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 .
Claim of Foreign Priority
Applicant did not claim foreign priority.
Election/Restrictions
Applicant’s election without traverse of Tideglusib, corresponding to claims 1, 3, 5, and 19-22 are acknowledged in the reply filed on July 20, 2026, is acknowledged.
Status of the Claims
Claims 1-22 are pending. Claims 2, 4, and 6-18 are preliminarily withdrawn. Claims 1, 3, 5, and 19-22 are examined.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
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.
Claim(s) 1, 3, 5, and 19-22 are rejected under 35 U.S.C. 103 as being unpatentable over Genovese et al., (US2016/0227830), in view of Martinez-Gonzalez et al., “Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3β as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis,” Int. J. Mol. Sci. 2021, 22, 8975, in view of Eldar-Finkelman et al., “GSK-3 inhibitors: preclinical and clinical focus on CNS,” October 2011, Volume 4, Article 32 Frontiers in Molecular Neuroscience, in view of Lovestone et al., “A Phase II Trial of Tideglusib in Alzheimer’s Disease,” Journal of Alzheimer’s Disease 45 (2015) 75–88, in view of Noori et al., “Identification of a Novel Selective and Potent Inhibitor of Glycogen Synthase Kinase-3,” American Journal of Physiology- Cell Physiology Volume 317, Issue 6, Dubruc et al., “A New Intellectual Disability Syndrome Caused by CTNNB1 Haploinsufficiency,” Am J Med Genet Part A 164A:1571–1575 (2014), in view of Kuechler et al., “De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum,” Hum Genet (2015) 134:97–109, and in view of Wang et al., “Tideglusib, a chemical inhibitor of GSK3β, attenuates hypoxic-ischemic brain injury in neonatal mice,” Biochimica et al Biophysica Acta 1860 (2016) 2076-2085.
Genovese teaches “the downstream phosphorylation target of GSK3β, beta-catenin (CTNNB1) may be mutated at the codons coding for residues phosphorylated by GSK3β, thereby preventing phosphorylation of CTNNB1 by GSK3β, resulting in a constitutively active, stable CTNNB1.” See par. 67. A representative GSK3β inhibitor is Tideglusib. See par. 68. Genovese provides the mechanistic basis by which GSK3β inhibitors activate and stabilize CTNNB1 (beta-catenin).
Martinez-Gonzalez teaches that when Tideglusib was orally administered at 200 mg/kg for 40 days provided in vivo neuroprotective effects by restoring TDP-43 homeostasis and good safety and tolerability in neurological diseases. See p9.
More specifically,
Tideglusib, a small thiadiazolidindione (TDZD), is an in-house designed non-ATP competitive GSK-3β inhibitor that has shown neuroprotective, anti-inflammatory, and neurogenic properties in different neurodegenerative models. Furthermore, good safety, tolerability, and efficacy have been reported in clinical trials for different neurological diseases. See p2, 4th full par.
Additionally, this drug was found to significantly reduce the increased TDP-43 phosphorylation in the spinal cord of TDP-43 transgenic mice, demonstrating that at the dose used, Tideglusib was able to reach the central nervous system. See p9, 2nd full par. Further, B-catenin accumulation was not found, which means that it can inhibit GSK3 without the negative effects. See p9, 3rd and 4th par.
Eldar-Finkelman teaches: inhibiting glycogen synthase kinase-3 (GSK-3) activity via pharmacological intervention has become an important strategy for treating neurodegenerative and psychiatric disorders. GSK inhibitors in an ATP-competitive manner, often have adverse secondary effects when used chronically. See p7, 1st par. Compound NP031112, also termed NP-12 or tideglusib is a brain permeable small molecule currently used in clinical trials phase II for AD and progressive supranuclear palsy (PSP). See p8, 2nd par. Data from the phase IIa trial of tideglusib were recently reported and indicated a trend in improved cognitive abilities of the mild to moderate AD patients treated for 24 weeks (delSer,2010). No side effects or off target effects were described. See p12, 1st par.
Lovestone teaches using water as a carrier for an oral suspension, e.g., for administration of Tideglusib to mice. See p77, 2nd full par.
Noori concludes:
GSK-3 plays a key role in a plethora of physiological and pathophysiological processes and GSK-3’s elevated activity has been implicated in a host of diseases. Therefore, reagents that inhibit GSK-3 activity provide a means to investigate the role of GSK-3 in cellular physiology and pathophysiology and could become valuable therapeutics. Our group has generated novel small organic compounds that appear to be potent and highly selective inhibitors of GSK-3 activity. This finding provides a critical first step in defining a region of chemical design space that contains compounds that could help unravel the molecular mechanisms of GSK-3 cellular activity and that have the potential to become therapeutics for a variety of diseases caused by aberrant GSK-3 activity.
Tideglusib is arguable the most clinically advanced GSK-3 inhibitor and it is found to be an irreversible inhibitor of GSK-3β. See p6. It has been used in clinical trials for AD, myotonic dystrophy, autism spectrum disorders, and other conditions. See p6. While tideglusib inhibited the β isoform more, it was also shown to inhibit the α isoform. See p22, lines 498-503.
Dubruc teaches: B-catenin knockout mice display loss of neurons, hair follicle defects, and impaired craniofacial development. “Thus, CTNNB1 haploinsufficiency causes neuronal loss, craniofacial anomalies and hair follicle defects in both humans and mice.”
Kuechler teaches: loss of function mutations to CTNNB1 are responsible for beta catenin deficiency, which causes intellectual disability, motor delay, speech impairment, abnormal muscle tone, and other phenotypes. The clinical features of individuals with inactivating CTNNB1 mutations constitute a distinct syndromic phenotype that is characterized by ID, significant motor delay with hypotonia of the trunk and (progressive) distal hyper tonia/spasticity of the legs, speech impairment, behavioral anomalies, frequent microcephaly and overlapping facial features. “Based on the number of patients that we identified in our cohorts we assume that this new CTNNB1 haploinsufficiency syndrome might actually be a relatively frequent cause of ID.” See p108. “Beta-catenin was also found to be critical for dendritic morphogenesis. Yu and Malenka (2003) showed that increasing intracellular levels of beta-catenin and other members of the cadherin/catenin complex enhance dendritic arborization in rat hippocampal neurons.” See p107.
Wang teaches: activity of GSK3B is upregulated after a stroke and Tideglusib is a GSK-3B inhibitor which has neuroprotection effects against neurodegenerative diseases. See Abstract. “Tideglusib can inhibit the activity of GSK-3β irreversibly, as it has been demonstrated by the lack of recovery in enzyme activity when the unbound drug has been removed from the reaction medium. Administration of tideglusib avoids tau hyperphosphorylation, lowers aggregation of β amyloid protein, improves the ability of learning and memory, and delays neuronal loss and apoptosis.” Wang explains that GSK3B inhibitors protect against hypoxia-ischemia. Tideglusib down regulates GSK-3β activity through phosphorylation on the Ser9 residue. Pharmacological inhibition of GSK-3β by tideglusib resulted in enhanced activation of Akt and reduced levels of apoptotic proteins, and ultimately reduced neuronal cell death, astrocyte activation, and infarct volume. See p2084.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to arrive at the claimed method in view of the cited prior art. One would be motivated to do so because the administration of GSK3 inhibitors, including Tideglusib, is taught to activate and stabilize CTNNB1 (beta-catenin). Tideglusib was orally administered at 200 mg/kg for 40 days provided in vivo neuroprotective while showing good safety and tolerability in neurological diseases. It was able to reach the central nervous system. The prior art also teaches that mutations, including loss of function mutations to CTNNB1 are responsible for beta catenin deficiency, which causes intellectual disability, motor delay, speech impairment, abnormal muscle tone, and other phenotypes. B-catenin knockout mice display loss of neurons, hair follicle defects, and impaired craniofacial development. “Thus, CTNNB1 haploinsufficiency causes neuronal loss, craniofacial anomalies and hair follicle defects in both humans and mice.” Tideglusib down regulates GSK-3β activity through phosphorylation on the Ser9 residue. It appears that CTNNB1 syndrome is caused by lower levels of B-catenin. The use of GSK inhibitors generally, including GSK3β inhibitors, and even more particularly Tideglusib is motivated because the inhibition of GSK3β will prevent the degradation of β-catenin and is shown to active and stabilize it. Even further, Tideglusib is shown to yield no side effects or off target effects and was shown to be brain permeable reaching the CNS without B-catenin accumulation. This is important because accumulation has been a concern as a cause for certain types of cancers and it inhibit GSK3 without the negative effects. Administration of tideglusib avoids tau hyperphosphorylation, lowers aggregation of β amyloid protein, improves the ability of learning and memory, and delays neuronal loss and apoptosis. As such, there is a reasonable and predictable expectation of success that when Tideglusib is administered to a subject orally, such as in the form of a suspension, that it will have an effect of irreversible inhibiting GSKβ in the CNS and brain of a subject. Such administration will be expected to yield a good safety profile with limited side effects and the inhibition will prevent the degradation of β-catenin and will stabilize CTNNB1 (beta-catenin) by preventing phosphorylation of the same. As such, a mitigation of CTNNB1 would be expected in view of the combination of cited prior art.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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