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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 7, 2026 has been entered.
Receipt of Arguments/Remarks filed on January 7, 2026 is acknowledged. Claims 2-7, 10, 12-17 and 70 are pending in this Application. Claim 70 is independent.
The claim amendments filed on 01/07/2026 do not change the patient population encompassed by the claims as previously filed on 09/12/2025.
Applicant previously elected the species compound of formula
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(found in at least p. 34 of specs).
Examination
In accordance with the election of species as detailed in the requirement for restriction, the examiner searched the elected species of formula (XII)
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in a method of treating mild cognitive impairment and found it unpatentable over the prior art as detailed below. In the interest of a compact prosecution the prior art search has been expanded to the full scope of the compounds of formula (I) of claim 70.
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.
Claims 2-7, 10, 12-17 and 70 remain rejected under 35 U.S.C. 103 as being unpatentable over Bourque et al. (WO 2012/129084-cited in parent case 15/556,444) in view of Krainc et al. (WO 2012/177997), and further in view of Mielke et al. ((2013) PLoS ONE 8(9): e73094), and Malec-Litwinowicz (Neurologia i Neurochirurgia Polska, Volume 48, Issue 4, 2014, pages 258-261), in view of Shayman JA. (Expert Rev Endocrinol Metab. 2013 Nov;8(6):491-504) and Boyd et al. (Bioorg Med Chem Lett. 2014 Jul 15;24(14):3001-5).
This rejection is the same exact rejection mailed on October 8, 2025 in the Final Office Action.
A subject in need thereof of claim 70 is a subject with mild cognitive impairment (MCI), which has one or more mutations in the gene GBA1 and which has been diagnosed as having an associated proteinopathy, wherein the proteinopathy is Parkinson’s disease or Gaucher’s disease.
Before the effective filing date of this invention, patients with a GBA1 deficiency, such as Gaucher’s or Parkinson’s disease patients, have been taught to be treated with inhibitors of glucosylceramide synthase (GSC).
Bourque discloses a method for treating Parkinson’s disease and Gaucher’s disease in a subject diagnosed as having a lysosomal storage disease of the lysosomal enzyme glucocerebrosidase (GCase, GBA1), comprising administering small molecule inhibitors of glucosylceramide synthase (GCS), wherein the inhibitors are of formula
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(venglustat) or
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. See pages 64-67. The compounds reduce glucosylceramide (also known as GluCer or glucocerebroside) and glucosylsphingosine (GluSph) build-up in the brain. See whole document, particularly, page 140, 144, Figures and Examples 122-125.
Krainc particularly discloses that inhibiting/ lowering glucosylceramide synthase (GCS, GlcCer) levels provides treatment for proteinopathies, such as those associated with accumulation of alpha-synuclein, such as Parkinson’s disease (p. 1-2). Krainc states that “mutations in the GCase gene (GBA1) and alterations in sphingolipid metabolism contribute to the pathogenesis of synucleinopathies” and that “genetic studies in large patient cohorts demonstrated that patients with parkinsonism have an increased incidence of GBA1 mutations, making GBA1 the most common known genetic risk factor for Parkinson’s Disease to date”. See paragraphs [00212-00213]. Further, Krainc teaches that mild cognitive impairment (MCI) is associated with Parkinson’s disease. Parkinson’s disease (PD) and mild cognitive impairment (MCI) associated with proteinopathies can be treated with the same glucosylceramide synthase (GCS) inhibitors (see at least claims 2, 90, 91 and para [00277]-[00279]). Note that a small molecule agent for treatment is eliglustat (Genz-112638), which is of the same family of venglustat (Krainc [00279] and claim 91).
James Shayman “Eliglustat tartrate, a prototypic glucosylceramide synthase inhibitor”: At page 496 identifies eliglustate tartrate and Genz-682452 (venglustat) as designed and developed to specifically inhibit glucosylceramide synthase.
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At page 500-501 recognized the potential use of these compounds for Parkinson’s disease patients that have GBA mutations:
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Boyd et al. “Correction of lysosomal dysfunction as a therapeutic strategy for neurodegenerative diseases”: Boyd disclosed “this study also demonstrated the inhibition of endogenous GCase activity by syn, thus providing a feedback loop for propagating the neuropathology of PD (p. 3003). In at least page 3004 Boyd taught
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Mielke et al. discloses that “PD patients who are GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia. These finding may suggest the critical role of glucosylceramide and ceramide metabolism in the development of PD and subsequent cognitive impairment”. Particularly, in Mielke’s discussion section: “mutations in the GBA gene coding for glucocerebrosidase result in a build-up of glucosylceramide…and decrease degradation of alpha-synuclein”. “A recent study suggested a positive feedforward loop between increased glucosylceramide and alpha-synuclein accumulation, leading to neurodegeneration [4]. These experimental results fit with research showing that mutations in glucocerebrosidase are associated with an increased risk of sporadic PD, and that these patients have earlier ages of onset and more cognitive impairment”. “The present results suggest that plasma ceramide metabolism is perturbed in PD, and may be particularly important in the development of cognitive impairment among PD patients”.
Malec-Litwinowicz et al. “Cognitive impairment in carriers of glucocerebrosidase gene mutation in Parkinson disease patients” provides more experimental evidence of a link between mutations in GBA1 and mild cognitive impairment (MCI) in patients with Parkinson’s disease or Gaucher’s disease. See the abstract and p. 260:
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.
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Ascertainment of the difference between the prior art and the claims
The difference between the prior art Bourque and claim 70 is that Bourque does not disclose reversing mild cognitive impairment (MCI) in the PD- or GD-GBA1 deficient patients.
Finding of prima facie obviousness – rationale and motivation
A person of ordinary skill in the art is a person with the knowledge and level of skill of the authors of the references cited in this action. It would have been prima facie obvious to a POSITA to treat mild cognitive impairment subsequent to Parkinson’s disease or Gaucher’s disease in patients having glucocerebrosidase (GCase) dysfunction due to GBA1 mutations with the compositions of Bourque. Per the references above, the ordinary skilled artisan knew that mild cognitive impairment in said patients is secondary to PD or GD due to GBA1 (GCase) enzyme deficiencies and the resulting build-up of glucosylceramide followed by alpha-synuclein accumulation. Thus, a POSITA would have been motivated to treat mild cognitive impairment in said patients by reducing glucosylceramide (also known as GluCer or glucocerebroside) and glucosylsphingosine (GluSph) build-up in the brain with the effective compositions of Bourque. There would have been a reasonable expectation that treating the primary condition would treat the secondary condition which is MCI.
Applicant’s arguments have been carefully considered but were found unpersuasive.
Applicant argues that the “reversing mild cognitive impairment” in the preamble of claim 70 is a limitation that must be considered due to “a subject in need thereof” in the preamble and that the examiner did not consider it. The examiner must disagree. It can be seen in the above rejection and previous examiner’s remarks that the examiner considered the preamble recitation of “reversing mild cognitive impairment” to understand the patient population encompassed by the claims and the expected result of the method. See page 9 of the Office action mailed on 10/08/2025:
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Applicant has now stated at page 9 of the arguments that “”reversing mild cognitive impairment” is construed as lowering the level of cognitive impairment in a subject suffering from mild cognitive impairment, such that the resulting post-treatment level of cognitive impairment is lower than the pre-treatment level.” While no definition for “reversing” was found in the specification, “reversing mild cognitive impairment” appears in the specification and previous claims as separate from reducing mild cognitive impairment. In view of the totality of the record, the broadest reasonable interpretation consistent with applicant’s statement is that “reversing mild cognitive impairment” means any lowering or reduction in the severity of cognitive impairment, which is any improvement in the symptoms of cognitive impairment compared to pre-treatment levels.
Applicant stated that they have added to the claims the recitation “wherein the subject has mild cognitive impairment” and that this is further limiting. This amendment does not make any difference in the rejection since the examiner interpreted in the previous Office action that the subjects in need of “reversing mild cognitive impairment” are subjects suffering from mild cognitive impairment secondary to PD or GD due to GBA1 (GCase) enzyme deficiencies.
Applicant argues that not all patients with proteinopathies and GBA1 mutations have MCI, and that therefore, MCI is not necessarily a “secondary condition” to Parkinson’s disease or Gaucher’s disease. In response, a secondary condition is an additional health issue or complication that arises as a result of a primary condition. As discussed above, Krainc, Mielke et al. and Malec-Litwinowicz et al. disclosed that MCI is a symptom of, and secondary to PD or GD with GBA1 mutations.
Regarding the argument that mild cognitive impairment is not experienced by all subjects with proteinopathies and GBA1, the subset of patients addressed in this rejection is the subset discussed by Krainc, Mielke et al. and Malec-Litwinowicz et al., which has PD or GD, GBA1 mutations and cognitive impairment.
Applicant stated that :
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In response, the claims recite PD, GBA1 mutations and MCI, and that is what the combination of references teaches.
Applicant argues that a POSITA would not have had a reasonable expectation of success in reversing mild cognitive impairment in the claimed population. Applicant argues that
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must be considered when determining the likelihood of success, and that the examiner has not provided reasons.
The examiner has responded to this argument in the body of the rejection above, and in at least the Office actions mailed on 06/12/2025 and 10/08/2025.
In addition, MPEP 2143.02 states that “the reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention and can be implicitly shown via the prior art teachings or as part of the obviousness analysis.”
Based on Bourque alone, a POSITA would have treated patients having PD or GD and GBA mutations with the GCS inhibitors because this is what Bourque teaches. Further, as evidenced by the secondary references, the artisan would have recognized that the subset of patient population having PD or GD, GBA mutations and mild cognitive impairment, would have benefited from the administration of the GCS inhibitors of Bourque because mild cognitive impairment in said patients is secondary to PD or GD due to GBA1 (GCase) enzyme deficiencies and the resulting build-up of glucosylceramide followed by alpha-synuclein accumulation. See also the reasons in examiner’s previous explanations/ responses. The references provided a reasonable expectation of success in performing the methods and in improving the disease condition. The reasonable expectation of success should not be confused here with a reasonable expectation of “reversing mild cognitive impairment”. The quality of “reversing mild cognitive impairment” is a latent quality that would naturally flow from administering the inhibitors of Bourque to the same patient population having PD or GD, GBA mutations and mild cognitive impairment. The examiner is following the guidance in MPEP 2145 II, which states: “ARGUING ADDITIONAL ADVANTAGES OR LATENT PROPERTIES
Prima Facie Obviousness Is Not Rebutted by Merely Recognizing Additional Advantages or Latent Properties Present But Not Recognized in the Prior Art”
"The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicant argues that the claimed invention produced unexpected results. Applicant states that the symptomatic GBA1 mice model regained the ability to investigate an unfamiliar object in a novel object recognition test, which applicant says it means that memory aberrations were reversed. This doesn’t appear to go beyond what could have reasonably been expected. It is the examiner’s position that the compound works like it is supposed to. The compounds of formula (I) were known to be GCS inhibitors and were known to reduce glucosylceramide (GluCer or glucocerebroside) and glucosylsphingosine (GluSph) build-up in the brain of mice that carry a GBA1 mutation. GCS inhibitors have also been found to reduce lipid build-up in the Gaucher disease mice model GBA1D409/D409V in the prior art. It was also known that reducing GCase substrates with GCS inhibitors deplete or reverse protein aggregates. Thus, when the compound was administered to GBA mutated mice as in Figure 16, their symptoms improved.
Applicant also argues that the underlying mechanism of cognitive impairment in PD is not well understood and likely includes multiple factors. However, here at least Mielke et al. and Malec-Litwinowicz et al. described the underlying mechanism of cognitive impairment in PD or GD patients that have GBA mutations.
For all the reasons provided, the examiner believes this rejection is proper.
Conclusion
Claims 2-7, 10, 12-17 and 70 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALERIE RODRIGUEZ-GARCIA whose telephone number is (571)270-5865. The examiner can normally be reached Monday-Friday 9:30am-5:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621