid (CSF) levels of TSPO can be detected using an implantable sensor system to determine a surrogate measure of pain intensity… TSPO levels at a tissue site can be detected using an implantable sensor system, and the detected level of TSPO at the tissue site can be used a surrogate for pain intensity of the patient.”).
As per dependent Claim 17, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include at least one of glutathionylation or cysteinylation (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0238] “see Dalie-Donne, I., Rossi, R., Colombo, G., Giustarini, D. and Milzani, A., Protein S-glutathionylation: a regulatory device from bacteria to humans. Trends in Biochemical Sciences 34, 86-96 (2008)”).
As per dependent Claim 18, the combination of Hershey and Maurer as a whole further discloses method, wherein the one or more biomarkers include NRF2 (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0233] “NRF2, which translocates to the nucleus upon activation by oxidative stimuli where they induce expression of genes that mediate an antioxidant response (see Kansanen, E., Kuosmanen, S. M., Leinonen, H. & Levonen, A.-L. The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biol 1, 45-49 (2013); Schmidlin, C. J., Dodson, M. B., Madhavan, L. & Zhang, D. D. Redox regulation by NRF2 in aging and disease. Free Radical Biology and Medicine 134, 702-707 (2019), expression of genes that are activated by NRF2 to mediate the antioxidant response: NAD(P)H dehydrogenase [quinone] 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase regulatory subunit (GCLM) (see Kansanen et al.)”).
As per dependent Claim 22, the combination of Hershey and Maurer as a whole further discloses method further comprising changing a dose for at least one of the electric field or the magnetic field based on the detected one or more biomarkers (Hershey in at least [0020], [0045-0046], [0087-0088] for example discloses changing a dose for at least one of the electric field or the magnetic field based on the detected one or more biomarkers. See at least Hershey [0045] “system can deliver the neuromodulation and sense the biomarker in the surrounding environment for indicating the patient's response to the delivery of the neuromodulation. The system can store patient data, such as a biomarker parameter associated with the tissue site, and can compare the biomarker parameter to a reference value. Based on the comparison, the system can adjust a parameter set controlling the delivery of the neuromodulation. As used in this document, a “biomarker parameter” can include a measure of the biomarker and/or a measure of a derivative of the biomarker.”).
As per dependent Claim 23, the combination of Hershey and Maurer as a whole further discloses method wherein changing the dose includes changing a duty cycle or a duration the therapy during a period of time (Hershey in at least [0045-0046], [0049] for example discloses wherein changing the dose includes changing a duty cycle or a duration the therapy during a period of time. See at least Hershey [0049] “neuromodulation parameters (also referred to as “the parameters”) can define a neuromodulation pattern (or waveform of stimuli), such as a stochastic pattern, a burst pattern, a frequency modulated pattern, a pulse width modulated pattern, an amplitude modulated pattern, or a biomimetic pattern. In an example, a biomimetic pattern includes a combination of two or more patterns, such as a stochastic pattern and a rate modulated pattern. In one example, the neuromodulation pattern can be a dynamic pattern that can change over time, such as in response to changing results of measurement of a biomarker of the tissue site.”).
As per dependent Claim 24, the combination of Hershey and Maurer as a whole further discloses method wherein changing the dose includes changing a strength of at least one of the magnetic field or the electric field (Hershey in at least [0045-0046], [0049] for example discloses wherein changing the dose includes changing a strength of at least one of the magnetic field or the electric field. See at least Hershey [0049] “neuromodulation parameters (also referred to as “the parameters”) can define a neuromodulation pattern (or waveform of stimuli), such as a stochastic pattern, a burst pattern, a frequency modulated pattern, a pulse width modulated pattern, an amplitude modulated pattern, or a biomimetic pattern. In an example, a biomimetic pattern includes a combination of two or more patterns, such as a stochastic pattern and a rate modulated pattern. In one example, the neuromodulation pattern can be a dynamic pattern that can change over time, such as in response to changing results of measurement of a biomarker of the tissue site.”).
As per dependent Claim 25, the combination of Hershey and Maurer as a whole further discloses method wherein changing the dose includes changing timing for delivering at least one of the magnetic field or the electric field (Hershey in at least [0045-0046], [0049] for example discloses changing the dose includes changing timing for delivering at least one of the magnetic field or the electric field. See at least Hershey [0049] “neuromodulation parameters (also referred to as “the parameters”) can define a neuromodulation pattern (or waveform of stimuli), such as a stochastic pattern, a burst pattern, a frequency modulated pattern, a pulse width modulated pattern, an amplitude modulated pattern, or a biomimetic pattern. In an example, a biomimetic pattern includes a combination of two or more patterns, such as a stochastic pattern and a rate modulated pattern. In one example, the neuromodulation pattern can be a dynamic pattern that can change over time, such as in response to changing results of measurement of a biomarker of the tissue site.”).
As per dependent Claim 26, the combination of Hershey and Maurer as a whole further discloses method wherein the electric field is a static electric field, and the magnetic field is a static magnetic field (Maurer in at least col. 10 lines 5-15 for example discloses the electric field is a static electric field, and the magnetic field is a static magnetic field. See at least Maurer col.10 lines 5-13 “the patient requires uninterrupted currents and magnetic flux fields. The apparatus can be provided with a mode whereby a static magnetic flux field is created by constantly energizing the coil assemblies… a static magnetic flux field can be created with the use of one or more permanent magnets located adjacent the patient. Direct current is provided to the electrodes simultaneously with the energization of the coil assemblies.”).
As per dependent Claim 27, the combination of Hershey and Maurer as a whole further discloses method wherein the delivering the therapy includes delivering the energy to one or more organs or tissues of a mammal to prevent, inhibit or treat one or more symptoms of a disease associated with aberrant reactive oxygen species levels in the mammal (Hershey in at least fig. 9, [0005], [0020], [0018], [0045-0047], [0058], [0061-0062], [0086-0088] for example discloses the delivering the therapy includes delivering the energy to one or more organs or tissues of a mammal to prevent, inhibit or treat one or more symptoms of a disease associated with aberrant reactive oxygen species levels in the mammal. See at least [0020] “a method for delivering neuromodulation to a patient … delivering the neuromodulation; controlling the delivery of the neuromodulation using a neuromodulation parameter set selected to modulate neural activity at a tissue site; sensing a biomarker parameter, and adjusting the neuromodulation parameter set using the biomarker parameter. The biomarker parameter may be a measure of a biomarker or a measure of a derivative of the biomarker. The biomarker may be indicative of neuroinflammation at the tissue site.”; [0061] “biomarker can be a metabolic biomarker… the biomarker parameter can be a measure of metabolism of the patient at a particular tissue site … using the biomarker parameter to optimize neuromodulation targeting.” [0062] “using the biomarker parameter to inform a treatment for the patient, such as an intervention that alleviates oxidative stress conditions … the treatment can be delivering neuromodulation to the inflamed tissue site”), and wherein
the monitoring the efficacy of the therapy includes monitoring efficacy of the magnetic and electric fields; or the calibrating or adjusting the therapy includes calibrating or adjusting at least one of the magnetic field or the applied electric field (Hershey in at least fig. 9, [0005], [0020], [0045-0046], [0086-0088] for example discloses detecting one or more biomarkers within at least one of a redox system and a metabolic system to perform at least one of: monitoring efficacy of the therapy; or calibrating or adjusting the therapy. See at least [0020] “a method for delivering neuromodulation to a patient … delivering the neuromodulation; controlling the delivery of the neuromodulation using a neuromodulation parameter set selected to modulate neural activity at a tissue site; sensing a biomarker parameter, and adjusting the neuromodulation parameter set using the biomarker parameter. The biomarker parameter may be a measure of a biomarker or a measure of a derivative of the biomarker. The biomarker may be indicative of neuroinflammation at the tissue site.”; [0046] “systems, devices, and methods for optimizing treatments for a patient. Metrics that quantify neuroinflammation can be used to determine optimal stimulation targets and parameters for the neuromodulation (e.g., temporal and spatial parameters in a parameter set), and to ensure therapy longevity. Examples of a biomarker can include a neuroinflammatory measure … cytokine concentration in the cerebrospinal fluid (CSF)…One application of the present subject matter can include determining patient-specific treatment approaches to meet a desired therapeutic goal.”).
As per dependent Claim 29, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include at least one of glutathione (GSH) or glutathione disulfide (GSSG) (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0233] “antioxidants such as the glutathione (GSH), glutathione disulfide (GSSG), cysteine (Cys), cystine (CysS)…which participate in neutralizing oxidants by supporting or directly donating reducing equivalents to reduce and neutralize oxidants (see Jones, D. P. Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 295, C849-C868 (2008); Jones, D. P. & Sies, H. The Redox Code. Antioxidants & redox signaling 23, 734-746 (2015); Harris, I. S., et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer cell 27, 211-222 (2015);”).
As per dependent Claim 30, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include at least one of cysteine (Cys) or cystine (CysS) (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0233] “antioxidants such as the glutathione (GSH), glutathione disulfide (GSSG), cysteine (Cys), cystine (CysS)…which participate in neutralizing oxidants by supporting or directly donating reducing equivalents to reduce and neutralize oxidants (see Jones, D. P. Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 295, C849-C868 (2008); Jones, D. P. & Sies, H. The Redox Code. Antioxidants & redox signaling 23, 734-746 (2015); Harris, I. S., et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer cell 27, 211-222 (2015);”).
As per dependent Claim 31, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include protein S-glutathionylation (PrSSG) (Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0238] “see Dalie-Donne, I., Rossi, R., Colombo, G., Giustarini, D. and Milzani, A., Protein S-glutathionylation: a regulatory device from bacteria to humans. Trends in Biochemical Sciences 34, 86-96 (2008)”).
As per dependent Claim 33, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include at least one of a redox potential of glutathione (GSH) or a redox potential of glutathione disulfide (GSSG)( Applicant in at least instant application specification as-filed [0233] discloses and admits use of the recited biomarkers as well-known prior art. See instant specification as-filed [0233] “Schafer, F. Q. & Buettner, G. R. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radical Biology and Medicine 30, 1191-1212 (2001).”).
As per dependent Claim 35, the combination of Hershey and Maurer as a whole further discloses method wherein the one or more biomarkers include F2-isoprostane(Applicant in at least instant application specification as-filed [0233] discloses and admits use of F2-isoprostane as an oxidative stress biomarker as well-known prior art. See instant specification as-filed [0233] “F2-isoprostanes … a product of free radical mediated oxidation of arachidonic acid (see Sampson, M. J., Gopaul, N., Davies, I. R., Hughes, D. A. & Carrier, M. J. Plasma. F2 Isoprostanes. Diabetes Care 25, 537 (2002); Milne, G. L., Sanchez, S. C., Musick, E. S. & Morrow, J. D. Quantification of F2-isoprostanes as a biomarker of oxidative stress. Nature protocols 2, 221-226 (2007); Il, et al. Urinary F2-Isoprostanes as a Biomarker of Reduced Risk of Type 2 Diabetes. Diabetes Care 35, 173 (2012)),”).
Claims 5 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Hershey in view of Maurer and further in view of Rossi et al. (Pub: Rossi R, Giustarini D, Milzani A, Dalle-Donne I. Cysteinylation and homocysteinylation of plasma protein thiols during ageing of healthy human beings. J Cell Mol Med. 2009 Sep;13(9B):3131-40, hereinafter referred to as “Rossi”).
As per dependent Claim 5, the combination of Hershey and Maurer as a whole discloses method of claim 1 (see claim 1 analysis above).
The combination of Hershey and Maurer as a whole does not explicitly disclose biomarkers that include protein S-cysteinylation.
However, in an analogous redox and/or metabolic biomarker use field of endeavor, Rossi discloses method wherein the one or more biomarkers include protein S-cysteinylation (PrCysS) (Rossi in at least abstract, page 3138 discloses wherein the one or more biomarkers include protein S-cysteinylation (PrCysS)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the biomarkers used in the method of Hershey, as modified with Maurer, by further including biomarkers that include protein S-cysteinylation as disclosed in Rossi. A person of ordinary skill would have been motivated to do so, with a reasonable expectation of success, for the advantage that analyses of reduced protein sulphydryls, S-homocysteinylated and S-cysteinylated protein levels in human plasma can be used to assess efficacy of intervention strategies against oxidative stress prior to or early after onset of clinical symptoms in ageing and age-related diseases (Rossi in at least abstract, page 3138).
As per dependent Claim 32, the combination of Hershey and Maurer as a whole discloses method of claim 27 (see claim 27 analysis above).
The combination of Hershey and Maurer as a whole does not explicitly disclose biomarkers that include protein S-cysteinylation.
However, in an analogous redox and/or metabolic biomarker use field of endeavor, Rossi discloses method wherein the one or more biomarkers include protein S-cysteinylation (PrCysS) (Rossi in at least abstract, page 3138 discloses wherein the one or more biomarkers include protein S-cysteinylation (PrCysS)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the biomarkers used in the method of Hershey, as modified with Maurer, by further including biomarkers that include protein S-cysteinylation as disclosed in Rossi. A person of ordinary skill would have been motivated to do so, with a reasonable expectation of success, for the advantage that analyses of reduced protein sulphydryls, S-homocysteinylated and S-cysteinylated protein levels in human plasma can be used to assess efficacy of intervention strategies against oxidative stress prior to or early after onset of clinical symptoms in ageing and age-related diseases (Rossi in at least abstract, page 3138).
Claims 7 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Hershey in view of Maurer and further in view of Grunwell et al. (Pub: Grunwell JR, Gillespie SE, Ward JM, Fitzpatrick AM, Brown LA, Gauthier TW and Hebbar KB (2015) Comparison of Glutathione, Cysteine, and Their Redox Potentials in the Plasma of Critically Ill and Healthy Children. Front. Pediatr. 3:46., hereinafter referred to as “Grunwell”).
As per dependent Claim 7, the combination of Hershey and Maurer as a whole discloses method of claim 1(see claim 1 analysis above)
The combination of Hershey and Maurer as a whole does not explicitly disclose the one or more biomarkers include at least one of a redox potential of cysteine (Cys) or a redox potential of cystine (CysS).
However, in an analogous redox and/or metabolic biomarker use field of endeavor, Grunwell discloses method wherein the one or more biomarkers include at least one of a redox potential of cysteine (Cys) or a redox potential of cystine (CysS) (Grunwell in at least abstract, page 5 col. 2 for example discloses use of biomarkers that include at least one of a redox potential of cysteine (Cys) or a redox potential of cystine (CysS). See Grunwell page col. “a decrease in the abundance of Total Cys, an increase in GSSG, and a more oxidized Eh GSH/GSSG may serve as potential markers of OS events in the plasma of critically ill children. Understanding changes that occur in redox metabolites, redox potentials, and redox signaling pathways in childhood diseases may lead to novel prognostic markers and therapeutic targets in pediatric critical illness. Future studies will work toward assessing the role of protein thiols, other markers of oxidative stress, and signal transduction pathways to elucidate the mechanism of oxidative stress in critically ill children. In addition to studying the biological mechanisms of how changes in Eh Cys/CySS and Eh GSH/GSSG correlate with other markers of OS and influence redox sensitive redox signaling pathways, we plan on evaluating whether the balance of Cys/CySS and GSH/GSSG can differentiate subpopulations of critically ill children with differing severity of critical illness”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the biomarkers used in the method of Hershey, as modified with Maurer, by further including biomarkers that include protein S-cysteinylation Grunwell. A person of ordinary skill would have been motivated to do so, with a reasonable expectation of success, for the advantage of understanding changes that occur in redox metabolites, redox potentials, and redox signaling pathways in diseases can serve as prognostic markers and therapeutic targets in critical ill patients (Grunwell, page 5 col. 2).
As per dependent Claim 34, the combination of Hershey and Maurer as a whole discloses method of claim 27 (see claim 27 analysis above)
The combination of Hershey and Maurer as a whole does not explicitly disclose the one or more biomarkers include at least one of a redox potential of cysteine (Cys) or a redox potential of cystine (CysS).
However, in an analogous redox and/or metabolic biomarker use field of endeavor, Grunwell discloses method wherein the one or more biomarkers include at least one of a redox potential of cysteine (Cys) or a redox potential of cystine (CysS) (Grunwell in at least abstract, page 5 col. 2 for example discloses use of biomarkers that include at least one of a redox potential of cysteine (Cys) or a redox potential of cystine (CysS). See Grunwell page col. “a decrease in the abundance of Total Cys, an increase in GSSG, and a more oxidized Eh GSH/GSSG may serve as potential markers of OS events in the plasma of critically ill children. Understanding changes that occur in redox metabolites, redox potentials, and redox signaling pathways in childhood diseases may lead to novel prognostic markers and therapeutic targets in pediatric critical illness. Future studies will work toward assessing the role of protein thiols, other markers of oxidative stress, and signal transduction pathways to elucidate the mechanism of oxidative stress in critically ill children. In addition to studying the biological mechanisms of how changes in Eh Cys/CySS and Eh GSH/GSSG correlate with other markers of OS and influence redox sensitive redox signaling pathways, we plan on evaluating whether the balance of Cys/CySS and GSH/GSSG can differentiate subpopulations of critically ill children with differing severity of critical illness”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the biomarkers used in the method of Hershey, as modified with Maurer, by further including biomarkers that include protein S-cysteinylation Grunwell. A person of ordinary skill would have been motivated to do so, with a reasonable expectation of success, for the advantage of understanding changes that occur in redox metabolites, redox potentials, and redox signaling pathways in diseases can serve as prognostic markers and therapeutic targets in critical ill patients (Grunwell, page 5 col. 2).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and/or the claims.
Prior art US 6443883 B1 to Ostrow discloses PEMF's developed in a multi-coil, multi-functional PEMF therapeutic device which optimizes penetration of focused electromagnetic fields at a treatment site for bone and soft tissue therapy. More pertinently, for disclosing a method, comprising: delivering a therapy by delivering energy to tissue, wherein delivering energy to the tissue includes: providing a magnetic field in a first direction to the tissue using a magnetic field system including a magnetic field source to produce the magnetic field, wherein the magnetic field produced by the magnetic field source includes a magnetic field produced by at least one of a permanent magnet, a temporary magnet or electric current flow through a conductor; providing an electric field in a second direction to the tissue using an electric field system including an electric field source to produce the electric field, wherein the second direction is non-parallel to the first direction similar to that claimed and disclosed.
Prior art US 20050197522 A1 to Pilla for disclosing apparatus and method for electromagnetic treatment of plants, animals, and humans including configuring at least one waveform according to a mathematical model having at least one waveform parameter, said at least one waveform to be coupled to a target pathway structure; choosing a value of said at least one waveform parameter so that said at least waveform is configured to be detectable in said target pathway structure above background activity in said target pathway structure; generating an electromagnetic signal from said configured at least one waveform; and coupling said electromagnetic signal to said target pathway structure using a coupling device. This prior art is similar in terms of disclosing therapy delivered to tissue via magnetic fields similar to that disclosed.
Prior art US 20110105828 A1 to Perless for disclosing wearable devices and methods for treating a body part using magnets and static magnetic fields similar to that disclosed and claimed. In certain embodiments, the invention provides a device for treating a body part including a carrier and a plurality of magnets, in which the magnets are configured to correspond with a plurality of acupuncture meridian points upon application of the device to the body part.
Prior art US 20160129273 A1 to Park discloses energy delivery device for emitting a combination of different types of energy. The device emits pulsed electromagnetic fields (PEMF) energy and another type of energy, including pulsed electrical energy similar to that disclosed and claimed. The combined energy provides both healing and pain therapy as well as therapy to shallow as well as deeper tissue.
Prior art US 20170224822 A1 to Liang for disclosing methods for achieving high-specificity killing of targeted cells using Magneto-Electric Nano-Particles (MENPs). Embodiments comprise injecting into a patient’s body manufactured MENPs that have a higher tendency to accumulate near or attach to targeted cells through one or more physical forces and/or biological mechanisms; and applying a magnetic field to the MENPs to generate actions that are sufficient to cause death of the targeted cells. This prior art is similar to that disclosed in terms of disclosing delivering therapy via magnetic fields.
Prior art US 6048302 A to Markoll for disclosing apparatus for the treatment of disorders of tissue of a patient via number of coils for generating at least one electromagnetic field which can be applied to the area to be treated similar to that disclosed.
Prior art US 6418345 B1 to Tepper for disclosing method for providing PEMF therapy to selected portions of a patient's body similar to that disclosed. The apparatus preferably includes at least two transducer coils. Electronics for driving the coils are contained in a housing. The housing is preferably connected to the transducer coil by a flexible cable.
Prior art Redox regulation by NRF2 in aging and disease. Free Radic Biol Med. 2019 Apr;134:702-707 to Schmidlin et al. for disclosing Redox regulation by NRF2 in aging and disease. More pertinently, it was made of record for establishing the prior art publication date.
Prior art Glutathione redox state regulates mitochondrial reactive oxygen production. J Biol Chem. 2005 Jul 8;280(27):25305-12 to Shen et al. for disclosing metabolism and bioenergetics of Glutathione redox state regulation of mitochondrial reactive oxygen production similar to that disclosed.
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/SUNITA REDDY/Primary Examiner, Art Unit 3791