ALDOSE REDUCTASE INHIBITORS FOR TREATMENT OF PHOSPHOMANNOMUTASE 2 DEFICIENCY

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 . Priority This application is a Continuation of PCT/US2020/054607 filed on 10/07/2020 which claims the benefit of U.S. Provisional Application No. 62/912,441 filed on 10/08/2019. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 12, 2026 has been entered. Response to Amendment No amendments to the claims were made by Applicant’s reply filed on June 12, 2026. Claims 1, 2, 4, 5, 10, 21, 22 and 28-36 are currently pending. Claims 3, 6-9, 11-20 and 23-27 are canceled. Response to Arguments Applicant's arguments and declaration under 37 CFR 1.132 filed June 12, 2026 with respect to the rejection under 35 USC 103 have been fully considered but they are not persuasive. The declaration under 37 CFR 1.132 discusses the studies of Iyer et al. which describes studies in which small molecules were screened in worm and fibroblast models of PMM2-CDG. Iyer et al. teaches that while all ten ARIs tested inhibited the activity of aldose reductase only two, CHCA and epalrestat, reproducibly increased PMM2 enzymatic activity, which means that eighty percent of the compounds tested were not efficacious, despite all compounds being well-known inhibitors of aldose reductase. Iyer teaches that epalrestat increased PMM2 activity by inhibiting aldose reductase and thus preventing the conversion of glucose to sorbitol, resulting in the accumulation of excess glucose that favors the production of glucose-1,6-bisphosphate, which is a known coactivator of PMM2. Since all ARIs inhibit aldose reductase and, thus, block AR mediated conversion of glucose to sorbitol, all ARIs would cause accumulation of glucose and favor production of glucose-1,6-bisphosphate, which, according to Iyer would have been expected to activate PMM2. However, lyer shows that eighty percent of ARIs tested failed to reproducibly increase PMM2 activity, which demonstrates that the effects of inhibition of aldose reductase can be complex and cannot be predicted. Thus, a person of ordinary skill in the art would not have a reasonable expectation that all ARI compounds could be used successfully to treat any condition in which the polyol pathway contributes to pathology, including PMM2 and hereditary neuropathy associated with SDH deficiency. The declaration further discusses unexpectedly improved results for compound B over other ARIs such as epalrestat. Applicant also argues that the prior art including Iyer demonstrates unpredictability in the art since Iyer is a publication by the same research group and based on the same underlying work as disclosed in Perlstein and a person of ordinary skill in the art would have considered Perlstein and Iyer together when evaluating the state of the art, and based on their disclosures, the person would understand there is a lack of predictability in applying ARIs to the Perlstein method. Applicant argues that while Perlstein reports that certain compounds increased PMM2 activity, Iyer provides the critical context missing from Perlstein: ten commercially available ARIs were tested, and only two (CHCA and epalrestat) reproducibly increased PMM2 activity. Applicant argues that this evidence directly contradicts the Examiner's assertion that ARIs can be interchanged with predictable results. These arguments are found not persuasive because Applicant argues that the use of ARIs for increasing PMM2 activity is unpredictable and an ordinary skilled artisan would not reasonably expect all ARIs to increase PMM2 activity. However, the claims are drawn to numerous untested ARI compounds and thus it would be unpredictable that all claimed compounds would be useful in the claimed method for the same reasons as argued by Applicant. Therefore, these arguments would be found persuasive if the claims were directed to one particular compound such as compound B shown in the instant specification to inhibit aldose reductase activity and increase PMM2 activity. However, Applicant’s arguments and declaration are not commensurate in scope with the claimed invention. The claims are drawn to the use of numerous compounds of formula (III) in spite of only demonstrating that compound B is able to increase PMM2 activity. Applicant has not provided any evidence that any compound other than compound B is able to increase PMM2 activity. Accordingly, Applicant’s arguments are found persuasive for claims 5 and 22 drawn specifically to compound B. However, Applicant’s arguments and declaration are found not persuasive for the remaining claims since the evidence provided is not commensurate in scope with the claimed invention. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). PNG media_image1.png 18 19 media_image1.png Greyscale Thus it is maintained that based on the teachings of Perlstein a reasonable expectation of success exists in using the aldose reductase inhibitors of Wasmuth in the methods of Perlstein. Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O ’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). Par Pharm., Inc. v. TWi Pharms., Inc., 773 F.3d 1186, 1198 (Fed. Cir. 2014). In the instant case, claims 34-43 of Perlstein et al. claim a method for increasing glycosylation in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor; a method for treating a condition or disorder mediated, at least in part, by phosphomannomutase-2 enzyme in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor; method for treating a congenital disorder of glycosylation in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor; a method for treating phosphomannomutase deficiency in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor. Thus, Perlstein et al. specifically teaches and claims a method for treating Phosphomannomutase deficiency disease (PMM2 or PMM2-CDG) in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor. Accordingly, a person of ordinary skill in the art would reasonably expect the aldose reductase inhibitor compounds of Wasmuth et al. to be useful for the same purpose as taught in Perlstein because exemplary rationales that support a conclusion of obviousness include the simple substitution of one known element for another to obtain predictable results, PNG media_image1.png 18 19 media_image1.png Greyscale or in the alternative, combining prior art elements according to known methods to yield predictable results. Thus a person of ordinary skill in the art would have been motivated to substitute the ARIs of Perlstein with the ARIs of Wasmuth with a reasonable expectation of obtaining similar results. In the alternative, it would have been obvious to a person of ordinary skill in the art to combine the ARIs of Wasmuth with the ARI compounds of Perlstein with a reasonable expectation of obtaining improved results. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980). Thus, for these reasons the previous rejection under 35 USC 103 is hereby maintained and reproduced below. Claims 5 and 22 are objected to for being dependent upon a rejected claim. 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. 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, 2, 4, 10, 21 and 28-36 are rejected under 35 U.S.C. 103 as being unpatentable over Perlstein et al. WO 2020/040831 A1 (Provided on IDS) in view of Wasmuth et al. WO 2017/223179 (Provided on IDS). Claims 1, 2, 4, 10, 21 and 28-36 of the instant application claim a method of treating PMM2-CDG, and increasing PMM2 enzymatic activity in a subject with PMM2-CDG comprising administering a therapeutically effective amount of an aldose reductase inhibitor to a subject in need thereof, wherein the aldose reductase inhibitor is a compound of Formula (III), or a salt thereof. Perlstein et al. teaches that congenital disorders of glycosylation (CDG) include more than 130 inborn errors of metabolism that affects N-linked, O-linked protein and lipid-linked glycosylation wherein Phosphomannomutase deficiency disease (PMM2 or PMM2-CDG) is the most common disorder of glycosylation with more than 800 patients reported worldwide [0003]. Perlstein et al. teaches that PMM2 is a rare congenital disorder of glycosylation with no cure that is an autosomal recessive disorder arising from a dysfunctional phosphomannomutase-2 gene [0004] and [0099]. Perlstein et al. teaches that the phosphomannomutase-2 enzyme is responsible for transforming mannose 6-phosphate into mannose 1-phosphate, which in turn leads to the synthesis of GDP-mannose and insufficient levels of GDP-mannose leads to under-glycosylated glycoproteins, lysosomal enzymes and serum proteins and this in turn is associated with increased proteasomal and oxidative stress [0004] and [0099]. Perlstein et al. teaches that resolving the glycosylation defect, decreasing proteasomal stress, and decreasing oxidative stress may all or singly contribute to a therapeutic effect in the disease [0004] and [0099]. Perlstein et al. teaches that PMM2-CDG patients suffer from neuromuscular abnormalities, developmental delays, failure to thrive and multiple organ system involvement from liver to kidneys [0005] and [0099]. Perlstein et al. teaches methods for increasing glycosylation in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor [0009]. Perlstein et al. further teaches methods for treating a condition or disorder mediated, at least in part, by phosphomannomutase-2 enzyme in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor [0017] and [0021]. Perlstein et al. further teaches methods for treating phosphomannomutase deficiency in a patient in need thereof comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an aldose reductase inhibitor [0037]. Perlstein et al. teaches an aldose reductase inhibitor is a compound that can inhibit the activity of the enzyme, aldose reductase wherein aldose reductase inhibitors may reduce the flux of glucose through the polyol pathway, which can lead to inhibition of tissue accumulation of sorbitol and fructose and prevention of reduction of redox potentials [0082]. Non-limiting examples of an aldose reductase inhibitor include but are not limited to alrestatin, epalrestat, fidarestat, imirestat, lidorestat, minalrestat, ponalrestat, ranirestat, salfredin B11, sorbinil, tolrestat, zenarestat, and zopolrestat [0082] and [0084]-[0085]. Perlstein et al. teaches the treatment of a congenital disorder of glycosylation (CDG) which is associated with deficient or defective glycosylation of various tissue proteins or lipids. Individuals with a CDG are missing an enzyme required for glycosylation [0098]. Perlstein et al. teaches the treatment of Phosphomannomutase deficiency disease (PMM2 or PMM2-CDG, and also previously known as CDG-Ia) a rare congenital disorder of glycosylation with no cure [0099]. Claims 34-43 of Perlstein et al. claim a method for increasing glycosylation in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor; a method for treating a condition or disorder mediated, at least in part, by phosphomannomutase-2 enzyme in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor; method for treating a congenital disorder of glycosylation in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor; a method for treating phosphomannomutase deficiency in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor. Thus Perlstein et al. specifically teaches and claims a method for treating Phosphomannomutase deficiency disease (PMM2 or PMM2-CDG) in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor. Perlstein et al. does not teach the claimed compounds of formula (III). Wasmuth et al. teaches that aldose reductase (AR) is a monomeric, NADPH-dependent oxidoreductase from the aldo-keto reductase family of enzymes that is present in many parts of the body and catalyzes the reduction of saturated and unsaturated aldehydes, including aldo sugars and monosaccharides, as well as a broad array of other substrates [0006]. Wasmuth et al. teaches that primarily, aldose reductase catalyzes the reduction of glucose to sorbitol, one of the steps in the sorbitol pathway that is responsible for fructose formation from glucose [0006]. Wasmuth et al. teaches the same compounds of formula (III) as claimed ([0009]-[0017] and [0066]-[0091]). Wasmuth et al. teaches a method of inhibiting aldose reductase activity in a human patient comprising the administration of the compounds disclosed therein [0035]-[0037]. Wasmuth et al. teaches that the compounds and/or compositions of the invention may be effective in treating, reducing, and/or suppressing complications related to aldose reductase activity [0054]. Wasmuth et al. teaches that the compounds or compositions of the invention can be useful in applications that benefit from inhibition of aldose reductase enzymes [0127]-[0128]. Wasmuth et al. teaches that the compound can be administered orally ([0139] [0152]-[0154]). Wasmuth et al. teaches that the compound can be administered once daily [0157]. Thus Wasmuth et al. teaches the same compounds as claimed in the instant claims useful for inhibiting aldose reductase activity, leading to decreases in sorbitol levels. Accordingly, prior to the effective filing date of the instant claims it would have been obvious to a person of ordinary skill in the art to combine the teachings of Perlstein et al. which specifically teaches and claims a method for treating Phosphomannomutase deficiency disease (PMM2 or PMM2-CDG) in a patient in need thereof comprising administering a therapeutically effective amount of an aldose reductase inhibitor, with the teachings of Wasmuth et al. which teaches compounds of formula (III) as claimed in the instant claims, useful for inhibiting aldose reductase activity in a human patient. Thus since the compounds of Wasmuth et al. are aldose reductase inhibitors, a person of ordinary skill in the art would have been motivated to administer said compounds of Wasmuth et al. in the method of Perlstein et al. with a reasonable expectation of similar success. Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings. Claim Objections Claims 5 and 22 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Conclusion Claims 1, 2, 4, 10, 21 and 28-36 are rejected. Claims 5 and 22 are objected to. Claims 3, 6-9, 11-20 and 23-27 are canceled. No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA R. MCMILLIAN whose telephone number is (571)270-5236. The examiner can normally be reached Tuesday-Friday 12:00 PM-6:00 PM. 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, Adam C. Milligan can be reached on (571)270-7674. 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. /KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623 KRM