DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/06/2025 has been entered.
Status of claim rejections
The rejections of record under 35 USC 103 have been modified in view of Applicant’s amendments in the response filed 11/06/2025.
Claim Interpretation
Amended claim 20 now recites “measuring a level of glutathionylated FUS protein from a subject-derived neuron sample using an immunoprecipitation or a tissue staining assay”. The examiner has interpreted this limitation under broadest reasonable interpretation to encompass that the use of any immunoprecipitation or tissue staining technique will measure a level of glutathionylated FUS in the tissue. This is supported by, e.g., Example 3 of the specification.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
First rejection
Claims 20, 34, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Kwiatkowski et al (WO2010011283A2), Dhar et al (Antioxid Redox Signal. 2014 Apr 1;20(10):1550-66; hereinafter “Dhar”; prior art of record), and Menon et al (J Biol Chem. 2013 Sep 6; 288(36): 25769–25779; prior art of record; hereinafter “Menon”).
Kwiatkowski teaches a method for diagnosing ALS or related motor neuron disease in a subject comprising detecting in a sample obtained from an individual one or more genetic markers in a FUS/TLS nucleic acid, protein or fragment (a method of diagnosing ALS in a subject from a subject-derived biological sample as in claim 20, in part) (see abstract; claim 1) and administering to the individual a therapeutically effective amount of a composition suitable to delay, reduce or prevent ALS or the related motor neuron disease in the individual and/or treating the individual with therapy (administering to a subject indicated as having ALS as in claim 20 in part) (see pg. 5; see also claim 10). Kwiatkowski also teaches that the sample can come from brain cells or the central nervous system (i.e., neuron as in claim 20 and brain neuron as in claim 39) (see pg. 10, lines 1-4). Kwiatowski also teaches using tissue staining of the brain and spinal cord tissue of ALS patients vs. controls, where the staining of the patient population sample showed prominent cytoplasmic staining vs the control (showing neucleus staining) (see Fig, 2A-B).
The difference between Kwiatkowski and the instant claims is that Kwiatkowski does not explicitly teach measurement of glutathionylated FUS protein.
However, Applicant’s specification discloses the use of tissue staining to confirm in vivo glutathionylation of FUS, where “the human wild-type FUS protein is located mainly in the nucleus of neurons of the brain of Drosophila, but as indicated by the arrows of FIG. 2A, when the human wild-type FUS protein is overexpressed, it was confirmed that a large amount of human wild-type FUS protein aggregates are observed in the cytoplasm (green). In addition, as indicated by the arrows of FIG. 2B, it was confirmed that the reduced glutathione (GSH) is observed in the cytoplasm (red). In addition, as indicated by the arrows of FIG. 2C in which FIGS. 2A and 2B are combined, it was confirmed that the FUS protein aggregate in the neuron cytoplasm of the brain is observed at the same location as the reduced glutathione (GSH). The above result means that both of a human wild-type FUS protein glutathionylated by the oxidized glutathione (glutathione disulfide, GSSH) and the reduced glutathione (GSH) generated by glutathionylation are present in the cytoplasm in vivo.” Applicant’s specification also evidences that the RanBP2 zinc-finger (ZnF) domain of FUS has four cysteines, and all four cysteines are well conserved from flies to humans, and among these, a glutathionylation site in the RanBP2-type ZnF domain, Cys-447. Thus, absent evidence to the contrary, the glutathionylation of Cys-447 is an inherent property of FUS protein as it relates to the ALS disease state. Further, as the claimed invention requires the use of the same active method step as Kwiatkowski (i.e., staining tissue to measure level of FUS protein in the cytoplasm of ALS patients vs. controls), the staining protocol of Kwiatkowski would also measure glutathionylated FUS protein associated with ALS (as in claim 20).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of diagnosing ALS as taught by Kwiatkowski by
Kwiatkowski does not teach comparison of comparing the glutathionylated FUS protein with a glutathionylated FUS protein of a normal control sample, wherein an increased level of the glutathionylated FUS protein compared to the FUS protein of the normal control sample is indicative of the subject having ALS (as in claim 20 in part).
However, Dhar teaches roles of wild-type and mutant FUS in MnSOD gene activation using cell culture models and skin biopsy samples from fALS patients with the R521G FUS mutation (abstract; pg. 1551, col 2, paragraph 1). Dhar teaches the comparison of glutathione levels in the skin fibroblasts (i.e., a biologically derived sample) from normal control (comparing glutathionylation level of FUS in a normal control sample as in claim 20) to the skin fibroblasts of fALS patients, and demonstrated that the overexpression of FUS led to the reduction of GSSG and an increase in GSH:GSSG ratio (Supplementary Fig. 6B). Consistently, GSSG levels were higher in primary fibroblasts from fALS patients compared to normal counterparts (indicating subject as having ALS as in claim 20). GSH levels remained unchanged in fALS patients compared to controls resulting in decreased GSH:GSSG ratio (Supplementary Fig. 6C; pg. 1559 col 1, paragraphs 2-3).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of diagnosing and treating ALS using FUS protein as taught by Kwiatkowski by comparing glutathionylation level of a FUS protein of a normal control sample as taught by Dhar to arrive at the claimed invention. As Kwiatkowski teaches a method of diagnosing ALS using FUS and Dhar teaches comparison of glutathione levels in the skin fibroblasts sample from normal control to samples of patients with ALS, one of ordinary skill would have been motivated to make the modification with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Dhar teaches that the glutathione levels of a normal control subject can be successfully compared with the glutathione levels in a subject identified as having ALS.
Kwiatkowski and Dhar do not teach administering omega class glutathione transferase 1 (GSTO1) or omega class glutathione transferase 2 (GstO2) gene or a protein encoding the same to a subject indicated as having ALS.
However, Menon teaches glutathionylation of intracellular protein thiols can protect against irreversible oxidation and can act as a redox switch regulating metabolic pathways (pg. 25769, col 1, paragraph 1). Menon also teaches that the omega class glutathione transferase 1 and 2 (GSTO1-1; also known as GSTO1) have been investigated in relation to a number of biologically significant pathways and clinical disorders including drug resistance, Alzheimer disease, Parkinson disease, vascular dementia and stroke, and amyotrophic lateral sclerosis (pg. 25769, col 2, paragraph 3). Menon specifically teaches the use of human GSTO-1 as well as variants of GSTO-1 that can catalyze the deglutathionylation of protein thiols in vitro and in cell culture and that GSTO-1 participates in the glutathionylation cycle to target specific proteins in the presence of GSH (i.e., demonstrating GTSO1 induces deglutathionylation as in claim 20) (Fig. 1; pg. 25771, col 2, paragraph 4; Fig. 6). Please note that Menon does not explicitly teach demonstrating induction deglutathionylation of the FUS protein specifically. However, one of ordinary skill in the art would have readily utilized GSTO1 to deglutathionylate protein (i.e., such as FUS protein) because Menon provides the teaching, suggestion, and motivation that GSTO1 is capable of deglutathionylating proteins associated with neurological disorders, including ALS.
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of diagnosing and treating ALS using FUS protein as taught by Kwiatkowskiand Dhar by administering GSTO1 as taught by Menon to arrive at the claimed invention. As Kwiatkowski and Dhar teach method of diagnosing ALS using FUS protein and administering a therapeutic to treat the disease and Menon teaches the use of human GSTO-1 to catalyze the deglutathionylation of proteins, one of ordinary skill would have been motivated to use the GSTO-1 of Menon with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Menon teaches that GSTO1 is advantageously capable of catalyzing the deglutathionylation of protein thiols in and that GSTO-1 participates in the glutathionylation cycle to target specific proteins in the presence of GSH.
Regarding claim 34, as further discussed above, Applicant’s specification evidences that the glutathionylation of Cys-447 is an inherent property of FUS protein as it relates to the ALS disease state. Thus, absent evidence to the contrary, the glutathionylation of Cys-447 (as in claim 34) is an inherent property of FUS protein as it relates to the ALS disease state. Furthermore, using the method of Kwiatkowski, Dhar, and Menon would inherently detect glutathionylation of Cys-447. The prior art combination teaches the detection of glutathionylation of FUS protein in the disease morphology of ALS, which would be indistinguishable from the detection of glutathionylation of FUS at the Cys-447 residue in the ALS context.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Second rejection
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Kwiatkowski, Dhar, and Menon as applied to claim 20 and 34 above, and further in view of Fujimoto et al (JP 2014217339 A; 20 November 2014; prior art of record; hereinafter “Fujimoto”).
As discussed above, claims 20 and 34 were rendered prima facie obvious by the combined teachings of Kwiatkowski, Dhar, and Menon.
The difference between Kwiatkowski, Dhar, and Menon and the instant claims is that neither Kwiatkowski, Dhar, nor Menon explicitly teach the FUS protein consists of the amino acid sequence represented by SEQ ID NO: 1.
However, Fujimoto (in the field of TLS/FUS proteins) teaches an anti-TLS monoclonal antibody which can specifically recognize TLS in which an arginine residue is unsymmetrically demethylated (title, abstract). TLS (Translocated in LipoSarcoma) is an RNA-binding protein and is also called FUS (Fused in Sarcoma) (pg. 2, paragraph 1). Fujimoto teaches that a method for producing an anti-TLS monoclonal antibody, wherein the recovered antibody recognizes TLS in which an arginine residue is asymmetrically demethylated (pg. 2, paragraph 10). Fujimoto also teaches the creation of a plasmid DNA that encodes a fusion protein of GST and TLS (pg. 6, paragraph 12), where the TLS/FUS protein (SEQ ID NO: 4) has 100% sequence identity to instant SEQ ID NO: 1 (as in claim 33) (see alignment below). Fujimoto further teaches that the antibody can specifically recognize TLS in which an arginine residue is asymmetrically 4emethylated, and can be suitably used as a reagent for examining the methylation state of an arginine residue, a biomarker of ALS, etc. (pg. 7, paragraph 6). Fujimoto does not explicitly teach that the TLS/FUS protein is glutathionylated, however, the sequence of Fujimoto has 100% sequence identity to the instantly claimed sequence. Thus, absent evidence to the contrary, the TLS/FUS protein of Fujimoto is glutathionylated (as in claim 33).
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Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of diagnosing ALS using FUS protein as taught by Kwiatkowski, Dhar, and Menon, and use the TLS/FUS protein as taught by Fujimoto to arrive at the claimed invention. As Kwiatkowski, Dhar, and Menon teach a method of diagnosing ALS using FUS glutathionylation and Fujimoto teaches a TLS/FUS protein for use in identification of a specific protein modification, one of ordinary skill would have been motivated to use the TLS/FUS protein of Fujimoto with a reasonable expectation of success. One of ordinary skill would have been motivated to use the protein sequence of Fujimoto because Fujimoto teaches a sequence of TLS/Fus protein that can successfully be used in a method to recognize a specific protein modification associated with ALS.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Third rejection
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Kwiatkowski, Dhar, and Menon as applied to claims 20 and 34 above, and further in view of AF212303; disclosed by Board et al (J. Biol. Chem. 275 (32), 24798-24806 (2000); hereinafter “AF2”).
As discussed above, claims 20 and 34 were rendered prima facie obvious by the combined teachings of Kwiatkowski, Dhar, and Menon.
As discussed above, Menon teaches that human GSTO1 is advantageously capable of catalyzing the deglutathionylation of protein thiols in and that GSTO-1 participates in the glutathionylation cycle to target specific proteins in the presence of GSH (see above).
The difference between Kwiatkowski, Dhar, and Menon and the instant claims is that neither none of the references explicitly teach the GSTO1 gene consists of the base sequence represented by SEQ ID NO: 2.
However, AF2 discloses a sequence of human GSTO1 that is 100% identical to SEQ ID NO: 2 (see alignment below). This sequence (as disclosed and evidenced by Board) is an Omega class GST (GSTO1/GSTO1-1) that exhibits an unusual N-terminal extension that abuts the C-terminus to form a novel structural unit (see Board, pg. 24798, col 1, abstract; paragraph 1-2). Unlike other mammalian GSTs, GSTO 1-1 appears to have an active site cysteine that can form a disulfide bond with glutathione (see pg. 24798, col 1). Furthermore, recombinant human Omega class GST (GSTO 1-1) exhibits a glutathione-dependent thiol transferase activity and catalyzes glutathione-dependent reduction of dehydroascorbate (see Table 1-2; Fig. 1).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of diagnosing ALS using FUS protein as taught by Kwiatkowski, Dhar, and Menon, and use the GSTO-1 nucleic acid as taught by AF2 to arrive at the claimed invention. As Kwiatkowski, Dhar, and Menon teach the diagnosis of ALS and administration of GSTO-1 and AF2 teaches a sequence of GSTO-1 capable of forming a disulfide bond with glutathione, one of ordinary skill would have been motivated to make the modification with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because AF2 teaches a suitable nucleic acid sequence of GSTO-1 that can advantageously form a disulfide bond with glutathione.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments filed 11/06/25 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to the Cayman reference have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Please note that the examiner will respond to the arguments as it relates to the other cited references.
On pg. 4-8, Applicant argues that the references do not teach the method of claim 20. Specifically, Applicant argues Kwiatkowski fails to teach the comparison step and measuring level of glutathionylated FUS using an immunoprecipitation or tissue staining assay. Applicant argues that while Dhar discloses comparison of glutathionylation in skin fibroblasts, it fails to disclose comparison in a subject’s neuron sample. Applicant argues that Kwiatowski is limited to sampling and assaying of neuronal derived genetic material and does not teach that CNS or brain cells are a suitable sample for measuring glutathionylated Fus protein that indicated ALS. Applicant argues that detecting glutathionylation and measuring glutathione levels are fundamentally different and the kit of Dharwould does not measure level of glutathionylated FUS protein at all, whereas claim 20 refers to actual FUS protein bound to glutathione and Dhar would be understood by a PHOSITA as limited to measuring GSH/GSSG concentrations and not glutathionylated FUS. Applicant further argues that the findings of Dhar are very basic, and that glutathionylation of specific proteins is a more complex biological event. Applicant then concedes that Dhar shows increase of GSSG/GSH ratio when FUS is overexpressed in Figure S6.B but that Dhar interprets it as a favorable outcome in protecting from ALS-related damage and that the results come from highly artificial experimental setting.
In response, the examiner disagrees. First, while Dhar (in a similar field of endeavor) uses skin fibroblast to detect overexpression of FUS, Kwiatkowski explicitly teaches a method for diagnosing ALS in a subject by detecting in a sample obtained from an individual one or more genetic markers in a FUS/TLS nucleic acid, protein or fragment (i.e., diagnosing ALS using a genetic marker from FUS protein) (see abstract; claim 1) and administering to the individual a therapeutically effective amount of a composition suitable to delay, reduce or prevent ALS or the related motor neuron disease in the individual and/or treating the individual with therapy (see pg. 5; see also claim 10), and that the sample can come from brain cells or the central nervous system (i.e., neuron/brain neuron) (see pg. 10, lines 1-4). Thus, Dhar and Kwiatkowski in combination provides one of ordinary skill the teaching, suggestion, and motivation to apply the measurement of glutathionylation to neuronal samples.
Second, as further discussed above, the claim (as amended) now requires measurement of glutathionylated FUS protein via immunoprecipitation or tissue staining. However, Applicant’s specification discloses the use of tissue staining to confirm in vivo glutathionylation of FUS, where “the human wild-type FUS protein is located mainly in the nucleus of neurons of the brain of Drosophila, but as indicated by the arrows of FIG. 2A, when the human wild-type FUS protein is overexpressed, it was confirmed that a large amount of human wild-type FUS protein aggregates are observed in the cytoplasm (green). In addition, as indicated by the arrows of FIG. 2B, it was confirmed that the reduced glutathione (GSH) is observed in the cytoplasm (red). In addition, as indicated by the arrows of FIG. 2C in which FIGS. 2A and 2B are combined, it was confirmed that the FUS protein aggregate in the neuron cytoplasm of the brain is observed at the same location as the reduced glutathione (GSH). The above result means that both of a human wild-type FUS protein glutathionylated by the oxidized glutathione (glutathione disulfide, GSSH) and the reduced glutathione (GSH) generated by glutathionylation are present in the cytoplasm in vivo.” Applicant’s specification also evidences that the RanBP2 zinc-finger (ZnF) domain of FUS has four cysteines, and all four cysteines are well conserved from flies to humans, and among these, a glutathionylation site in the RanBP2-type ZnF domain, Cys-447. Thus, absent evidence to the contrary, the glutathionylation of Cys-447 is an inherent property of FUS protein as it relates to the ALS disease state. Further, as the claimed invention requires the use of the same active method step as Kwiatkowski (i.e., staining tissue to measure level of FUS protein in the cytoplasm of ALS patients vs. controls), the staining protocol of Kwiatkowski would also measure glutathionylated FUS protein associated with ALS.
Third, as Applicant readily concedes, Dhar explicitly teaches that FUS overexpression leads to increased GSSG/GSH ratio (see Supplementary Fig. S6.8), which runs contrary to Applicant’s assertion that the reference does not teach it. Whether or not the teachings of Dhar comes from “a highly artificial experimental setting” does not negate the fact that Dhar provides explicit teachings that, when combined with Kwiatkowski, would lead one of ordinary skill to the claimed invention before the filing date of the instant application because Dhar teaches that the glutathione levels of a normal control subject can be successfully compared with the glutathione levels in a subject identified as having ALS.
On pg. 8-11, Applicant argues that measurement of GSH/GSSG concentrations in fibroblasts merely reflects changes in cellular stress and the measurement used in the present invention is different in both target and methodology (detecting glutathione covalently bound to cysteine residues of FUS protein using immunoprecipitation and tissue staining) from Dhar. Applicant also argues that changes in GSH/GSSG levels are widely studied for a variety diseases, Kwiatowski recites detecting genetic markers in FUS/TLS nucleic acid or fragment, and Kwiatkowski fails to teach that CNS or brain cells are a suitable sample for measuring glutathionylation of FUS. Applicant further argues that Menon, in combination with the previously recited references, fails to make up for the deficiencies of the art, in particular Dhar. Applicant argues that Menon fails to teach comparison of glutathionylation of FUS protein in a subject-derived neuron sample versus normal control sample or administering GSTO1 to a subject identified as having ALS and one of ordinary skill would not have had a reasonable expectation of success without improper hindsight.
In response, the examiner disagrees for much of the reasons as set forth above. Kwiatkowski explicitly teaches a method for diagnosing ALS in a subject by detecting in a sample obtained from an individual one or more genetic markers in a FUS/TLS nucleic acid, protein or fragment (i.e., diagnosing ALS using a genetic marker from FUS protein) (see abstract; claim 1) and administering to the individual a therapeutically effective amount of a composition suitable to delay, reduce or prevent ALS or the related motor neuron disease in the individual and/or treating the individual with therapy (see pg. 5; see also claim 10), and that the sample can come from brain cells or the central nervous system (i.e., neuron/brain neuron) (see pg. 10, lines 1-4).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Menon does not have to disclose the comparison step because Menon is used for the specific teaching, suggestion, and motivation provided to one of ordinary skill to use human GSTO-1 as well as variants of GSTO-1 to catalyze the deglutathionylation of because GSTO-1 participates in the glutathionylation cycle to target specific proteins in the presence of GSH (Fig. 1; pg. 25771, col 2, paragraph 4; Fig. 6). Thus, the use of the Menon reference is maintained with respect to the instant claims.
On pg. 11-18, Applicant argues much of the same as it relates to the Kwiatkowski, Dhar, and Menon references for the same reasons as set forth above (and which will not be repeated here). Specifically, Applicant argues that Fujimoto (used to reject claim 33) fails to make up for the deficiencies of the references. Applicant concedes that Fujimoto teaches a GSTO1 that is 100% identical to SEQ ID NO:1 but does not teach administration of an agent to a subject identified as having ALS by using comparison of glutathionylation of FUS in a subject’s neuron sample. Applicant further argues that Board/AF2 (used to reject claim 35) fails to make up for the deficiencies of the references. Applicant concedes that Board/AF2 teaches a GSTO1 that is 100% identical to SEQ ID NO:2 but does not teach administration of an agent to a subject identified as having ALS.
In response, the examiner disagrees for much of the reasons as set forth above. The comparison step was rendered prima facie obvious by the combination of Kwiatkowski, Cayman, and Dhar for the reasons set forth above. Neither the Fujimoto or Board reference need to disclose the comparison step because the comparison step was rendered prima facie obvious by the combination of Kwiatkowski, and Dhar and Menon for the reasons set forth above. The administration of GTSO1 was rendered obvious by the Menon reference via the specific teaching, suggestion, and motivation provided to one of ordinary skill to use human GSTO-1 as well as variants of GSTO-1 to catalyze the deglutathionylation of because GSTO-1 participates in the glutathionylation cycle to target specific proteins in the presence of GSH (Fig. 1; pg. 25771, col 2, paragraph 4; Fig. 6). Fujimoto and Board are specifically used for their teachings regarding the specific amino acid and nucleotide sequences known in the prior art, which when taken in light of the other prior art references, would be useful for the method as instantly claimed. Thus, the Fujimoto and Board references are maintained with respect to the instant claims.
Conclusion
NO CLAIMS ALLOWED.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IR. Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol. 2009 Nov;118(5):605-16
Scekic-Zahirovic, J., Oussini, H.E., Mersmann, S. et al. Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis. Acta Neuropathol 133, 887–906 (2017).
Scekic-Zahirovic et al. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. EMBO J. 2016 May 17;35(10):1077-97.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGIANA C REGLAS whose telephone number is (571)270-0995. The examiner can normally be reached M-Th: 8:00am-2:00pm.
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672