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. Election/Restrictions 2. Applicant’s election without traverse of Group II, in the reply filed on January 28, 2026, is acknowledged with appreciation . Applicant additionally elected the species (1) amlexanox as the single compound, and (2) PP1R1B as the single mediator protein, without traverse. 3. Claims 15, 18, 19, 21 and 24 are readable on the species amlexanox, and of these, claims 15, 18, 21 and 24 are readable on the protein PP1R1B (listed in Table 3B ). 4. C laim s 16, 17, 19, 22, 23 and 25-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter , there being no allowable generic or linking claim. Application Status 5. A method of administering amlexanox for increasing the activity of the elected species of mediator protein PPP1R1B was found to be free of the prior art. However, no claim reads solely on the elected species of mediator protein . In accord with MPEP 803.02 the search was extended to the extent necessary to determine patentability of the Markush-type claim. As discussed in the 10 3 rejection below, art was found that reads on the Markush-type claim. In accord with MPEP 803.02 the search is not extended unnecessarily to all species. The scope of the independent invention that encompasses the elected species is as follows: A method of increasing the activity, level, or any combination thereof of a mediator protein in a subject, wherein the mediator protein is selected from the list of mediator proteins in Table 3B, comprising administering amlexanox. 6 . Claims 15, 18, 21 and 24 are under examination with the elected species and are the subject of this office action. Information Disclosure Statement 7 . The information disclosure statement (IDS) submitted on October 1, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner , please refer to the signed copy of Applicant’s PTO-1449 form, attached herewith. Specification 8 . Applicant is reminded of the proper content of an abstract of the disclosure. In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class. For processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary. 9 . The abstract of the disclosure is objected to because the abstract fails to state the instantly recited methods of use: (1) the method of increasing the activity, level, or any combination thereof of a mediator protein selected from the list of mediator protein in Tables 3B and 3D in a subject, the method comprising administering a compound selected from: metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib or a pharmaceutically acceptable salt, prodrug, or derivative thereof; or any combination thereof ; and (2) the method of decreasing the activity, level, or any combination of a mediator protein selected from the list of mediator protein in Tables 3C and 3E in a subject, the method comprising administering a compound selected from: metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib, or a pharmaceutically acceptable salt, prodrug, or derivative thereof; or any combination thereof. 10 . A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b). Claim Rejections - 35 USC § 112(b) 1 1 . The following is a quotation of 35 U.S.C. 112(b): (b ) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the appl icant regards as his invention. 1 2 . Claim s 15 , 18, 21, and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. 1 3 . Claim 15 is rejected as being unclear for reciting the administration of a compound without specifying who or what is receiving the administration. Specifically, claim 15 recite s : “… the method comprising administering a compound selected from…,” but fail to identify the subject /patient receiving the administration such that one skilled in the art would not know how to practice the claimed invention. Clarification is requested. In view of a broadest reasonable interpretation, claim 15 is construed to mean: “A method of increasing the activity, level, or combination thereof of a mediator protein selected from the list of mediator proteins in Tables 3B and 3D, below, in a subject in need thereof, comprising administering to said subject a compound selected from: metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib, or a pharmaceutically acceptable salt, prodrug, or derivative thereof; or any combination thereof. ” 1 4 . Claims 18, 21 and 24 are rejected as being dependent upon and including all of the limitations of claim 15 . Claim Rejections - 35 USC § 112(a) 1 5 . The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 1 6 . Claim s 15, 18, and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement , regarding the full scope of compounds selected from metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib, or a pharmaceutically acceptable salt, prodrug, or derivative thereof; or any combination thereof . The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. 1 7 . In particular, support cannot be found for the full scope of compounds selected from metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib, or a pharmaceutically acceptable salt, prodrug, or derivative thereof; or any combination thereof , as instantly recited in the claims . 18 . The MPEP §2163 states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. In the case of chemical entities, Applicant's attention is further directed to Regents of the University of California v. Eli Lilly & Co. , 119 F.3d 1559 (Fed. Cir. 1997), cert. denied , 523 U.S. 1089, 118 S. Ct. 1548 (1998), which notes that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, “not a mere wish or plan for obtaining the claimed chemical invention.” While the court recognizes that, “[i]n claims involving chemical materials, generic formulae usually indicate with specificity what the generic claims encompass” ( Id. ), it is also recognized that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim and/or the genus must be sufficiently detailed to show that applicant was in possession of the claimed invention as a whole (see Vas-Cath, Inc. v. Mahurkar , 935 F.2d 1555 (Fed. Cir. 1991)). If a genus has substantial variance, the disclosure must present a sufficient number of representative species that encompass the genus in order to adequately describe the genus (i.e., the disclosure must describe a sufficient variety of species to reflect the variation within that genus). See MPEP § 2163. Otherwise, as stated by the court in Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company (Fed. Cir. 2010), “a generic claim may define the boundaries of a vast genus of chemical compounds, and yet the question may still remain whether the specification, including original claim language, demonstrates that the A pplicant has invented species sufficient to support a claim to a genus. 19 . I t is evident that the genus of drugs embraced by the claims has substantial variance . The claims embrace the use of any compound selected from : metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, or baricitinib, as well as any pharmaceutically acceptable salt, prodrug or derivative thereof . A “ prodrug ” is defined as a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation. There are numerous reasons why one would utilize a prodrug in the pharmaceutical arts: to increase solubility, to improve absorption and distribution, for organ or tissue specificity, to enhance stability, for prolonged release, to make temporarily non-toxic, for patient acceptability, and to correct formulation problems, for example. There are several classifications of prodrugs, including carrier-linked prodrugs and bio-precursors, which can be activated at various functional groups to produce, for example, ester analogs of alcohols as prodrugs, and prodrug analogs of amines. The instant ly recited compounds have multiple sites of possible cleavage for prodrug activation, i.e. , any -OH or -NH moieties, for example. However, Applicant is silent as to specific prodrugs of the instant invention . A “derivative” embraces any compound formed from a parent compound by replacing, adding, or modifying one or more atoms or functional groups, which results in a new compound having distinct properties. Thus, the recite d derivatives embrace hundreds of thousands of potential compounds or alternatives that bear no structural resemblance to one another what-so-ever. Yet the instant Specification fails to define any such derivatives and discloses the preparation of only one of said compounds, i.e., amlexanox (Example 3 at pages 64-67) , and fails to disclose any prodrugs, or derivatives thereof . 2 0 . While the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad generic. For example, in In re Gostelli , the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli , 872 F.2d 1008 (Fed. Cir. 1989). In the instant case, it is similarly determined that the disclosure of just one compound ( i.e ., amlexanox ) does not adequately describe a genus embracing hundreds of thousands of compounds and their salts, prodrugs, or derivatives thereof, that bear no structural relationship with amlexanox . That is, the Specification does not disclose a sufficient variety of species to reflect the breadth of the possible compound selections recited in the claims . 2 1 . The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder , 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate”) . Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of compounds and their salts, prodrugs, or derivatives thereof recited in the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention. As such, claim s 15, 18, and 21 are rejected. 2 2 . Claims 15, 18, 21 and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for a method of increasing the activity and/or expression level of certain mediator proteins in Tables 3B and 3D including PIGK, NRBP1, APOD, and LAMTOR2, comprising administering an effective amount of amlexanox (see Figure 7) , does not reasonably provide enablement for a method of administering an y amount of the full scope of compounds and their salts, prodrugs, or derivatives thereof, as instantly claimed. T he specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. 2 3 . The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde , 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands , 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below : 1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention, 5) the state of the prior art, 6) the relative skill of those in the art, 7) the predictability of the art, and 8) the breadth of the claims. 2 4 . These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher , 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons. 2 5 . Nature of the Invention : As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e ., the subject matter to which the claimed invention pertains.” In the instant case, the claims are drawn to a method of increasing the activity, level, or any combination thereof of a mediator protein selected from the list of mediator protein in Tables 3B and 3D in a subject, the method comprising administering a compound selected from: metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib or a pharmaceutically acceptable salt, prodrug, or derivative thereof; or any combination thereof. 2 6 . The state of the prior art, level of predictability and relative skill level : A s stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.” 2 7 . As discussed above, the instantly claimed invention pertains to a method of increasing the activity, level, or any combination thereof of a mediator protein selected from the list of mediator protein in Tables 3B and 3D in a subject, comprising administering a compound selected from: metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib or a pharmaceutically acceptable salt, prodrug, or derivative thereof; or any combination thereof. 28 . The relative skill of those in the art is high, that of an MD or PhD. That factor is outweighed, however, by the unpredictable nature of the art. T he state of the art regarding the recited compounds, metformin is a known antidiabetic agent ; pentosan polysulfate is known to treat intersitial cystitis ; amlexanox is known for the treatment of canker sores and certain inflammatory conditions ; leflunomide is known for treating rheumatoid arthritis ; prasterone is known for treating menopause or adrenal insufficiency ; glutathione disulfide is a known antioxidant ; pazopanib, bosuitinib, dabrafenib, and baricitinib are known tyrosine kinase inhibitors that are useful for treating cancer and/or certain immune disorders. 29 . As illustrative of the state of the art regarding age-associated dendritic spine loss, or age related cognitive decline, Huang et al . teach that the effects of aging on cognitive decline and dendritic spine plasticity remain complicated and unclear: “ Despite many efforts, the cellular basis of age-related cognitive decline remains unclear. It was once believed that a generalized neuronal loss in the cerebral cortex and deterioration of dendritic branching occurs during normal aging and contributes to cognitive impairment (Brody, 1955 ; Coleman and Flood, 1987 ). Yet stereological studies have documented minimal aging-related neuronal loss in the cortex and hippocampus (West et al., 1994 ; Morrison and Hof, 1997 ) … “ Recent in vivo imaging studies reported that aging alters the dynamics of dendritic spines in the cortex of old mice (Mostany et al., 2013 ; Davidson et al., 2020 ). But how aging affects dendritic spine plasticity associated with learning remains unknown. ” (Frontiers in Neural Circuits, 2020 , page 1, last paragraph- page 2, second paragraph ). 3 0 . The amount of direction or guidance provided and the presence or absence of working examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples . In the instant case, the specification provides no direction or guidance for the use of the full scope of possible compounds, salts, prodrugs or derivatives thereof embraced by the claims . In this case, t he instant Specification discloses the use of only one of said compounds, salts, prodrugs, or derivatives thereof, i.e., amlexanox (Example 3 at pages 64-67). 3 1 . No reasonably specific guidance is provided concerning useful therapeutic protocols comprising administering any other compound, salt, prodrug or derivative thereof according to the claims. 3 2 . The breadth of the claims : As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation.” Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, the Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright , 999 F.2d 1557 (Fed. Cir. 1993) (emphasis added). At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt , 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner , 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art. 3 3 . Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims . " Amgen, Inc . , v. Chugai Pharmaceutical Co., Ltd . (Fed. Cir. 1991). As noted by the court in In re Fisher , 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac , 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore , 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”. 3 4 . As to the first inquiry, as discussed above i t is evident that the genus of formulations embraced by the claims has substantial variance , i.e., any compound selected from metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib, or any pharmaceutically acceptable salt, prodrug, or derivative thereof . A “ prodrug ” is defined as a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation. There are numerous reasons why one would utilize a prodrug in the pharmaceutical arts: to increase solubility, to improve absorption and distribution, for organ or tissue specificity, to enhance stability, for prolonged release, to make temporarily non-toxic, for patient acceptability, and to correct formulation problems, for example. There are several classifications of prodrugs, including carrier-linked prodrugs and bio-precursors, which can be activated at various functional groups to produce, for example, ester analogs of alcohols as prodrugs, and prodrug analogs of amines. The instant ly recited compounds have multiple sites of possible cleavage for prodrug activation, i.e. , any -OH or -NH moieties, for example. However, Applicant is silent as to specific prodrugs of the instant invention . A “derivative” embraces any compound formed from a parent compound by replacing, adding, or modifying one or more atoms or functional groups, which results in a new compound having distinct properties. Thus, the recite d derivatives embrace hundreds of thousands of potential compounds or alternatives that bear no structural resemblance to one another what-so-ever. 3 5 . Considering that the scope of said formulations encompasses hundreds of thousands of possible combinations of ingredients , it is evident that the claims are broad . Yet, as discussed above, the instant Specification discloses the use of only one of said compounds, salts, prodrugs, or derivatives thereof, i.e., amlexanox (Example 3 at pages 64-67). 3 6 . It is also noted that Applicant fails to recite a subject “in need thereof” in the preamble of the claims, such that claims 15 and 19 presently embrace modulating the activity, level, or combination thereof of a mediator protein in any subject, rather than a subject in need of treatment. As such, the claim is extremely broad with respect to the disclosure. The second inquiry is discussed in detail below. 3 7 . The amount of experimentation necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to a method of to a method of increasing the activity, level, or any combination thereof of a mediator protein selected from the list of mediator protein in Tables 3B and 3D in a subject, the method comprising administering a compound selected from: metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib or a pharmaceutically acceptable salt, prodrug, or derivative thereof; or any combination thereof. 38 . Since identifying any compound which is capable of successfully treating age-related dendritic spine density loss or cognitive decline is complex, t he nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of the scope of claim s 15 , 18, 21 and 24 with respect to the disclosure since the scope of possible compounds, salts, prodrugs and derivatives encompasses hundreds of thousands of alternatives, whereas the instant Specification discloses the administration of just one compound , exerting the desired activity on proteins of Tables 3B, and 3D (see Example 3 and Figure 7) . Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan could not reasonably predict which of the thousands of compounds encompassed by the claims would exert the alleged activity based on the limited disclosure. Thus, it is highly unpredictable whether administering any compound, salt, prodrug or derivative, or combination thereof within the scope encompassed by the claims, based on the instant disclosure would, in fact, be usable. Whether the other compounds encompassed by the claims would be usable is even less predictable. As such, the only way to ascertain which of the thousands, and potentially hundreds of thousands of claimed compounds presently embraced by the claims are usable based on the limited disclosure would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation. 39. To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure, i.e., limit the claims to the method disclosed in Example 3. Claim Rejections - 35 USC § 103 4 0 . 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. 4 1 . 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. 4 2 . 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. 4 3 . Claim s 15, 18, 21 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over FILLIN "Insert the prior art relied upon." \d "[ 2 ]" X u et al ., Chemistry Open (2021 ) , as evidenced by Querfurth and LaFerla , N Engl J Med (2010), and further in view of Xia et al ., Frontiers in Immunology (2018). Claim 15 is drawn to a method of increasing the activity, level, or any combination thereof of a mediator protein selected from the list of mediator protein in Tables 3B and 3D in a subject, (more specifically, a protein of Table 3B), wherein the subject has age-associated dendritic spine density loss, age-related cognitive decline, or a combination thereof ( claim 18 ), the method comprising administering a compound selected from: metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib or a pharmaceutically acceptable salt, prodrug, or derivative thereof; or any combination thereof (more specifically, amlexanox ( claim s 21 and 24 ) ). In view of a broadest reasonable interpretation, claim 15 is construed to mean: “A method of increasing the activity, level, or combination thereof of a mediator protein selected from the list of mediator proteins in Tables 3B and 3D, below, in a subject in need thereof, comprising administering to said subject a compound selected from: metformin, pentosan polysulfate, amlexanox, leflunomide, prasterone, glutathione disulfide, pazopanib, bosutinib, dabrafenib, baricitinib, or a pharmaceutically acceptable salt, prodrug, or derivative thereof; or any combination thereof. ” 4 4 . Xu et al . teach the critical role of up-regulated glutaminyl cyclase (QC) in the pathology of Alzheimer’s disease ( AD ) and go on to teach that teach that “ QC, distributed mainly in brain, is thus regarded as a critical target to prevent and treat AD ,” (see abstract and page 878, right column, last pargraph). Xu et al. suggest the administration of known QC inhibitors as a therapeutic strategy for improving cognitive deficits /decline in a murine model of AD: “ a number of QC inhibitors have been reported, which improve behavioral and cognitive deficits in AD mice by inhibiting QC activity. ” (page 878, left column, first paragraph). I n Table 1, Xu et al . specifically name Amlexanox as one of five “[t]op FDA-approved drugs exhibiting QC inhibitory activities” (page 878, see Table 1 and). 4 5 . And, it is clear as evidenced by Querfurth th at Alzheimer’s disease is characterized by a dvanced age and cognitive decline : “Alzheimer’s disease may be primarily a disorder of synaptic failure. 45 Hippocampal synapses begin to decline in patients with mild cognitive Impairment (a limited cognitive deficit often preceding dementia)” (see abstract and page 331, right column, last paragraph). 4 6 . As such, one of skill in the art before the effective filing date of the claimed invention would have been motivated to treat cognitive decline in a n aged subject with Alzheimer’s disease, comprising administering the QC inhibitor amlexanox to said subject, and would have had a reasonable expectation of success. 4 7 . Xu et al . do not teach the mechanism of increasing the activity of a protein listed in Table 3B as recited in the preamble of claim 15 . 4 8 . Yet, Xia et al . teach that “ S100 proteins are considered as potential therapeutic targets for various human disorders, including arthritis, cancer, and Alzheimer’s disease ,” [emphasis added] (page 1, last paragraph-page 2, left column, first paragraph) . Xia et al . disclose the protein S100A6, and go on to teach that amlexanox binds to S100 proteins, and suggest that amlexanox “may serve as a therapeutic approach to target S100 proteins” ( page 2, right column, first paragraph, and page 6, left column, second paragraph). 49 . Therefore, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention that when administered to a subject with Alzheimer’s disease, amlexanox would necessarily target S100 proteins in said subject, including S100A6 (listed in Applicant’s Table 3B). One of skill in the art before the effective filing date of the claimed invention would have been motivated to administer amlexanox to a patient suffering from AD and cognitive decline, wherein said administration would have resulted in an increase in S100 proteins, including S100A6, with a reasonable expectation of success. 5 0 . And, the fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya , 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). As such, claims 15, 18, 21 and 24 are prima facie obvious. Claim Objections 5 1 . Claim 15 is objected to because the second occurrence of the term “mediator protein” in line 2 should be plural. 5 2 . Claim 18 is objected to because a hyphen is missing in the term “age related” in line 2. Conclusion 5 3 . Claims 15-19 and 21-30 are present in the application, and claims 16, 17, 19, 22, 23 and 25-30 are withdrawn from consideration. Claims 15, 18, 21 and 24 are rejected. Claims 15 and 18 are also objected to. No claim is presently allowed. 5 4 . Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT JANET L COPPINS whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-0680 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday-Friday 8:30AM-5PM EST . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Amy L Clark can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 571-272-1310 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JANET L COPPINS/ Examiner, Art Unit 1628 /AMY L CLARK/ Supervisory Patent Examiner, Art Unit 1628