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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 16th, 2025 has been entered.
All previous objections and rejections not reiterated herein were overcome by claim amendments and arguments, filed December 16th, 2025, have been fully considered and found persuasive. As such all objections and rejections not reiterated herein have been withdrawn.
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.
Claims 1, 5, 7 – 9, 13, and 15 – 20 are rejected under 35 U.S.C. 103 as being unpatentable over Johnson et al. (American College of Clinical Pharmacology, Published June 30, 2015) (hereinafter Johnson) in view of Lockhardt et al (US 2010/0266571, Oct. 21, 2010) (hereinafter Lockhardt).
Johnson teaches that renal function may progressively decline in patients with Fabry disease. Johnson conducted a study to assess the pharmacokinetics, safety, and tolerability of a single oral dose of migalastat HCl 150 mg in subjects with normal or mildly, moderately, or severely impaired renal function (abstract). Migalastat HCl is a low molecular weight, orally administered, investigational iminosugar that functions as a pharmacological chaperone and is being developed for the treatment of Fabry disease (page 257, left column). Migalastat HCl is currently an investigational agent in Phase 3 trials and is administered orally in 150 mg capsules every other day (page 261, left column).
Johnson differs from the instant claims insofar as not disclosing wherein free base equivalent of migalastat or migalastat HCL is administered once every four days; or once every seven days; or at a first frequency of once every other day for a first time period and then a second frequency of less than once every day for a second time period, wherein administration at the second frequency begins after a reduction in the patient’s estimated glomerular filtration rate (eGFR).
However, Lockhardt teaches that approximately half of all Fabry patients have an abnormally low GFR (<90 ml/min/1.73 m2). As shown in FIG. 17A-B, the good responders maintained a mean eGFR within the normal eGFR range of 90-120 ml/min/1.73 m2 during the entire treatment procedure (FIG. 17A), while the predicted mean eGFR level of untreated individual is projected to continue declining below 90 ml/min/1.73 m2 (FIG. 17B). (¶ [0311]). Lockhardt also teaches dosing regimens for administering pharmacological chaperones to a subject in need thereof (abstract). The pharmacological chaperone, “1-deoxygalactonojirimycin” (DGJ) refers to (2R,3S,4R,5S)-2-(hydroxymethyl) piperdine-3,4,5-triol. This term includes both the free base and any salt forms. (¶ [0101]). The dosing regimen may be for Fabry Disease (¶ [0194]). Dosing is determined using a simplified model which depends on certain observable factors identified by in vitro and in vivo evaluation. Such factors include the pharmacokinetics of the candidate pharmacological chaperone in plasma and tissue, the rate of enzyme accumulation in the lysosome; the rate of enzyme turnover (half-life in the lysosome); and the binding affinity of drug to enzyme as determined in vitro (¶ [0114]). Since pharmacological chaperones are potent inhibitors of the intended target enzymes, it was hypothesized that a dosing regimen involving peaks and “troughs' would be necessary to prevent sustained inhibition of the target enzyme. Accordingly, the need for non-daily dosing as opposed to daily dosing appeared likely, in which the goal would be to achieve plasma concentrations of the drug that are initially above the cellular ECs (as determined in vitro cellular enzyme activity assays) for some period of time, so as to maximize the amount of enzyme that is trafficked to lysosomes, followed by some period of time where the concentration of drug falls below the ICs (as determined in vitro using cell lysate at the lysosomal pH of 5.2). Accordingly, a simple model was devised wherein certain PK and PD parameters could be used to estimate dosing regimens that would both (i) achieve a plasma concentration above the EC50 and (ii) permit the plasma concentration to fall below the IC50 (¶ [0119]). In one embodiment, from about 75 mg to about 300 mg of a pharmacological chaperone is orally administered once daily for about 4 to about 10 days, followed by orally administering a maintenance dose of about 75 to 225 mg of the pharmacological chaperone once every about 3 to about 8 days (¶ [0046]).
As discussed above, migalastat HCl is a pharmacological chaperone and pharmacological chaperones are potent inhibitors of the intended target enzymes and a dosing regimen involving peaks and “troughs' would be necessary to prevent sustained inhibition of the target enzyme. Thus, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed dosing regimen based on achieving a dosing regimen of migalastat HCl that would be necessary to prevent sustained inhibition of the target enzyme as taught by Lockhardt. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144(II)(A).
In regard to instant claim 20 reciting wherein the administration at the second frequency begins after a reduction in the patient’s eGFR, as discussed above by Lockhardt, half of all Fabry patients have an abnormally low GFR, wherein eGFR level of untreated individual is projected to continue declining. Accordingly, it would have been obvious to one of ordinary skill in the art to have administered the drug at a time period when there is a reduction in the patient’s eGFR since a reduction in eGFR means that treatment is necessary as taught by Lockhardt.
Furthermore, generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. As discussed above, Johnson discloses wherein pharmacological chaperones may be used to treat Fabry Disease. Accordingly, it would have been obvious to one of ordinary skill in the art to have administered free base 1-deoxygalactonojirimycin (i.e., free base Migalastat) instead of Migalastat HCl to treat Fabry Disease since pharmacological chaperones are used to treat Fabry Disease and free base 1-deoxygalactonojirimycin (i.e., free base Migalastat) is a known and effective pharmacological chaperone as taught by Lockhardt.
Claims 4 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Johnson et al. (American College of Clinical Pharmacology, Published June 30, 2015) (hereinafter Johnson) in view of Lockhardt et al (US 2010/0266571, Oct. 21, 2010) (hereinafter Lockhardt), and further in view of Benjamin et al. (Genetics in Medicine, Published Sep. 22, 2016) (hereinafter Benjamin).
The teachings of Johnson and Lockhardt are discussed above.
Johnson and Lockhardt do not disclose wherein the patient has a HEK assay amendable mutation in α-galactosidase A.
However, Benjamin teaches that Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. GLP-HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat (Abstract).
Accordingly, it would have been obvious to one of ordinary skill in the art that the patient has a HEK assay amendable mutation in α-galactosidase A since the patient of Johnson has Fabry Disease and a HEK assay amendable mutation in α-galactosidase A is a known characteristic of patients with Fabry Disease as taught by Benjamin.
Response to Arguments
Applicant's arguments filed December 16th, 2025, see page 5 paragraph 3 – 4 and page 6 paragraph 1 – 3, have been fully considered but they are not persuasive.
Applicant argues that the claimed invention is not routine optimization (page 5 paragraph 2). Moreover applicant argues that neither the prior at of Lockhart nor Johnson discuss the administration of about 123 mg FBE migalastat in the frequency of once every four days or once every seven days (page 5 paragraph 2).
The examiner contends that, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As stated above in the prior art rejection, Johnson taught the oral administration of Migalastat HCl in 150 mg (claim 7) capsules every other day. Whereas the prior art of Lockhardt teach the administration of a maintenance dose of about 75 to 225 mg of the pharmacological chaperone once every about 3 to about 8 days (¶ [0046]). Moreover, Lockhardt taught that dosing is determined using a simplified model which depends on certain observable factors identified by in vitro and in vivo evaluation which include the pharmacokinetics of the candidate pharmacological chaperone in plasma and tissue, the rate of enzyme accumulation in the lysosome; the rate of enzyme turnover (half-life in the lysosome); and the binding affinity of drug to enzyme as determined in vitro (¶ [0114]). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical (MPEP 2144.05(II)A).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4, 5, 7 – 9, 12, 13, and 15 – 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 5, 11, 12, 19, 20, and 21 of U.S. Patent No. 10,251,873 in view of Lockhardt et al (US20100266571, Oct. 21,20210).
Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims are drawn to the treatment of Fabry disease in patients with a degree of renal impairment. The pending claims differ from the conflicting claims insofar as the dosing regimen. However, as discussed above, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed dosing regimen based on achieving a dosing regimen of Migalastat HCl that would be necessary to prevent sustained inhibition of the target enzyme as taught by Lockhardt. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144(II)(A).
Response to Arguments
Applicant's arguments filed December 16th, 2025, see page 6 paragraph 6, have been fully considered but they are not persuasive. The arguments against the double patenting rejections reiterate the same points made against the prior art rejections. These arguments were previously addressed in this Office action and are not persuasive for the reasons set forth above.
Conclusion
Claims 1, 4 – 5, 7 – 9, 12 – 13, and 15 – 20 are rejected.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682