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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 31, 2025 has been entered.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on July 31, 2025, wherein claims 1 and 42 are amended; claims 2-11 and 16 are unchanged; and claims 12-15 and 17-41 are cancelled.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-11, 16 and 42 are pending and under examination.
Priority
The instant application 17/424,979 filed on July 22, 2021 is a 371 of PCT/US2020/014531 filed on January 22, 2020, which claims priority to, and the benefits of U.S. Provisional Application No. 62/795,524 filed on January 22, 2019.
Action Summary
Acknowledgement is made of the receipt and entry of the amendment to the abstract and the specification filed on July 31, 2025. Applicant’s amendment to the claims, the abstract and the specification have overcome each and every objection previously sets forth in the Final Office Action mailed on January 31, 2025.
Claims 1-8, 16 and 42 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296) are withdrawn in view of the claim amendment.
Claims 1-8, 12-13, 16 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296), as evidenced by Castelli et al. (US 2016/0324839 A1; cited in the previous non-final office action mailed on April 23, 2024) are withdrawn in view of the claim amendment.
Claims 1-9, 12-13, 16 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296), as applied to claims 1-8, 12-13, 16 and 42 above, and further in view of Castelli et al. (US 2016/0324839 A1) are withdrawn in view of the claim amendment.
Claims 1-8, 10-13, 16 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over
Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296), as applied to claims 1-8, 12-13, 16 and 42 above,
and further in view of Germain et al. (N Engl J Med., 2016. Vol. 375(6): 545-55) are withdrawn in view of the claim amendment.
Specification
The disclosure is objected to because of the following informalities:
“Table 2. Medical History of CBV Events” on page 34 of the specification: it is noted that the term “Table 2” is also used to refer to a different table recites in page 33, and there is no Table 3 found in the specification; However, paragraph [00117] of the specification described the medical history of CBV event is demonstrate in Table 3, which appears to be referring to “Table 2. Medical History of CBV Events” on page 34. Therefore, the “Table 2” on page 34 appears to contain a typographical error and should read –Table 3–.
Appropriate correction is required.
Claim Objections
Claims 2, 3, 8-9 and 42 are objected to because of the following informalities:
Regarding claim 2, the recitation of “wherein the CBV event comprises one or more…” should read –wherein the CBV event is selected from the group consisting of… and a combination thereof–, because the claim language is not being consistent with the Markush claim language.
Regard claims 3 and 42, the recitation of “prior to initiating administration of the migalastat” should read –prior to initiating the administration of the migalastat--, such that an article –the—is used to refer the “administration” is the administration previously set forth in the claim it depends upon.
Regarding claim 8, the recitation of “the formulation comprises an oral dosage form” should read –the formulation is an oral dosage from–, because the claim language is not being consistent with the Markush claim language.
Regarding claim 9, the recitation of “wherein the oral dosage form comprises a tablet, a capsule or a solution” should read –wherein the oral dosage form is selected from the group consisting of– or –wherein the oral dosage form is a tablet, a capsule or a solution, because the claim language is not being consistent with the Markush claim language.
Please note a “Markush” claim recites a list of alternatively useable members. In re Harnisch, 631 F.2d 716, 719-20, 206 USPQ 300, 302-304 (CCPA 1980); Ex parte Markush, 1925 Dec. Comm'r Pat. 126, 127 (1924). The listing of specified alternatives within a Markush claim is referred to as a Markush group or Markush grouping. Abbott Labs v. Baxter Pharmaceutical Products, Inc., 334 F.3d 1274, 1280-81, 67USPQ2d 1191, 1196-97 (Fed. Cir. 2003) (citing to several sources that describe Markush groups). Claim language defined by a Markush grouping requires selection from a closed group “consisting of” the alternative members. Id. at 1280, 67 USPQ2d at 1196. See MPEP § 2111.03, subsection II, for a discussion of the term “consisting of” in the context of Markush groupings.
Appropriate correction is required.
Claim Interpretation
The claims recite the term “ERT-experienced patient”, when construed in view of paragraph [0063] of the specification shown below:
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, is taken to refer to a Fabry patient that was receiving ERT immediately prior to initiating migalastat therapy.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-8, 16 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296 and supplemental material), in view of Bikkina et al. (JAMA, 1994. Vol. 272(1): 33-36), as evidenced by Castelli et al. (US 2016/0324839 A1; cited in the previous non-final office action mailed on April 23, 2024).
Please note Hughes et al. has been cited and provided in the previous Final Office Action mailed on January 31, 2025; However, the supplemental material published with Hughes et al. has not been cited or provided in the previous Office Action, thus, the Examiner has provided a legible copy of the reference with the supplemental material in this Office Action.
Hughes et al. teaches oral migalastat, a pharmacological chaperone, is being developed
as an alternative to enzyme replacement therapy (ERT) in the treatment of Fabry disease, which is a X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal subtract (see e.g., abstract; p. 293, left column, “Discussion” section, line 1). Hughes et al. further teaches migalastat stabilizes specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking (see e.g., abstract). Please note the migalastat taught by Hughes et al. is a migalastat that enhance a-galactosidase A activity in patients with Fabry disease. Hughes et al. further teaches a randomized phase III ATTRACT study that compares the safety and efficacy of migalastat to ERT in male and female patients with Fabry disease and amenable mutation previously treated with ERT (see e.g., p. 289, left column, line1-4); wherein the study comprised an 18-month open-labeled comparison between oral migalastat and enzyme replacement therapy (ERT), followed by a 12-month open-labeled extension with oral migalastat shown below:
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(see e.g., p. 289, left column, 1st paragraph under the “Study design and participants” section; and the title; Figure 1). Hughes et al. further teaches in the 18-month controlled period, patients previously treated with ERT (agalsidase alfa and agalsidase beta) for >12 months were randomized 1.5:1 to switch to migalastat HCl (150 mg every other day) or continue ERT (see e.g., p. 289, left column, 1st paragraph under the “Study design and participants” section). Please note the 150 mg of migalastat HCl taught by Hughes et al. is equivalent to about 123 mg of migalastat in free base, as evidenced by Castelli et al. (see e.g., [0084] and [0108]). Hughes et al. further teaches at baseline, the majority of patients with amenable mutations had multiorgan system disease shown below:
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(see e.g., Table S1; p. 291, left column, line 3-5). Hughes et al. further teaches the percentage of patients who experienced renal, cardiac or cerebrovascular events during the 18-month treatment period was 0% for CBV (TIA) for migalastat and 6% for ERT in Table 4 shown below:
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(see e.g., p. 292, left column, the “Composite clinical outcome assessment” section), wherein the cerebrovascular events includes stroke and transient ischemic attack (TIA) (see e.g., p. 290, left column, “Composite clinical outcome assessment” section). Hughes et al. further teaches the frequency of events noted above indicates that the effect of migalastat compares favorably to ERT in these composite clinical events (see e.g., p. 293, right column, 3rd column). Hughes et al. further teaches in patients switched from ERT to migalastat, left ventricular mass index (LVMi) decreased significantly from baseline over 18 months, and the LVMi changes were largest for patient with left ventricular hypertrophy; and plasma lyso-Gb3 levels remained low and stable in patients with amenable mutations (see e.g., p. 292, “Echocardiography” section and “Plasma lyso-Gb3” section). Hughes et al. further teaches a smaller, nonsignificant change in LVMi was observed in patient who remained on ERT (see e.g., p. 292, left column, “Echocardiography” section) Hughes et al. further teaches the LVMi is determined using echocardiography (see e.g., p. 290, left column, “Echocardiography” section; p. 292, left column, “echocardiography” section). Hughes et al. further teaches migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy, stabilizes specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking (see e.g., abstract). Hughes et al. further teaches enrolled patients were required to have responsive mutant α-Gal forms based on a preliminary HEK assay (see e.g., p. 289, “determination of amenability of GLA mutation”). Please note the patients with Fabry disease and amenable mutation, and have responsive mutant α- galactosidase forms based on a preliminary HEK assay taught by Hughes et al. is a patient with HEK
assay amenable mutation in α-galactosidase A as claimed in claim 16.
Bikkina et al. teaches a Framingham Heart Study that evaluates the association of echocardiographically determined left ventricular mass (LVM) with incidence of stroke or transient ischemic attack in an elderly cohort (see e.g., abstract). Bikkina et al. further teaches the echocardiographically determined LVM was associated with risk for cerebrovascular events in men and women; and this increased risk persisted even after adjusting for other risk factors for stroke including age, systolic blood pressure, hypertension treatment, diabetes, cigarette smoking, blood lipid levels, left atrial size, and mitral annular calcification (see e.g., p. 35, right column, “comment” section to p. 35, left column, line 1-2); wherein the cerebrovascular events includes stroke and transient ischemic attack (see e.g., abstract, “results” section). Bikka et al. further teaches the hazard ratio for stroke or transient ischemic attack was 3.08 comparing the highest and lowest quartiles of LVM-to-height ratio (see e.g., p. 35, middle section, “Association of LVM and Outcome” section, 2nd paragraph).
In Summary, Hughes et al. clearly teaches the administration of oral migalastat HCl (150 mg every other day, which is equivalent to about 123 mg of migalastat in free base, as evidenced by Castelli et al.) to the patient with Fabry disease for 18 + 12 months provides favorable results for a composite clinical endpoint of renal, cardiac, and cerebrovascular events (including stroke and transient ischemic attack); and significantly decrease left ventricular mass index. Please note the 18 +12 months taught by Hughes et al., which when calculated by:
18
+
12
=
30
m
o
n
t
h
s
30
m
o
n
t
h
s
÷
12
m
o
n
t
h
s
y
e
a
r
=
2.5
y
e
a
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s
, gives 2.5 years. Hughes et al. further teaches the patient is previously treated with ERT for >12 month prior to initiating migalastat HCl, and that is an ERT-experienced patient having Fabry disease and a patient received ERT for at least 12 months immediately prior to initiating the administration of the
migalastat or salt thereof. Hughes et al. further teaches the majority of patients had multiorgan system disease at baseline, including central nervous system (CNS) events based on medical history findings (stroke/transient ischemic attack). It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to administer oral migalastat HCl at 150 mg every other day (about 123 mg of migalastat in free base) for 2.5 years to an ERT-experienced patient with Fabry disease and a medical history of transient ischemic attack prior to administering the migalastat. One would have been motivated to do so, because Hughes et al. teaches the patient who switched from ERT to the migalastat significantly decrease left ventricular mass index, and has favorable results for a composite clinical endpoint of renal, cardiac, and cerebrovascular events (including stroke and transient ischemic attack) during the 18 month treatment period; and Bikkina et al. teaches increased LVM is associated with higher incidence of cerebrovascular events (including stroke and transient ischemic attack). One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of oral migalastat HCl at 150 mg every other day (about 123 mg of migalastat in free base) for 2.5 years to an ERT-experienced patient having Fabry disease and a medical history of transient ischemic attack at baseline would have successfully provide a favorable results for the composite clinical endpoint (including cerebrovascular events) and reduce the risk of a cerebrovascular event by decreasing left ventricular mass index of said patient.
Regarding the limitation of “wherein the CBV event comprises one or more…transient ischemic attack” in claim 2, the claimed limitation simply expresses the intended outcome of the method step positively recited. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to reduce the risk of transient ischemic attack as the cerebrovascular event in the ERT-experienced patient having Fabry disease and a medical history of transient ischemic attack at baseline in the method of Hughes et al. and Bikkina et al. set forth above. One would have been motivated to do so, because Bikkina et al. teaches increased LVM is associated with higher incidence of cerebrovascular events, including transient ischemic attack. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of migalastat HCl at 150 mg every other day (about 123 mg of migalastat in free base) for 2.5 years to an ERT-experienced patient having Fabry disease and a medical history of transient ischemic attack at baseline would have successfully reduce the risk of transient ischemic attack as the cerebrovascular event by decreasing left ventricular mass index of said patient.
Regarding the limitation of “wherein the patient has an increased risk of a CBV event prior to initiating administration of the migalastat or salt thereof” in claim 3, the claimed limitation is drawn to the characteristic of the patient that received the formulation comprising the migalastat. In this case, the patient in the method of Hughes et al. and Bikkina et al. set forth above is a patient with an increased risk of a CBV even prior to initiating the administration of the migalastat HCl, because Hughes et al. teaches 6% of the ERT-experienced patients who did not switch to the migalastat HCl and continue on ERT experienced a CNS event (transient ischemic attack) during the study, and none of the patient who switched from ERT to the migalastat HCl experienced a CNS event; and the patients who did not switched to the migalastat HCI has no change in LVMi. In other words, the fact that the patients who did not switch to migalastat HCl experienced transient ischemic attack during the study demonstrates that the patient who does not switch to the migalastat HCI has an increased risk of transient ischemic attack event, and that is the patient with as increased risk of a CBV event prior to initiating the administration of the migalastat HCl. Therefore, the teachings of Hughes et al. renders obvious the limitation instantly claimed.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1-9, 16 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296 and supplemental material), in view of Bikkina et al. (JAMA, 1994. Vol. 272(1): 33-36) as applied to claims 1-8, 16 and 42 above, and further in view of Castelli et al. (US 2016/0324839 A1).
Please note Castelli et al. has been cited in the previous Non-Final Office Action mailed on April 23, 2024.
The teachings of Hughes et al. and Bikkina et al. are set forth above and applied as before.
Hughes et al. and Bikkina et al. does not teach a tablet, a capsule or a solution as claimed in claim 9.
Castelli et al. teaches a method of treating Fabry disease in a patient in need thereof, the method comprising administering to the patient a formulation comprising an effective amount of 1-deoxy-galactonojirimycin or salt thereof every other day, wherein the effective amount is about 123 mg free base equivalent (see e.g., claim 14); wherein the patient is administered about 150 mg of migalastat hydrochloride every other day (see e.g., claim 17); wherein the formulation comprises an oral dosage form (see e.g., claim 18); wherein the oral dosage form comprises a tablet, a capsule or a solution (see e.g., claim 19). Castelli et al. further teaches the term “1-deoxygalactonojirimycin” is also known as migalastat (see e.g., [0108]).
The difference between the method of Hughes et al. and Bikkina et al. set forth above and the claimed method is that Hughes et al. and Bikkina et al. does not specifically teach the oral migalastat is a tablet, a capsule, or a solution. It would have been prima facie obvious for one of ordinary skill in the art at the time the application was filed to modify the method of Hughes et al. and Bikkina et al. set forth above to selectively choose to administer the oral migalastat HCI in the form of tablet, capsule or solution as the oral dosage form. One would have been motivated to do so, because Castelli et al. teaches oral migalastat in the form of a tablet, a capsule or a solution are the suitable for treating the patient with Fabry disease. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of the oral migalastat HCl in a form of a tablet, a capsule, or a solution to the patient with Fabry disease would successfully treat said patient.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1-8, 10-11, 16 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296 and supplemental material), in view of Bikkina et al. (JAMA, 1994. Vol. 272(1): 33-36) as applied to claims 1-8, 16 and 42 above, and further in view of Germain et al. (N Engl J Med., 2016. Vol. 375(6): 545-55) and Swift et al. (Molecular Genetics and Metabolism, 2018. Vol. 123: S15–S153).
Please note Germain et al. has been cited in the previous Non-Final Office Action mailed on April 23, 2024.
The teachings of Hughes et al. and Bikkina et al. are set forth above and applied as before.
Hughes et al. and Bikkina et al. does not teach the migalastat or salt thereof is administered for at least 3 years in claim 10. Hughes et al. and Bikkina et al. also does not teach the migalastat or salt thereof is administered for at least 4 years in claim 11.
Germain et al. teaches migalastat may obviate the burden of lifelong administration of enzyme-replacement infusions every 2 weeks and immunogenicity associated with enzyme-replacement therapy (see e.g., p. 546, left column, 3rd paragraph). Germain et al. further teaches the higher volume of distribution of migalastat than of recombinant [Symbol font/0x61]-galactosidase hints at the possibility of better diffusion in organs and tissues (see e.g., p. 546, left column, 3rd paragraph). German et al. further teaches migalastat may better mimic natural enzyme trafficking and result in more consistent [Symbol font/0x61]-galactosidase activity than enzyme-replacement infusions every 2 weeks (see e.g., p. 546, left column). Germain et al. further teaches Fabry’s disease patients who completed the study were eligible to enroll in the open-label study for up to 5 years (see e.g., p. 546, right column, 1st paragraph).
Swift et al. teaches a case report that describes the efficacy of long term migalastat treatment in managing Fabry disease-associated pain in a 47-year-old male patient with an amenable GLA mutation; wherein the patient was treated with migalastat 150 mg every other day for > 10 years. Swift et al. further teaches the migalastat ameliorate Fabry disease-associated pain in this patient, resulting in discontinuation of pain medications and enabling him to resume normal daily activities that were not possible prior to treatment. Swift et al. further teaches no drug related adverse events were observed; and cardiac and renal function remain stable (see e.g., p. S138, left column).
The difference between the method of Hughes et al. and Bikkina et al. set forth above and the claimed method is that the prior art administer the migalastat HCl for 2.5 years and the claimed invention administer the migalastat or salt thereof for at least 3 years or at least 4 years. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Hughes et al. and Bikkina et al. set forth above to extend the treatment duration to include the claimed years through routine experimentation. One would have been motivated to do so, because Germain et al. teaches the migalastat may be an alternative treatment option for the lifelong administration of ERT as it provides more consistent [Symbol font/0x61]-galactosidase activity, and suggests that the current study enrolled eligible patients for up to 5 years; and Swift et al. teaches the patient with Fabry disease treated with migalastat greater than 10 years successfully ameliorate Fabry disease-associated pain with no drug-related adverse events. One would have a reasonable expectation of success to arrive at the claimed invention through routine experimentation, because one would have reasonably expected that by extending the treatment duration of the oral migalastat starting from 2.5 years to up to 5 years as suggested by Bikkina et al. would successfully provide more consistent [Symbol font/0x61]-galactosidase activity compared to ERT as well as ameliorating Fabry-disease associated pain.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on July 31, 2025 with respect to the rejection of claims 1-8, 12-13, 16 and 42 under 35 U.S.C. 103 as being unpatentable over Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296) have been fully considered but they are not persuasive.
Applicant's arguments filed on July 31, 2025 with respect to the rejection of claims 1-9, 12-13, 16 and 42 under 35 U.S.C. 103 as being unpatentable over Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296), as applied to claims 1-8, 12-13, 16 and 42 above, and further in view of Castelli et al. (US 2016/0324839 A1) have been fully considered but they are not persuasive.
Applicant's arguments filed on July 31, 2025 with respect to the rejection of claims 1-8, 10-13, 16 and 42 under 35 U.S.C. 103 as being unpatentable over Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296), as applied to claims 1-8, 12-13, 16 and 42 above, and further in view of Germain et al. (N Engl J Med., 2016. Vol. 375(6): 545-55) have been fully considered but they are not persuasive.
All rejections pertaining to claim 12 is moot because the claim is cancelled in view of the amendments to the claims filed on July 31, 2025.
In this case, Applicant amends claim 1 by adding the limitation of “wherein the patient has a first CBV event prior to initiating the administration of the migalastat or salt thereof”, which is previously recited in claim 13. This finding demonstrate that the amendments to the claim changes the scope of the claims and that necessitated a modification of the previous rejection on the record, including prior arts.
In Summary, applicant argues Hughes fails to disclose that any patients with a history of transient ischemic attack were administered migalastat for any particular period of time, and certainly not for the claimed time period of at least 2 years. Applicant further argues only 1 out of 18 patients in the ERT arm had transient ischemic attack (TIA), and Hughes et al. does not specify whether that one patient with transient ischemic attack are specifically enrolled in the 12-month open-label extension with migalastat as 3 out of the 18 patients did not continue into the open-label extension. Applicant further argues that the instant specification shows a significant reduction in CBV events in the claimed patent population by directing attention to the previous response.
In response, applicant’s argument is not found persuasive. First, applicant’s assertion that the patients in the ATTRACT study taught by Hughes et al. does not include patients with a history of transient ischemic attack is not found persuasive, because Hughes et al. clearly teaches at baseline, the majority of patients with Fabry disease and amenable mutations had multiorgan system disease shown below:
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(see e.g., Table S1; p. 291, left column, line 3-5). In other words, the patients taught by Hughes et al. includes patients with a medical history of CNS events, including stroke and transient ischemic attack, prior to switching them to the migalastat HCl or continue ERT in the ATTRACT study (see e.g., p. 289, left column, “Study design and participants” section). Therefore, one would have a reasonable expectation of success to arrive at the claimed invention by administering the migalastat to the patient with Fabry disease and a medical history of transient ischemic attack for the reasons set forth in the new ground of rejection above.
In addition, the Examiner believes the unexpected results that applicant relies upon (“Moreover, as described in Applicant’s prior response, the present patent application shows the significant reduction in CBV events in the claimed patient population”, see page 8 of the Remark) are referring to page 7 of the reply filed on October 23, 2025 shown below:
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. In the previous remark, applicant’s argues the results of migalastat therapy in ERT-experience patients are demonstrated in the ATTRACT study described in the specification shown below:
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(see paragraph [00107] of the specification). Specifically, Table 2 on page 34-35 of the specification discloses 8 out of the 49 ERT-experienced patients (16%) had a medical history of CBV events in the ATTRACT study prior to the migalastat treatment; and Table 4 further discloses 2 out of the 49 ERT-experienced patient (4%) had a CBV event during the treatment with migalastat 150 mg every other day. In other words, the unexpected results that applicant relies upon specifically administer migalastat 150 mg every other day to ERT-experienced patients with Fabry disease, including those with or without a medical history of CBV events at baseline. In contrast, claim 1 recites “[a] method of reducing the risk of a cerebrovascular (CBV) event in an enzyme replacement therapy (ERT)-experienced patient having Fabry disease, the method comprising administering to the patient a formulation comprising an effective amount of migalastat or salt thereof every other day for at least 2 years, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE)”. Given that the treatment outcome of migalastat in these 8 ER-experienced patients with Fabry disease and a history of CBV event are not disclosed in Table 2 and Table 4, and Table 4 does not specify whether the 2 out of the 49 ERT-experienced patient are the one with or without a CBV event prior to initiating the migalastat, it is not clear what results disclosed in the specification demonstrates the administration of migalastat significantly reduces the CBV event in the claimed patient population, which is ERT-experienced patients with Fabry disease and a medical history of CBV event prior to initiating the administration of the migalastat.
Solely to rebut applicant’s argument that the administration of migalastat reduce CBV events in the patient with Fabry disease and a history of CBV event prior to initiating the migalastat is unexpected, said unexpected results would have been expected, because Hughes et al. teaches the patient who switched from ERT to the migalastat significantly decrease left ventricular mass index, and has favorable results for a composite clinical endpoint of renal, cardiac, and cerebrovascular events (including stroke and transient ischemic attack) during the 18 month treatment period; and Bikkina et al. teaches increased LVM is associated with higher incidence of cerebrovascular events (including stroke and transient ischemic attack). Therefore, one would have reasonably expected that the administration of migalastat HCl at 150 mg every other day (about 123 mg of migalastat in free base) for 2.5 years to an ERT-experienced patient having Fabry disease and a medical history of transient ischemic attack at baseline would have successfully reduce the risk of transient ischemic attack as the cerebrovascular event by decreasing left ventricular mass index of said patient.
Therefore, the new ground of rejection has been applied for the reasons set forth herein.
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 1-11, 16 and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, 9-13 and 20 of copending Application No. 17/172,846 (reference application) in view of Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296 and supplemental material) and Bikkina et al. (JAMA, 1994. Vol. 272(1): 33-36).
The claims of the reference application are drawn to a method of reducing the risk of composite clinical outcomes comprising, inter alia, cerebrovascular events in an ERT-experienced female patient having Fabry disease, the method comprising administering to the female patient a formulation comprising an effective amount of migalastat or salt thereof every other day for at least 18 months, wherein the effective amount is about 100 mg to about 150 free base equivalent (FBE); wherein the cerebrovascular events comprises one or more of stroke or transient ischemic attack (see claim 1); wherein the migalastat or salt thereof enhances α-galactosidase A activity (see claim 6); wherein the female patient is administered about 123 mg FBE of the migalastat or salt thereof every other day (see claim 7); wherein the female patient is administered about 150 mg of migalastat hydrochloride every other day (see claim 9); wherein the formulation comprises an oral dosage form (see claim 10); wherein the oral dosage form comprises a tablet, a capsule, or a solution (see claim 11); wherein the migalastat or salt thereof is administered for at least 3 years (see claim 12); wherein the migalastat or salt thereof is administered for at least 4 years (see claim 13); wherein the female patient has a HEK assay amenable mutation in α-galactosidase A (see claim 20).
The claims of the reference application does not teach the patient had a first CBV even prior to initiation the administration of the migalastat or salt thereof.
Hughes et al. teaches a randomized phase III ATTRACT study that compares the safety and efficacy of migalastat to ERT in male and female patients with Fabry disease and amenable mutation previously treated with ERT (see e.g., p. 289, left column, line1-4); wherein the study comprised an 18-month open-labeled comparison between oral migalastat and enzyme replacement therapy (ERT), followed by a 12-month open-labeled extension with oral migalastat (see e.g., p. 289, left column, 1st paragraph under the “Study design and participants” section; and the title; Figure 1). Hughes et al. further teaches in the 18-month controlled period, patients previously treated with ERT (agalsidase alfa and agalsidase beta) for >12 months were randomized 1.5:1 to switch to migalastat HCl (150 mg every other day) or continue ERT (see e.g., p. 289, left column, 1st paragraph under the “Study design and participants” section). Hughes et al. further teaches at baseline, the majority of patients with amenable mutations had multiorgan system disease shown below:
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(see e.g., Table S1; p. 291, left column, line 3-5). Hughes et al. further teaches the percentage of patients who experienced renal, cardiac or cerebrovascular events during the 18-month treatment period was 0% for CBV (TIA) for migalastat and 6% for ERT in Table 4 (see e.g., p. 292, left column, the “Composite clinical outcome assessment” section), wherein the cerebrovascular events includes stroke and transient ischemic attack (TIA) (see e.g., p. 290, left column, “Composite clinical outcome assessment” section). Hughes et al. further teaches the frequency of events noted above indicates that the effect of migalastat compares favorably to ERT in these composite clinical events (see e.g., p. 293, right column, 3rd column). Hughes et al. further teaches in patients switched from ERT to migalastat, left ventricular mass index (LVMi) decreased significantly from baseline over 18 months, and the LVMi changes were largest for patient with left ventricular hypertrophy; and plasma lyso-Gb3 levels remained low and stable in patients with amenable mutations (see e.g., p. 292, “Echocardiography” section and “Plasma lyso-Gb3” section).
Bikkina et al. teaches a Framingham Heart Study that evaluates the association of echocardiographically determined left ventricular mass (LVM) with incidence of stroke or transient ischemic attack in an elderly cohort (see e.g., abstract). Bikkina et al. further teaches the echocardiographically determined LVM was associated with risk for cerebrovascular events in men and women; and this increased risk persisted even after adjusting for other risk factors for stroke including age, systolic blood pressure, hypertension treatment, diabetes, cigarette smoking, blood lipid levels, left atrial size, and mitral annular calcification (see e.g., p. 35, right column, “comment” section to p. 35, left column, line 1-2); wherein the cerebrovascular events includes stroke and transient ischemic attack (see e.g., abstract, “results” section). Bikka et al. further teaches the hazard ratio for stroke or transient ischemic attack was 3.08 comparing the highest and lowest quartiles of LVM-to-height ratio (see e.g., p. 35, middle section, “Association of LVM and Outcome” section, 2nd paragraph).
In Summary, the claims of the reference application are also drawn to a method of reducing the risk of stroke or transient ischemic attack as the composite clinical outcome of cerebrovascular events in an ERT-experienced female patient having Fabry disease comprising administering to the female patient a formulation comprising an effective amount of migalastat or salt thereof every other day for at least 18 months, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE). The difference between the claims of the reference application and the claimed invention is that the reference application does not teach the ERT-experienced patient had a first CBV event prior to initiating the administration of the migalastat or salt thereof. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of the reference application to administer the migalastat for 2.5 years, and then incorporate an ERT-experienced patient with Fabry disease and a medical history of transient ischemic attack prior to administering the migalastat. One would have been motivated to do so, because Hughes et al. teaches in the 18+12 month study, the patient who switched from ERT to the migalastat significantly decrease left ventricular mass index, and has favorable results for a composite clinical endpoint of renal, cardiac, and cerebrovascular events (including stroke and transient ischemic attack) during the 18 month treatment period; and Bikkina et al. teaches increased LVM is associated with higher incidence of cerebrovascular events (including stroke and transient ischemic attack). One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of migalastat at about 100 mg to about 150 free base equivalent (FBE) for at least 18 months to an ERT-experienced patient having Fabry disease and a medical history of transient ischemic attack at baseline would have successfully provide a favorable results for the composite clinical endpoint (including cerebrovascular events) and reduce the risk of a cerebrovascular event by decreasing left ventricular mass index of said patient.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). In this case, the claims of the reference application clearly teaches the administration of the migalastat or salt thereof every other day for at least 18 months, at least 3 years, or at least 4 years, and each of these overlap with the treatment duration instantly claimed.
Therefore, this is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments filed on July 31, 2025 with respect to the provisional rejection of claims 1-2, 4-11, and 16 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7 and 9-13 of copending Application No. 17/172,846 (reference application) have been considered but are moot because the new ground of rejection has been applied for the reasons set forth herein.
Claims 1-9, 16 and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 201 and 203-207 of copending Application No. 18/199,120 (the reference application) in view of Hughes et al. (J Med Genet, 2017. Vol. 54(4): 288-296 and supplemental material) and Bikkina et al. (JAMA, 1994. Vol. 272(1): 33-36).
The claims of the reference application is drawn to a method of reducing left ventricular mass index (LVMi) in an enzyme replacement therapy (ERT) experienced human patient having Fabry disease, the method comprising administering to the patient a formulation comprising an effective amount of 1-deoxygalactonojirimycin or salt thereof every other day, wherein the effective amount is about 123 mg free base equivalent (FBE) and wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of the 1-deoxygalactonojirimycin or salt thereof (see claim 1); wherein the 1-deoxygalactonojirimycin or salt thereof enhances -galactosidase A activity (see claim 203); wherein the patient is administered about 123 mg of 1-deoxygalactonojirimycin every other day (see claim 204); wherein the patient is administered about 150 mg of migalastat hydrochloride every other day (see claim 205); the formulation comprises an oral dosage form (see claim 206); the oral dosage form comprises a tablet, a capsule or a solution (see claim 207). Please note the 1-deoxygalactonojirimycin taught by the reference application is a migalastat according to paragraph [0077] of the instant specification.
The claims of the reference application does not teach the migalastat or salt thereof is administered for at least 2 years. The claims of the reference application also does not teach the patient had a first CBV even prior to initiation the administration of the migalastat or salt thereof. The claims of the reference application also does not teach the migalastat or salt thereof reduce the risk of a cerebrovascular event. The claims of the reference application also does not teach the patient has a HEK assay amenable mutation in [Symbol font/0x61]-galactosidase A.
Hughes et al. teaches a randomized phase III ATTRACT study that compares the safety and efficacy of migalastat to ERT in male and female patients with Fabry disease and amenable mutation previously treated with ERT (see e.g., p. 289, left column, line1-4); wherein the study comprised an 18-month open-labeled comparison between oral migalastat and enzyme replacement therapy (ERT), followed by a 12-month open-labeled extension with oral migalastat (see e.g., p. 289, left column, 1st paragraph under the “Study design and participants” section; and the title; Figure 1). Hughes et al. further teaches in the 18-month controlled period, patients previously treated with ERT (agalsidase alfa and agalsidase beta) for >12 months were randomized 1.5:1 to switch to migalastat HCl (150 mg every other day) or continue ERT (see e.g., p. 289, left column, 1st paragraph under the “Study design and participants” section). Hughes et al. further teaches at baseline, the majority of patients with amenable mutations had multiorgan system disease shown below:
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(see e.g., Table S1; p. 291, left column,