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 .
Status of Claims
Claims 1, 17, 23-26, and 28-37 are pending as of the response and amendments filed on 1/26/26. Claims 2-16, 18-22, and 27 have been canceled.
Claims 1, 3-4, 6, 8, 12, 17, 23-26, 28-30, and 32-34 were previously rejected under 103 over Bourque in view of Bremova-Ertl; and claim 31 was previously rejected under 103 over Bourque in view of Bremova-Ertl, and further in view of Stirnemann. Applicants’ reasons for traversal are summarized below.
Applicants have stated the examiner cites Bourque for its disclosure of GCS inhibitors for treating Gaucher disease (types 1, 2, and 3) and Bremova-Ertl for disclosing ataxia as being a feature of Gaucher type 3 which is assessed via SARA score. Applicants have argued neither Bourque nor Bremova-Ertl would have provided a POSITA with a reasonable expectation of success in achieving a reduction on the SARA ataxia scale of at least 0.5, or reducing the SARA score to between 0.00 to 3.00 by administering a compound of formula (I) to a person with Gaucher type 3 disease. Applicants have stated while Bourque discloses a compound falling within the scope of the previous formula (I) of the pending claims “may mitigate disease progression and neurological symptoms in type 3 Gaucher disease” nothing in Bourque would provide a POSITA with a reasonable expectation of success in administering the compound of amended claim 1 and treating each and every possible symptom of Gaucher type 3, let alone achieving the required reduction in SARA score. Applicants have maintained Bremova-Ertl doesn’t cure the deficiencies of Bourque.
Applicants’ arguments are not persuasive. Bourque teaches GCS inhibitors for treating metabolic lysosomal storage diseases, including Gaucher disease type 1, 2, and 3; additionally, Bourque includes the species recited in amended claim 1 (see p. 65, top structure). Bourque also teaches a GCS inhibitor reduced brain GluCer and GluSph and brain neuropathology in a mouse model of type 2 Gaucher disease, and that accumulation of GluCer and GluSph in the brain is what results in neurologic impairment. Although it was acknowledged Bourque doesn’t each a reduction in the SARA score, Bremova-Ertl supports accumulation of GluCer in the brain results in neurologic symptoms in type 3 Gaucher disease, and that ataxia in this disease is evaluated using SARA. Since Bourque teaches the GCS inhibitors, inclusive of the compound of amended claim 1 reduces brain GluCer and GluSph levels, which are taught to result in neurological symptoms of Gaucher disease, including ataxia and cerebellar ataxia, one of ordinary skill in the art would have been clearly motivated to have administered the compound of amended claim 1 to a subject having type 3 Gaucher disease, with the reasonable expectation that brain GluCer and GluSph levels would have been reduced, resulting in reduction of ataxia and cerebellar ataxia, leading to a reduction of the SARA score. The 103 rejection over Bourque in view of Bremova-Ertl is maintained for reasons of record as well as those discussed here. This rejection will be reiterated with modification to account for the amended claims.
Applicants have argued with respect to the rejection of claim 31 that Stiremann is a review of Gaucher disease pathophysiology and doesn’t cure the deficiencies of Bourque and Bremova-Ertl.
Applicants’ arguments are not persuasive. As discussed above, it is maintained that one of ordinary skill in the art would have arrived at the method of improving symptoms of cerebellar ataxia in a Gaucher type 3 disease patient by administering the compound of amended claim 1, in view of the combined teachings of Bourque and Bremova-Ertl. Stirnemann was cited for the teaching of Gaucher disease (types 1, 2, and 3) to be due to a mutation in the GBA1 gene. Therefore, it is maintained a POSITA would have been motivated to have arrived at the method of the instant claims and have administered the compound of amended claim 1 to a subject having type 3 Gaucher disease caused by a mutation in the GBA1 gene, based on the combined cited art, and have had a reasonable expectation of success.
Claims 1, 3-4, 6, 8, 12, 17, 23-26, and 28-34 were previously provisionally rejected for nonstatutory double patenting over the claims of 17242016 in view of Bourque, Bremova-Ertl., and Stiremann. Applicants have stated in response the copending application has been abandoned as of 11/26/2025, therefore this rejection should be withdrawn.
In consideration of the abandonment of 17242016, this rejection is withdrawn.
Claims 1, 17, 23-26, and 28-37 were examined. Claims 35-37 are allowed. Claims 1, 17, 23-26, and 28-34 are rejected.
Claim Rejections-35 USC § 103
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.
Claim(s) 1, 17, 23-26, 28-30, and 32-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bourque et. al., WO 2012129084 A2, publ. 9/27/2012 (cited in an IDS) in view of Bremova-Ertl et. al., Frontiers in Neurol., vol. 8, pp. 1-19, publ. Jan. 2018.
Bourque teaches inhibitors of glucosylceramide synthase (GCS) for the treatment of metabolic diseases, e.g., lysosomal storage diseases, either alone or as a combination treatment with enzyme replacement therapy (ERT) (title & abstract; p. 1, 1st para). Bourque teaches GCS inhibitors are thought to be useful for treating diseases associated with glycolipid accumulation, e.g., Gaucher disease (p. 2, middle para). Bourque exemplifies the following GCS inhibitors for treating a subject diagnosed with a lysosomal storage disease (p. 65, last 3 lines-p. 66, middle of page):
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. Both of the above shown compounds are included within formula (I) of the instant claims having R1=hydrogen; R2, R3=both methyl; A=thiazole or phenyl; R4=fluoro; and R5, R6=hydrogen. Bourque discloses administration of a GCS inhibitor in a pharmaceutical composition for oral or intravenous, e.g., systemic administration to a human (p. 102, last para), and a therapeutically effective dose ranges from about 0.1 mg to about 2000 mg, with preferred doses ranging from about 0.1 mg. to about 200 mg., administered from one to four times daily (p. 105, middle para). Bourque further teaches an embodiment wherein the GCS inhibitor, either alone or in combination with ERT is used for treatment of the lysosomal storage disease, types 1, 2, or 3 Gaucher disease (p. 125, last para-p. 126, top para; p. 140, middle para); in a specific embodiment, Bourque teaches the GCS inhibitor as either (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or quinuclidine-3-yl (2-(4’-fluoro-[1,1’-biphenyl]-3-yl)propan-2-yl)carbamate for reducing the level of GluCer and GluSph in the brain of a subject diagnosed with Gaucher disease (p. 127-p. 128, top 2 lines), wherein GluCer represents glucosyl ceramide and GluSph represents glucosyl sphingosine (p. 78, see description of Fig. 9). Bourque teaches ERT therapy to include glucocerebrosidase (p. 136, last para-p. 137, top para), wherein the combination therapy results in a decrease in glucocerebroside (p. 137, middle para). Treatment of a subject with Parkinson’s disease is taught (p. 64).
Bourque teaches Gaucher disease to result in a deficiency of glucocerebrosidase, and although type 1 Gaucher disease doesn’t result in neuropathic symptoms, types 2 and 3 are neuropathic, as the deficiency of glucocerebrosidase causes GluCer and GluSph to accumulate in the brain, causing neurologic impairment (p. 142, last para-p. 143, top para). Bourque additionally teaches evaluation of the GCS inhibitor, quinuclidine-3-yl (2-(4’-fluoro-[1,1’-biphenyl]-3-yl)propan-2-yl)carbamate in a mouse model of type 2 Gaucher disease showed a reduction in brain GluCer and GluSph levels, and a reduction in brain neuropathology and extended lifespan (p. 144, top para). Bourque further teaches the small molecule GCS inhibitors as described above are particularly preferred in treatment of a central nervous system manifestation of a lysosomal storage disease, such as Gaucher types 2 and 3, as they can more readily cross the blood-brain barrier (p. 150, last para-p. 151, top para).
Bourque doesn’t explicitly teach or suggest improving symptoms of cerebellar ataxia, a reduction in a SARA ataxia scale or at least 0.5, or reduction of the SARA score to between 0.00 to 3.00.
Bremova-Ertl. et. al. teaches Gaucher disease as an autosomal recessive lysosomal storage disease caused by a deficiency in beta-glucosidase, resulting in accumulation of glucosylceramide in the liver, spleen, and bone marrow; in type 3 Gaucher disease, there is accumulation in the CNS as well, resulting in progressive neurological symptoms (p. 2, 1st para). Bremova-Ertl. et. al. teaches ataxia as a feature of type 3 Gaucher disease, which is assessed using the Scale for the Assessment and Rating of Ataxia (SARA) (p. 1, method section of abstract; pp. 3-7, Table 1). SARA was used to evaluate cerebellar status in patients (p. 8, see para under Disease evaluation). Other specific manifestations of type 3 Gaucher disease include cerebellar and gait ataxia, dysmetria, cognitive impairment, dysarthria, among others (pp. 3-7, Table 1). Gaucher disease is caused by mutations in the GBA gene (pp. 3-7, Table 1).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have arrived at the claimed method of treating a human patient having Gaucher disease type 3 and improved symptoms of cerebellar ataxia comprising administering a compound of formula (I) in an effective amount, wherein the method would have been expected to be effective in reducing the score on the SARA ataxia scale of at least 0.5., or to reduce the SARA score to between 0.00 and 3.00, in consideration of the combined teachings of Bourque and Bremova-Ertl. Bourque exemplifies two GCS inhibitors, (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate and quinuclidine-3-yl (2-(4’-fluoro-[1,1’-biphenyl]-3-yl)propan-2-yl)carbamate for treating a lysosomal storage disease, including types 1, 2, or 3 Gaucher disease. Bourque further teaches an embodiment wherein the lysosomal storage disease to be treated is neuropathic Gaucher disease, i.e., type 2 or 3, and that the compounds described above are particularly preferred in treatment of a central nervous system manifestation of a lysosomal storage disease, such as Gaucher types 2 and 3, as they can more readily cross the blood-brain barrier and reduce neuropathology. Bourque further teaches these compounds reduce brain GluCer and GluSph levels. Although Bourque doesn’t explicitly teach a reduction in cerebellar ataxia, Bremova-Ertl. et. al. teaches ataxia, including cerebellar ataxia as a feature of type 3 Gaucher disease, which is assessed using the Scale for the Assessment and Rating of Ataxia (SARA). One of ordinary skill in the art would have had a reasonable expectation that administration of a GCS inhibitor, (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or quinuclidine-3-yl (2-(4’-fluoro-[1,1’-biphenyl]-3-yl)propan-2-yl)carbamate to a human patient with type 3 Gaucher disease would have experienced a reduction in cerebellar ataxia as measured by SARA, such as a reduction of at least 0.5 or a decrease in the SARA score to between 0.00 and 3.00, as Bourque teaches (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or quinuclidine-3-yl (2-(4’-fluoro-[1,1’-biphenyl]-3-yl)propan-2-yl)carbamate to reduce neuropathology by reducing brain GluCer and GluSph levels.
Regarding instant claim 30, wherein the method is effective to reduce cognitive deficits, Bourque teaches the GSC inhibitors effectively pass the blood-brain barrier, reducing neuropathology and brain GluCer and GluSph levels. As the accumulation of brain GluCer and GluSph levels is associated with the CNS features of type 2 and 3 Gaucher disease, and as cognitive impairment is taught by Bremova-Ertl as a CNS manifestation of this disease, one of ordinary skill in the art would have reasonably expected a reduction in cognitive impairment by administering (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or quinuclidine-3-yl (2-(4’-fluoro-[1,1’-biphenyl]-3-yl)propan-2-yl)carbamate.
Regarding instant claim 33, wherein the method results in reduction in glycosylceramide (GluCer) concentration in CSF and/or plasma of at least 30% after 6 months of treatment, Bourque teaches the GSC inhibitors effectively pass the blood-brain barrier, reducing neuropathology and brain GluCer and GluSph levels. Therefore, one of ordinary skill in the art would have reasonably expected treatment with (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or quinuclidine-3-yl (2-(4’-fluoro-[1,1’-biphenyl]-3-yl)propan-2-yl)carbamate would have provided the same effect as recited by instant claim 33.
Claim(s) 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bourque et. al., WO 2012129084 A2, publ. 9/27/2012 (cited in an IDS) in view of Bremova-Ertl et. al., Frontiers in Neurol., vol. 8, pp. 1-19, publ. Jan. 2018, as applied to claims 1, 17, 23-26, 28-30, and 32-34, further in view of Stirnemann et. al., Int. J. Molecular Sciences, vol. 18, pp. 1-30, publ. 2/17/2017.
The teachings of Bourque and Bremova-Ertl as discussed previously are incorporated herein. Neither explicitly teaches Gaucher type 3 in a patient having a mutation in GBA1.
Stirnemann et. al. teaches Gaucher disease is caused by mutations in the GBA1 gene, resulting in significantly decreased activity in the lysosomal enzyme, glucocerebrosidase and accumulation of GluCer in macrophages (p. 2, 2nd para; p. 3, Fig. 1 and section 4-p. 4, top 4 lines).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have arrived at the instantly claimed method of treating a human subject having type 3 Gaucher disease, wherein the subject was diagnosed as having a mutation in the GBA1 gene, in view of the teachings of Bourque, Bremova-Ertl, and Stirnemann. Bourque and Bremova-Ertl teach as discussed previously, while Stirnemann teaches Gaucher disease is caused by mutations in the GBA1 gene, leading to a decrease in the activity of glucocerebrosidase and accumulation of GluCer. As Bourque teaches embodiments wherein the subject to be treated with GCS inhibitors has Gaucher disease type 3, one of ordinary skill in the art would have been motivated to have applied the method to treat a human patient diagnosed with Gaucher disease type 3 having a mutation in the GBA1 gene, and have had a reasonable expectation of success.
Information Disclosure Statement
The IDS filed on 1/26/26 has been considered.
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.
Correspondence
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SARAH . PIHONAK
Primary Examiner
Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627