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.
Response to Amendment
Applicant’s amendment filed on August 19, 2025, amending claims 1, 2, 4 and 21, canceling claims 3, 6-8, 20 and 23-27, and adding new claims 29-36 has been entered. Claims 9 and 11-19 were previously canceled. Claims 1, 2, 4, 5, 10, 21, 22 and 28-36 are currently pending.
Response to Arguments
Due to the cancellation of claims 12-15 and 31-33 of copending Application No. 17,489,022, the previous double patenting rejections are hereby withdrawn. Applicant’s arguments with respect to said rejections have been fully considered but are moot in view of the withdrawal of the rejections.
Due to Applicant’s amendments to the claims, the previous rejection under 35 U.S.C. 102(a)(2) over Perlstein et al. WO 2020/040831 A1 is hereby withdrawn. Applicant’s arguments with respect to said rejection have been fully considered but are moot in view of the withdrawal of the rejections.
Due to the cancellation of claims 6-8 and 23-27 the previous rejection of claims 6-8 and 23-27 under 35 U.S.C. 103 over Perlstein et al. WO 2020/040831 A1 in view of Wasmuth et al. is hereby withdrawn. Applicant’s arguments with respect to said rejection have been fully considered but are moot in view of the withdrawal of the rejections.
Applicant's arguments filed August 19, 2025 with respect to the remaining rejection under 35 USC 103 have been fully considered but they are not persuasive.
Applicant argues that a person of ordinary skill in the art would not have had a reasonable expectation of success in using a compound of Formula (III) to treat PMM2-CDG or increase PMM2 activity in a subject with PMM2-CDG, based on the disclosure of Perlstein. A person of ordinary skill in the art would not have reasonably expected success by using an aldose reductase inhibitor of Wasmuth in the Perlstein method, because the art demonstrates that some aldose reductase inhibitors do not work. Applicant discusses Iyer et al. which discloses the same studies that are disclosed in Perlstein, but Iyer also includes additional information about the studies. Applicant argues that Perlstein discloses that a-cyano-4-hydroxycinnamic acid (CHCA; referred to as Compound 1 in Perlstein), epalrestat, and rhetsinine, each of which has some aldose reductase inhibitory activity, increased PMM2 enzyme activity in yeast and fibroblast models of PMM2- CDG, and that two of those molecules, CHCA and epalrestat, rescued growth in yeast models. (See, e.g., Perlstein at Example 2, [0145]-[0150]). Applicant argues that no data for other aldose reductase inhibitors is presented in Perlstein as Perlstein also discloses a nematode model, but aldose reductase inhibitors were not included in the disclosed tests. (Example 3, [0151]-[0155]).
Applicant argues that Iyer provides results from testing CHCA, epalrestat and additional aldose reductase inhibitors in the same yeast, nematode and fibroblast models described in Perlstein and Iyer demonstrates that only two aldose reductase inhibitors (CHCA and epalrestat) reproducibly increased PMM2 enzyme activity in both worms and fibroblasts models. Thus, Applicant argues that Iyer clearly demonstrates that increasing PMM2 activity is not a common effect of aldose reductase inhibitors as only one of the nine commercially available aldose reductase inhibitors tested, and CHCA, reproducibly worked. Thus, Applicant argues that a person of ordinary skill in the art would not have considered that another aldose reductase inhibitor, such as one disclosed in Wasmuth, can be reliably substituted into the method of Perlstein with a reasonable expectation that this would lead to a successful method of treating PMM2-CDG or increasing PMM2 enzymatic activity in a subject with PMM2-CDG.
These arguments are found not persuasive because 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,
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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).
Furthermore, even though Applicant attempts to present the data of the Iyer reference as objective evidence to rebut a prima facie case of obviousness, objective evidence must be factually supported by an appropriate affidavit or declaration to be of probative value including evidence of unexpected results. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results. Permitting a publication to substitute for expert testimony would circumvent the guarantees built into the statute. Ex parte Gray, 10 USPQ2d 1922, 1928 (Bd. Pat. App. & Inter. 1989).
Furthermore, although Iyer et al. demonstrates that some ARIs do not reproducibly increase PMM2 enzymatic activity in both worms and fibroblast, does not mean that the compounds of Wasmuth will not be useful in the methods as claimed. This is because Iyer et al. demonstrates that at least some carboxylic acid-containing ARIs do reproducibly increase PMM2 enzymatic activity and therefore based on these teachings it would have been at least
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obvious to try the carboxylic acid-containing ARIs of Wasmuth with the expectation that they would increase PMM2 enzymatic activity as well. An "obvious to try" rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. " [A] person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 538, 421, 82 USPQ2d 1385, 1397 (2007).
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Thus, for these reasons the previous rejection under 35 USC 103 is hereby maintained and detailed below with modifications to address Applicant’s amendments to the claims.
This action is FINAL.
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, 5, 10, 21, 22 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, 5, 10, 21, 22 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) such as
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wherein X1 and X2 are H; Y is C=O, R1 is COOR2; R2 is H; A2 is N; A1 is S; R4 is CF3; and R3, R5 and R6 are H, 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 compounds of formula (III) ([0009]-[0017] and [0066]-[0091]). Wasmuth et at. teaches that a preferred compound is
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([0018], [0031], [0092]-[0093], claims 10 and 23). 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 wherein a preferred compound is
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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.
Conclusion
Claims 1, 2, 4, 5, 10, 21, 22 and 28-36 are rejected. Claims 3, 6-9, 11-20, 23-27 9 and 11-19 are canceled. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM
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