Granted Patent
B2
US 12,715,839 · App. 18/539,781 · Granted Aug 25, 2026
Branched-chain amino acid derivatives to treat disease
View Patent ↗
Loading inventors, assignments & file history…
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 29, 2026
From: CHURCHILL, GRANT CHARLES
To: INTRABIO LTD.
Reel/Frame 074513/0542 →
Continuity (3)
Continuation In Part
PCTIB2022055513
· Jun 14, 2022
Provisional Application
63210362
· Jun 14, 2021
References Cited (400)
US 8202525B2
· Crain et al.
· 2012
[cited by applicant]
US 9155719B2
· Rekik
· 2015
[cited by applicant]
US 9283181B2
· Calias et al.
· 2016
[cited by applicant]
US 9296723B2
· Curtin et al.
· 2016
[cited by applicant]
US 20020095135A1
· Meeker et al.
· 2002
[cited by applicant]
US 20040127501A1
· Chen et al.
· 2004
[cited by applicant]
US 20060063827A1
· Yu et al.
· 2006
[cited by applicant]
US 20080214649A1
· Yu et al.
· 2008
[cited by applicant]
US 20090318555A1
· Fabre et al.
· 2009
[cited by applicant]
US 20130317036A1
· Rekik
· 2013
[cited by applicant]
US 20140080885A1
· Pennypacker et al.
· 2014
[cited by applicant]
US 20190046486A1
· De Rienzo et al.
· 2019
[cited by applicant]
US 20220142959A1
· Factor et al.
· 2022
[cited by applicant]
US 20220362189A1
· Factor et al.
· 2022
[cited by applicant]
US 20230201150A1
· Strupp
· 2023
[cited by applicant]
US 20230210799A1
· Strupp
· 2023
[cited by applicant]
US 20240189267A1
· Strupp
· 2024
[cited by applicant]
US 20250129011A1
· Mann
· 2025
[cited by applicant]
CN 103079550A
· 2013
[cited by applicant]
CN 103814046A
· 2014
[cited by applicant]
EP 0226304A1
· 1987
[cited by applicant]
EP 0288447A1
· 1988
[cited by applicant]
FR 2905600A1
· 2008
[cited by applicant]
JP H08103242A
· 1996
[cited by examiner]
JP 2009269856A
· 2009
[cited by applicant]
JP 2014503596A
· 2014
[cited by applicant]
JP 2016513084A
· 2016
[cited by applicant]
RU 2012151575A
· 2014
[cited by applicant]
RU 2680413C1
· 2019
[cited by applicant]
WO WO9526325A2
· 1995
[cited by applicant]
WO WO9621464A1
· 1996
[cited by applicant]
WO WO2005079300A2
· 2005
[cited by applicant]
WO WO2006036634A2
· 2006
[cited by applicant]
WO WO2006097527A1
· 2006
[cited by applicant]
WO WO2006101940A2
· 2006
[cited by applicant]
WO WO2008032222A2
· 2008
[cited by applicant]
WO WO2008101693A2
· 2008
[cited by applicant]
WO WO2008101693A3
· 2008
[cited by applicant]
WO WO2009079790A1
· 2009
[cited by applicant]
WO WO2010128504A2
· 2010
[cited by applicant]
WO WO2011019393A2
· 2011
[cited by applicant]
WO WO2011097148A2
· 2011
[cited by applicant]
WO WO2011151685A1
· 2011
[cited by applicant]
WO WO2012064892A1
· 2012
[cited by applicant]
WO WO2012085650A1
· 2012
[cited by applicant]
WO WO2012106343A2
· 2012
[cited by applicant]
WO WO2013095275A1
· 2013
[cited by applicant]
WO WO2013106643A2
· 2013
[cited by applicant]
WO WO2013170113A1
· 2013
[cited by applicant]
WO WO2013170115A1
· 2013
[cited by applicant]
WO WO2013182274A1
· 2013
[cited by applicant]
WO WO2013182652A1
· 2013
[cited by applicant]
WO WO2014122184A1
· 2014
[cited by applicant]
WO WO2015065891A1
· 2015
[cited by applicant]
WO WO2017015660A1
· 2017
[cited by applicant]
WO WO2017049470A1
· 2017
[cited by applicant]
WO WO2017050259A1
· 2017
[cited by applicant]
WO WO2017182802A1
· 2017
[cited by applicant]
WO WO2018007864A1
· 2018
[cited by applicant]
WO WO2018029657A1
· 2018
[cited by applicant]
WO WO2018029658A1
· 2018
[cited by applicant]
WO WO2018132759A1
· 2018
[cited by applicant]
WO WO2018229738A1
· 2018
[cited by applicant]
WO WO2019078915A1
· 2019
[cited by applicant]
WO WO2019079536A1
· 2019
[cited by applicant]
WO WO2019159110A1
· 2019
[cited by applicant]
WO WO2019224171A1
· 2019
[cited by applicant]
WO WO2020052620A1
· 2020
[cited by applicant]
WO WO2020084435A1
· 2020
[cited by applicant]
WO WO2020115715A1
· 2020
[cited by applicant]
WO WO2020146263A1
· 2020
[cited by applicant]
WO WO2020178721A1
· 2020
[cited by applicant]
WO WO2020200335A1
· 2020
[cited by applicant]
WO WO2020261230A1
· 2020
[cited by applicant]
WO WO2021048431A1
· 2021
[cited by applicant]
WO WO2021144720A1
· 2021
[cited by applicant]
WO WO2021234642A1
· 2021
[cited by applicant]
WO WO2022264037A1
· 2022
[cited by applicant]
WO WO2023196841A2
· 2023
[cited by applicant]
WO WO2025175092A1
· 2025
[cited by applicant]
WO WO2025264957A2
· 2025
[cited by applicant]
Angelini, C., et al., “Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant,” Eur J Med Genet 62(6):103530, Elsevier, Netherlands (Aug. 2018).
[cited by applicant]
Ashizawa, T., and Xia, G., “Ataxia,” Continuum (Minneap Minn) 22(4) Movement Disorders):1208-1226, Wolters Kluwer, United States (Aug. 2016).
[cited by applicant]
Beaudin, M., et al., “Systematic review of autosomal recessive ataxias and proposal for a classification,” Cerebellum Ataxias 4:3, BioMed Central, United Kingdom (Feb. 2017).
[cited by applicant]
Bird, T.D., “Hereditary Ataxia Overview,” in
[cited by applicant]
Cheng, K.K., et al., “Highly stabilized curcumin nanoparticles tested in an in vitro blood-brain barrier model and in Alzheimer's disease Tg2576 mice,” AAPS J 15(2):324-336, American Association of Pharmaceutical Scient…
[cited by applicant]
Choi, K.D., and Choi, J.H., “Episodic Ataxias: Clinical and Genetic Features,” J Mov Disord 9(3):129-135, Korean Movement Disorder Society, Korea (Sep. 2016).
[cited by applicant]
Denier, C., et al., “High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2,” Neurology 52(9):1816-1821, Wolters Kluwer, United States (Jun. 1999).
[cited by applicant]
Feil, K., et al., “Update on the Pharmacotherapy of Cerebellar Ataxia and Nystagmus,” Cerebellum 15(1):38-42, Springer, United States (Feb. 2016).
[cited by applicant]
Gandini, J., et al., “The neurological update: therapies for cerebellar ataxias in 2020,” J Neurol 267(4):1211-1220, Springer Nature, Germany (Apr. 2020).
[cited by applicant]
Griggs, R.C., et al., “Hereditary paroxysmal ataxia: response to acetazolamide,” Neurology 28(12):1259-1264, Wolters Kluwer, United States (Dec. 1978).
[cited by applicant]
Guterman, E.L., et al., “Pearls & Oy-sters: Episodic ataxia type 2: Case report and review of the literature,” Neurology 86(23):e239-241, Wolters Kluwer, United States (Jun. 2016).
[cited by applicant]
Hanson, L.R., and Frey, W.H., 2nd., “Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease,” BMC Neurosci 9(Suppl 3):S5, BioM…
[cited by applicant]
Ilg, W., “Consensus paper: management of degenerative cerebellar disorders,” Cerebellum 13(2):248-268, Springer, United States (Apr. 2014).
[cited by applicant]
Imbrici, P., et al., “Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A,” Neurology 65(6):944-946, Wolters Kluwer, United States (Sep. 2005).
[cited by applicant]
Patterson, M.C., et al., “Oral Miglustat in Niemann-Pick type C (NPC) Disease: 1-year Interim Analysis,” 11th International Congress of Human Genetics—Brisbane, Australia (Aug. 6-10, 2006) Final Program and Abstract Boo…
[cited by applicant]
Isaacs, D.A., et al., “Case report of novel CACNA1A gene mutation causing episodic ataxia type 2,” SAGE Open Med Case Rep 5:1-3, SAGE Publications, United Kingdom (May 2017).
[cited by applicant]
Jen, J., et al., “Clinical spectrum of episodic ataxia type 2,” Neurology 62(1):17-22, Wolters Kluwer, United States (Jan. 2004).
[cited by applicant]
Jen, J.C., et al., “Primary episodic ataxias: diagnosis, pathogenesis and treatment,” Brain 130(Pt 10):2484-2493, Oxford University Press, United Kingdom (Oct. 2007).
[cited by applicant]
Jen, J.C., and Wan, J., “Episodic ataxias,” Handb Clin Neurol 155:205-215, Elsevier, Netherlands (2018).
[cited by applicant]
Kabanov, A. V., and Batrakova, E.V., “New technologies for drug delivery across the blood brain barrier,” Curr Pharm Des 10(12):1355-1363, Bentham Science Publishers, United Arab Emirates (2004).
[cited by applicant]
Kalla, R., and Strupp, M., “Aminopyridines and Acetyl-DL-leucine: New Therapies in Cerebellar Disorders,” Curr Neuropharmacol 17(1):7-13, Bentham Science Publishers, United Arab Emirates (Jan. 2019).
[cited by applicant]
Kim, J.M., et al., “Episodic Ataxia Type 2 due to a Deletion Mutation in the CACNA1A Gene in a Korean Family,” Journal of Clinical Neurology 2(4):268-271, Korean Neurological Association, Korea (Dec. 2006).
[cited by applicant]
Kipfer, S., and Strupp, M., “The Clinical Spectrum of Autosomal-Dominant Episodic Ataxias,” Mov Disord Clin Pract 1(4):285-290, Wiley, United States (Jul. 2014).
[cited by applicant]
Lahde, A., et al. “Production of L-Leucine Nanoparticles under Various Conditions Using an Aerosol Flow Reactor Method,” Journal of Nanomaterials 2008: Article 680897, Hindawi Publishing Corporation, United Kingdom (Jun…
[cited by applicant]
Maksemous, N., et al., “Next-generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2,” Mol Genet Genomic Med 4(2):211-222, Wiley, United States (Jan. 2016).
[cited by applicant]
Mantuano, E., et al., “Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2,” J Neurol Sci 291(1-2):30-36, Elsevier, Netherlands (Apr. 2010).
[cited by applicant]
Ophoff, R.A., et al., “Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4,” Cell 87(3):543-552, Cell Press, United States (Nov. 1996).
[cited by applicant]
Patel, M.M., and Patel, B.M., “Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain,” CNS Drugs 31(2):109-133, Springer Nature, Germany (Feb. 2017).
[cited by applicant]
Penkava, J., et al., “A novel pathogenic CACNA1A variant causing episodic ataxia type 2 (EA2) spectrum phenotype in four family members and a novel combined therapy,” J Neurol 267(Suppl 1):181-184, Springer Nature, Germ…
[cited by applicant]
Riant, F., et al., “Ataxies épisodiques génétiques [Hereditary episodic ataxia],” Rev Neurol 167(5):401-407, Elsevier, France (May 2011).
[cited by applicant]
Richards, S., et al., “Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pa…
[cited by applicant]
Schniepp, R., et al., “Acetyl-DL-leucine improves gait variability in patients with cerebellar ataxia-a case series,” Cerebellum Ataxias 3:8, BioMed Central, United Kingdom (Apr. 2016).
[cited by applicant]
Sintas, C., et al., “Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia,” Sci Rep 7(1):2514, Nature Publishing Group, United Kingdom (May 2017).
[cited by applicant]
Strupp, M., et al., “Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine,” Neurology 62(9):1623-1625, Wolters Kluwer, United States (May 2004).
[cited by applicant]
Strupp, M., et al., “A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias,” Neurology 77(3):269-275, Wolters Kluwer, United States (Jul. 2011).
[cited by applicant]
Strupp, M., et al., “Fampridine and acetazolamide for the treatment of episodic ataxia type 2 (EAT2TREAT): a randomised, double-blind, placebo-controlled, three-period crossover trial (2331),” Neurology 94(15_supplement…
[cited by applicant]
Abdulkhaleq, L.A., et al., “The Crucial roles of Inflammatory Mediators in Inflammation: A Review,” Veterinary World 11(5):627-635, Veterinary World, India (May 2018).
[cited by applicant]
Abel, L.A., et al., “Saccades in Adult Niemann-pick Disease Type C Reflect Frontal, Brainstem, and Biochemical Deficits,” Neurology 72(12):1083-1086, Lippincott Williams & Wilkins, United States (Mar. 2009).
[cited by applicant]
Oxbridge Solutions Limited, “Acetylation of drugs,” GPnotebook, published on Jan. 1, 2018, accessed at https://gpnotebook.com/pages/surgery/acetylation-of-drugs, accessed on Feb. 26, 2025, 2 Pages.
[cited by applicant]
Aerts, J.M.F.G., et al., “Biomarkers in the Diagnosis of Lysosomal Storage Disorders: Proteins, Lipids, and Inhibodies,” Journal of Inherited Metabolic Disease 34(3):605-619, Wiley, United States (Jun. 2011).
[cited by applicant]
Akita, H., et al., “Creation of a Thermostable NADP+-dependent D-amino Acid Dehydrogenase from Ureibacillus Thermosphaericus Strain A1 Meso-diaminopimelate Dehydrogenase by Site-directed Mutagenesis,” Biotechnology Lett…
[cited by applicant]
Akita, H., et al., “Spectrophotometric Assay of D-isoleucine Using an Artificially Created D-amino Acid Dehydrogenase,” Biotechnology Letters 36(11):2245-2248, Kluwer Academic Publishers, Netherlands (Nov. 2014).
[cited by applicant]
Almanov, G.A., et al., Structure of Free Radicals in Irradiated Acetyl-L-leucine Single Crystals at 77 K, Journal of Structural Chemistry 29(2):216-220, Plenum Publishing Corporation, United States (Mar.-Apr. 1988).
[cited by applicant]
Almanov, G.A., et al., “Structure of Free Radicals in Irradiated Acetyl-L-leucine Single Crystals,” Khimia Vysokikh Energii 20(5):430-435, Nauka, Union of Soviet Socialist Republics (Sep.-Oct. 1986).
[cited by applicant]
Amor, S., et al., “Inflammation in Neurodegenerative Diseases—an Update,” Immunology 142(2):151-166, Blackwell Scientific Publications, United Kingdom (Jun. 2014).
[cited by applicant]
Antonenko, L.M., “The Second Congress International Academy of Dizziness,” Neurological Journal 20(4):51-53, Federal State Autonomous Institution “National Medical Research Center for Children's Health” of the Ministry …
[cited by applicant]
Arbuthnott, K., and Frank, J., “Trail Making Test, Part B as a Measure of Executive Control: Validation Using a Set-switching Paradigm,” Journal of Clinical and Experimental Neuropsychology 22(4):518-528, Taylor and Fra…
[cited by applicant]
August, R.A., et al., “Stereospecific Synthesis of (2S,4R)-[5,5,5-2H3]-leucine,” Tetrahedron Letters 33:4617-4620, Elsevier, Netherlands (Aug. 1992).
[cited by applicant]
Baci, D., et al., “Acetyl-L-Carnitine Downregulates Invasion (CXCR4/CXCL12, MMP-9) and Angiogenesis (VEGF, CXCL8) Pathways in Prostate Cancer Cells: Rationale for Prevention and Interception Strategies,” Journal of Expe…
[cited by applicant]
Barclay, L.L., et al., “The String Test: an Early Behavioral Change in Thiamine Deficiency,” Pharmacology, Biochemistry, and Behavior 14(2):153-157, Elsevier, United States (Feb. 1981).
[cited by applicant]
Battisti, C., et al., “Adult Onset Niemann-pick Type C Disease: A Clinical, Neuroimaging and Molecular Genetic Study,” Movement Disorders 18(11):1405-1409, Wiley, United States (Nov. 2003).
[cited by applicant]
Beck, A.T., et al., “An Inventory for Measuring Depression,” Archives of General Psychiatry 4:561-571, American Medical Association, United States (Jun. 1961).
[cited by applicant]
Becker-Bense, S., et al., “P37. Effects of Acetyl-dl-leucine on the Cerebral Activation Pattern in Cerebellar Ataxia (FDG-PET Study),” Clinical Neurophysiology 126(8):e115, 1 page, Elsevier, (Aug. 2015).
[cited by applicant]
Belarbi, K., et al., “TNF-a Protein Synthesis Inhibitor Restores Neuronal Function and Reverses Cognitive Deficits Induced by Chronic Neuroinflammation,” Journal of Neuroinflammation 9:23, pp. 1-13, BioMed Central, Unit…
[cited by applicant]
Belikov, V.G., Pharmaceutical Chemistry: Manual, 4th edition, pp. 27-29, MEDpress-inform, Moscow, Russia (2007).
[cited by applicant]
Benussi, A., et al., “Phenotypic Heterogeneity of Niemann-pick Disease Type C in Monozygotic Twins,” Journal of Neurology 262(3):642-647, Springer Science+Business Media, United States (Mar. 2015).
[cited by applicant]
Beyer, L., et al., “Clinical Routine FDG-PET Imaging of Suspected Progressive Supranuclear Palsy and Corticobasal Degeneration: A Gatekeeper for Subsequent Tau-PET Imaging?” Frontiers in Neurology 9:483, pp. 1-9, Fronti…
[cited by applicant]
Bingham, A.L., et al., “Over one Hundred Solvates of Sulfathiazole,” Chemical Communications, pp. 603-604, The Royal Society of Chemistry, United Kingdom (2001).
[cited by applicant]
Boland, B., et al., “Macroautophagy is Not Directly Involved in the Metabolism of Amyloid Precursor Protein,” The Journal of Biological Chemistry 285(48):37415-37426, American Society for Biochemistry and Molecular Biol…
[cited by applicant]
Brandt, T., et al., “Plasticity of the Vestibular System: Central Compensation and Sensory Substitution for Vestibular Deficits,” Advances in Neurology 73:297-309, Lippincott Williams & Wilkins, United States (1997).
[cited by applicant]
Waring, M.J., “Defining optimum lipophilicity and molecular weight ranges for drug candidates—Molecular weight dependent lower logD limits based on permeability,” Bioorg Med Chem Lett 19(10):2844-2851, Elsevier Ltd., Un…
[cited by applicant]
Bremova, T., et al., “Vestibular Function in Patients With Niemann-pick Type C Disease,” Journal of Neurology 263(11):2260-2270, Springer Science+Business Media, United States (Nov. 2016).
[cited by applicant]
Bremova-Ertl, A., et al., “EPR1131 Acetyl-Leucine Slows Disease Progression in Lysosomal Storage Disorders,” European Journal of Neurology 27(1):181, XP009522922, (May 2020).
[cited by applicant]
Bremova-Ertl, T., et al., “Clinical, Ocular Motor, and Imaging Profile of Niemann-pick Type C Heterozygosity,” Neurology 94(16):e1702-e1715, Lippincott Williams & Wilkins, United States (Apr. 2020).
[cited by applicant]
Bremova-Ertl, T., et al., “Oculomotor and Vestibular Findings in Gaucher Disease Type 3 and Their Correlation with Neurological Findings,” Frontiers in Neurology 8:711, pp. 1-19, Frontiers Research Foundation, Switzerla…
[cited by applicant]
Brendel, M., et al., “[18F]-THK5351 PET Correlates with Topology and Symptom Severity in Progressive Supranuclear Palsy,” Frontiers in Aging Neuroscience 9:440, pp. 1-12, Frontiers Media, Switzerland (Jan. 2018).
[cited by applicant]
Caira, M.R., et al., “Preparation and Crystal Characterization of a Polymorph, a Monohydrate, and an Ethyl Acetate Solvate of the Antifungal Fluconazole,” Journal of Pharmaceutical Sciences 93(3):601-611, Elsevier, Unit…
[cited by applicant]
Cardellicchio, C., et al., “Synthesis of a-amino Acid Derivatives by Copper(I)-catalyzed Conjugate Addition of Grignard Reagents to Methyl Acetamidoacrylate,” Tetrahedron Letters 26(36):4387-4390, Pergamon Press Ltd, Un…
[cited by applicant]
Chakrabarti, S., et al., “Upregulation of Suppressor of Cytokine Signaling 3 in Microglia by Cinnamic Acid,” Current Alzheimer Research 15(10):894-904, Bentham Science Publishers, United Arab Emirates (2018).
[cited by applicant]
Champion, H., et al., “Dietary Modifications in Patients Receiving Miglustat,” Journal of Inherited Metabolic Disease 33 (Suppl 3):S379-83, Wiley, United States (Dec. 2010).
[cited by applicant]
Chatterjee, B., et al., “Selective a-Deuteration of Amines and Amino Acids Using D
[cited by applicant]
Chen, W-W., et al., “Role of Neuroinflammation in Neurodegenerative Diseases (Review),” Molecular Medicine Reports 13(4):3391-3396, D. A. Spandidos, Greece (Apr. 2016).
[cited by applicant]
Cherry, J.D., et al., “Neuroinflammation and M2 Microglia: the Good, the Bad, and the Inflamed,” Journal of Neuroinflammation 11:98, pp. 1-15, BioMed Central, United Kingdom (Jun. 2014).
[cited by applicant]
Chida, J., et al., “An Efficient Extraction Method for Quantitation of Adenosine Triphosphate in Mammalian Tissues and Cells,” Analytica Chimica Acta 727:8-12, Elsevier, Netherlands (May 2012).
[cited by applicant]
Coccia, M., et al., “IL-1β Mediates Chronic Intestinal Inflammation by Promoting the Accumulation of IL-17A Secreting Innate Lymphoid Cells and CD4(+) Th17 Cells,” The Journal of Experimental Medicine 209(9):1595-609, R…
[cited by applicant]
Cortina-Borja, M., et al., “Annual Severity Increment Score as a Tool for Stratifying Patients with Niemann-Pick disease type C and for Recruitment to Clinical Trials,” Orphanet Journal of Rare Diseases 13(1):143, BioMe…
[cited by applicant]
Cupidi, C., et al., “Role of Niemann-Pick Type C Disease Mutations in Dementia,” Journal of Alzheimer's Disease 55(3):1249-1259, SAGE Publications, United States (2017).
[cited by applicant]
Davies, S.G., et al., “Asymmetric Conjugate Reductions with Samarium Diiodide: Asymmetric Synthesis of (2S,3R)- and (2S,3S)-[2-2H,3-2H]-leucine-(S)-phenylalanine Dipeptides and (2S,3R)- [2-(2)H,3-2H]-phenylalanine Methy…
[cited by applicant]
Debray, F-G., et al., “Disorders of Mitochondrial Function,” Current Opinion in Pediatrics 20(4):471-482, Lippincott Williams and Wilkins, United States (Aug. 2008).
[cited by applicant]
Dieringer, N., “‘Vestibular Compensation’: Neural Plasticity and Its Relations to Functional Recovery After Labyrinthine Lesions in Frogs and Other Vertebrates,” Progress in Neurobiology 46(2-3):97-129, Elsevier, Nether…
[cited by applicant]
Disabato, D.J., et al., “Neuroinflammation: the Devil Is in the Details,” Journal of Neurochemistry 139 Suppl 2(Suppl 2):136-153, Wiley on behalf of the International Society for Neurochemistry, United Kingdom (Oct. 201…
[cited by applicant]
Douglass, A., et al., “Behavioral Variant Frontotemporal Dementia Performance on a Range of Saccadic Tasks,” Journal of Alzheimer's Disease 65(1):231-242, SAGE Publications, United States (2018).
[cited by applicant]
Dyck, L.E., et al., “Effects of Deuterium Substitution on the Catabolismof Beta- Phenylethylamine: an in Vivo Study,” Journal of Neurochemistry 46(2):399-404, Wiley, United Kingdom (Feb. 1986).
[cited by applicant]
Dyson, G., et al., “The Mechanism of Action of Medicinal Substances,” in
[cited by applicant]
Ehrensperger, M.M., et al., “Early Detection of Alzheimer's Disease With a Total Score of the German CERAD,” Journal of the International Neuropsychological Society 16(5):910-920, Cambridge University Press, United King…
[cited by applicant]
English language translation of Office Action for Russian Patent Application No. 2021119633, dated May 22, 2023, Federal Service for Intellectual Property, Moscow, Russia, 6 pages.
[cited by applicant]
Fang, J., et al., “Dose Staggering as a Strategy to Reduce Drug—drug Interactions Due to Reversible Enzyme Inhibition Between Orally Administered Drugs With High First Pass Effect: A Computer Simulation Study,” Biopharm…
[cited by applicant]
Final Office Action for U.S. Appl. No. 17/247,757, mailed on May 5, 2023, 17 pages.
[cited by applicant]
Fletcher, M.D., et al., “Three Approaches to the Synthesis of L-leucine Selectively Labelled with Carbon-13 or Deuterium in Either Diastereotopic Methyl Group ,” Journal of the Chemical Society 43-52, 10 pages, Royal So…
[cited by applicant]
Frank-Cannon, T.C., et al., “Does Neuroinflammation Fan the Flame in Neurodegenerative Diseases?” Molecular Neurodegeneration 4:47, pp. 1-13, BioMed Central, United Kingdom (Nov. 2009).
[cited by applicant]
Frankola, K.A., et al., “Targeting TNF-a to Elucidate and Ameliorate Neuroinflammation in Neurodegenerative Diseases,” CNS & Neurological Disorders Drug Targets 10(3):391-403, Bentham Science Publishers, United Arab Emi…
[cited by applicant]
Giese, A.K., et al., “A Novel, Highly Sensitive and Specific Biomarker for Niemann-pick Type C1 Disease,” Orphanet Journal of Rare Diseases 10:78, 8 pages, BioMed Central, United Kingdom (Jun. 2015).
[cited by applicant]
Ginger, M.L., et al., “The Biosynthetic Incorporation of the Intact Leucine Skeleton Into Sterol by the Trypanosomatid Leishmania Mexicana,” The Journal of Biological Chemistry 276(15):11674-11682, Elsevier Inc, United …
[cited by applicant]
Gray, A.J., et al., “Olfactory Identification is Impaired in Clinic-based Patients With Vascular Dementia and Senile Dementia of Alzheimer Type,” International Journal of Geriatric Psychiatry 16(5):513-517, Wiley, Unite…
[cited by applicant]
Greer, W.L., et al., “Mutations in NPC1 Highlight a Conserved NPC1-specific Cysteine-rich Domain,” American Journal of Human Genetics 65(5):1252-1260, Cell Press, United States (Nov. 1999).
[cited by applicant]
Gu, Y., et al., “Role of TNF in Mast Cell Neuroinflammation and Pain,” Journal of Biological Regulators and Homeostatic Agents 29(4):787-791, Biolife, Italy (Oct.-Dec. 2015).
[cited by applicant]
Günther, L., et al., “N-Acetyl-L-Leucine Accelerates Vestibular Compensation after Unilateral Labyrinthectomy by Action in the Cerebellum and Thalamus,” PLoS One, 10(3): e0120891, 18 pages, Plos One, United States (Mar.…
[cited by applicant]
Habbas, S., et al., “Neuroinflammatory TNFa Impairs Memory via Astrocyte Signaling,” Cell 163(7):1730-1741, Cell Press, United States (Dec. 2015).
[cited by applicant]
Hammond, N., et al., “The Complexity of a Monogenic Neurodegenerative Disease: More Than Two Decades of Therapeutic Driven Research Into Niemann-pick Type C Disease,” Biochimica et Biophysica Acta—Molecular and Cell Bio…
[cited by applicant]
Harris, R.A., et al., “Overview of the Molecular and Biochemical Basis of Branched-chain Amino Acid Catabolism,” The Journal of Nutrition 135(6 Suppl):1527S-1530S, Elsevier, United States (Jun. 2005).
[cited by applicant]
Harris, R.A., et al., “Physiological Covalent Regulation of Rat Liver Branched-chain Alpha-ketoacid Dehydrogenase,” Archives of Biochemistry and Biophysics 243(2):542-555, Academic Press, United States (Dec. 1985).
[cited by applicant]
Harzer, K., et al., “Niemann-pick Disease Type C: New Aspects in a Long Published Family—Partial Manifestations in Heterozygotes,” JIMD Reports 12:25-29, Springer, Germany (May 2013).
[cited by applicant]
Havla, J., et al., “Retinal Axonal Degeneration in Niemann-pick Type C Disease,” Journal of Neurology 267(7):2070-2082, Springer Science+Business Media, United States (Jul. 2020).
[cited by applicant]
Heitz, C., et al., “Cognitive Impairment Profile in Adult Patients With Niemann Pick Type C Disease,” Orphanet Journal of Rare Diseases 12(1):166, pp. 1-10, BioMed Central, United Kingdom (Oct. 2017).
[cited by applicant]
Heron, B., et al., “Miglustat Therapy in the French Cohort of Paediatric Patients with Niemann-Pick Disease Type C,” Orphanet Journal of Rare Diseases 7:36, pp. 1-14, BioMed Central, United Kingdom (Jun. 2012).
[cited by applicant]
Hill, R.K., et al., “Synthesis of (2S,4S)- and (2S,4R)-[5,5,5-
[cited by applicant]
Homer, R.J., et al., “The Use of Cystathionine Gamma-synthase in the Production of Alpha and Chiral Beta Deuterated Amino Acids,” Analytical Biochemistry 215(2):211-215, Elsevier, United States (Dec. 1993).
[cited by applicant]
Hong, H., et al., “Pathophysiological Role of Neuroinflammation in Neurodegenerative Diseases and Psychiatric Disorders,” International Neurourology Journal 20(Suppl 1):S2-S7, Korean Continence Society, Korea (May 2016).
[cited by applicant]
Hoyles, K., and Sharma, J.C., “Olfactory Loss as a Supporting Feature in the Diagnosis of Parkinson's Disease: A Pragmatic Approach,” Journal of Neurology 260(12):2951-2958, Springer Science+Business Media, United State…
[cited by applicant]
Huang, H., et al., “Effects of Acetylleucine on the Recovery of Motor Balance and Discharge Activity of Neurons in the Medial Vestibular Nucleus in Rats after Labyrinthine Injury,” Collection of Abstracts of the 21st Na…
[cited by applicant]
Huang, J-Y., et al., “Neuroimaging Findings in a Brain with Niemann-pick Type C Disease, ” Journal of the Formosan Medical Association 110(8):537-542, Formosan Medical Association, Singapore (Aug. 2011).
[cited by applicant]
Hummel, T., et al., “‘Sniffin’ Sticks : Olfactory Performance Assessed by the Combined Testing of Odor Identification, Odor Discrimination and Olfactory Threshold,” Chemical Senses 22(1):39-52, Oxford University Press, …
[cited by applicant]
Inacio, A.R., et al., “Endogenous IFN-β Signaling Exerts Anti-inflammatory Actions in Experimentally Induced Focal Cerebral Ischemia,” Journal of Neuroinflammation 12:211, pp. 1-18, BioMed Central, United Kingdom (Nov. …
[cited by applicant]
International Search Report and Written Opinion for Application No. PCT/IB2019/060525, mailed on Feb. 3, 2020, 14 pages.
[cited by applicant]
International Search Report and Written Opinion for Application No. PCT/IB2020/056096, mailed on Sep. 29, 2020, 11 pages.
[cited by applicant]
International Search Report and Written Opinion for Application No. PCT/IB2021/050236, mailed on Apr. 12, 2021, 10 pages.
[cited by applicant]
International Search Report and Written Opinion of International Application No. PCT/IB2020/051767, mailed on Jul. 30, 2020, 19 pages.
[cited by applicant]
Jeyakumar, M., et al., “Central Nervous System Inflammation is a Hallmark of Pathogenesis in Mouse Models of GM1 and GM2 Gangliosidosis,” Brain 126(Pt 4):974-987, Oxford University Press, United Kingdom (Apr. 2003).
[cited by applicant]
Jeyakumar, M., et al., “Delayed Symptom Onset and Increased Life Expectancy in Sandhoff Disease Mice Treated With N-butyldeoxynojirimycin,” Proceedings of the National Academy of Sciences of the United States of America…
[cited by applicant]
Jha, M.K., et al., “Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders,” Current Neuropharmacology 10(4):393-403, Bentha…
[cited by applicant]
Johnen, A., et al., “Distinguishing Neurocognitive Deficits in Adult Patients With NP-C From Early Onset Alzheimer's Dementia,” Orphanet Journal of Rare Diseases 13(1):91, 10 pages, BioMed Central, United Kingdom (Jun. …
[cited by applicant]
Josephs, K.A., et al., “Heterozygous Niemann-Pick Disease type C Presenting with Tremor,” Neurology 63(11):2189-2190, Lippincott Williams & Wilkins, United States (Dec. 2004).
[cited by applicant]
Karve, I.P., et al., “Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury,” eNeuro 3(1):ENEURO.0128-15, Society for Neuroscience, United States (Feb. 2016).
[cited by applicant]
Kato, M., et al., “Structural Basis for Inactivation of the Human Pyruvate Dehydrogenase Complex by Phosphorylation: Role of Disordered Phosphorylation Loops,” Structure 16(12):1849-1859, Cell Press, United States (Dec.…
[cited by applicant]
Kelly, N.M., et al., “Chemo-enzymatic Synthesis of Isotopically Labelled L-valine, L-isoleucine and Allo-isoleucine, ” Tetrahedron Letters 37(9):1517-1520, Elsevier, United Kingdom (Feb. 1996).
[cited by applicant]
Kelly, N.M., et al., “Methods for the Synthesis of L-Leucine Selectively Labelled with Carbon-13 or Deuterium in either Diastereotopic Methyl Group,” Tetrahedron Letters 36:8315-8318, Elsevier, United Kingdom (Nov. 1995…
[cited by applicant]
Kelly, N.M., et al., “Syntheses of Amino Acids Incorporating Stable Isotopes,” Nat Prod Rep 14:205-219, Royal Society of Chemistry, United Kingdom (Jan. 1997).
[cited by applicant]
Kennedy, B.E., et al., “Pre-symptomatic Activation of Antioxidant Responses and Alterations in Glucose and Pyruvate Metabolism in Niemann-pick Type C1-deficient Murine Brain,” PloS One 8(12):e82685, pp. 1-18, Public Lib…
[cited by applicant]
Kennedy, B.E., et al., “Presymptomatic Alterations in Amino Acid Metabolism and DNA Methylation in the Cerebellum of a Murine Model of Niemann-pick Type C Disease,” The American Journal of Pathology 186(6):1582-1597, El…
[cited by applicant]
Khelimsky, A.M., et al.,
[cited by applicant]
Kimball,S.R., et al., “Leucine Regulates Translation of Specific mRNAs in L6 Myoblasts through mTOR-mediated Changes in Availability of eIF4E and Phosphorylation of Ribosomal Protein S6,” The Journal of Biological Chemi…
[cited by applicant]
Kinney, C.R., and Adams, R., “Dideuteriovaline and Dideuterioleucine,” Journal of the American Chemical Society 59(5):897-898, American Chemical Society, United States (May 1937).
[cited by applicant]
Kirkegaard, T., et al., “Heat Shock Protein-based Therapy as a Potential Candidate for Treating the Sphingolipidoses,” Science Translational Medicine 8(355):355ra118, American Association for the Advancement of Science,…
[cited by applicant]
Klionsky, D.J., and Emr, S.D., “Autophagy as a Regulated Pathway of Cellular Degradation,” Science 290(5497):1717-1721, American Association for the Advancement of Science, United States (Dec. 2000).
[cited by applicant]
Kluenemann, H.H., et al., “Parkinsonism Syndrome in Heterozygotes for Niemann-Pick C1,” Journal of the Neurological Sciences, 335(1-2):219-220, Elsevier, Netherlands (Dec. 2013).
[cited by applicant]
Kresojevic, N., et al., “Mutations in Niemann Pick Type C Gene Are Risk Factor for Alzheimer's Disease,” Medical Hypotheses 83:559-562, Elsevier, United States (Nov. 2014).
[cited by applicant]
Kumar, A., et al., “Niemann-Pick Disease Type C: Unique 2-Deoxy-2[18F] Fluoro-D-Glucose PET Abnormality,” Pediatric Neurology, 44(1): 57-60, Elsevier, Netherlands (Jan. 2011).
[cited by applicant]
Kummerer, K., “Pharmaceuticals in the Environment, ” Annual Review of Environment and Resources 35:57-75, Annual Reviews, United States (Aug. 2010).
[cited by applicant]
Lappalainen, U., et al., “Interleukin-1beta Causes Pulmonary Inflammation, Emphysema, and Airway Remodeling in the Adult Murine Lung,” American Journal of Respiratory Cell and Molecular Biology 32(4):311-318, American T…
[cited by applicant]
Lee, J.H., et al., “Anti-inflammatory and Anti-genotoxic Activity of Branched Chain Amino Acids (BCAA) in Lipopolysaccharide (LPS) Stimulated Raw 264.7 Macrophages,” Food Science and Biotechnology 26(5):1371-1377, Korea…
[cited by applicant]
Liang, H., and Ward, W.F., “PGC-1alpha: A Key Regulator of Energy Metabolism,” Advances in Physiology Education 30(4):145-151, American Physiological Society, United States (Dec. 2006).
[cited by applicant]
Liu, S.Q., et al., Leucine Alters Immunoglobulin a Secretion and Inflammatory Cytokine Expression Induced by Lipopolysaccharide via the Nuclear Factor-?b Pathway in Intestine of Chicken Embryos, Animal: An International…
[cited by applicant]
Lloyd-Evans, E., and Platt, F.M., “Lipids on Trial: the Search for the Offending Metabolite in Niemann-Pick type C Disease,” Traffic 11(4):419-428, John Wiley & Sons, United Kingdom (Apr. 2010).
[cited by applicant]
Lobato, J.B., et al., “Biomarkers in Lysosomal Storage Diseases,” Diseases 4(4):40, 17 pages, MDPI AG, Switzerland (Dec. 2016).
[cited by applicant]
Luppa, M., et al., “Age-related predictors of institutionalization: results of the German study on ageing, cognition and dementia in primary care patients (AgeCoDe),” Social Psychiatry and Psychiatric Epidemiology 47(2)…
[cited by applicant]
Miyanoiri, Y., et al., “Differential Isotope-labeling for Leu and Val Residues in a Protein by
[cited by applicant]
Moss, G.P., “Basic Terminology of Stereochemistry,” Pure and Applied Chemistry 68(12):2193-2222, IUPAC, United Kingdom (1996).
[cited by applicant]
Murphy, M.P., and Hartley, R.C., “Mitochondria as a Therapeutic Target for Common Pathologies,” Nature Reviews Drug Discovery 17(12):865-886, Nature Pub. Group, United Kingdom (Dec. 2018).
[cited by applicant]
Nagamori, S., et al., “Structure-activity Relations of Leucine Derivatives Reveal Critical Moieties for Cellular Uptake and Activation of mTORC1-mediated Signaling,” Amino Acids 48(4):1045-1058, Springer-Verlag, Austria…
[cited by applicant]
Nakajima, N., et al., “Enzymatic Conversion of Racemic Methionine to the L-enantiomer,” Journal of the Chemical Society 13:947-948, Royal Society of Chemistry, United Kingdom (1990).
[cited by applicant]
Neuzil, E., et al., “N-acetyl-DL-leucine, a Symptomatic Drug for Vertigo,” Bulletin-societe De Pharmacie De Bordeaux 141(1-4):15-38, La Société, France (2002).
[cited by applicant]
Neville, D.C., et al., “Analysis of Fluorescently Labeled Glycosphingolipid-derived Oligosaccharides Following Ceramide Glycanase Digestion and Anthranilic Acid Labeling,” Analytical Biochemistry 331(2):275-282, Academi…
[cited by applicant]
Niyazov, D.M., et al., “Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment,” Molecular Syndromology 7(3):122-137, S. Karger, Switzerland (Jul. 20…
[cited by applicant]
Non-Final Office Action for U.S. Appl. No. 17/247,757, mailed on Oct. 4, 2023, 16 pages.
[cited by applicant]
Non-Final Office Action for U.S. Appl. No. 17/247,757, mailed on Oct. 6, 2022, 14 pages.
[cited by applicant]
Notice of Allowance for U.S. Appl. No. 17/247,757, mailed on Apr. 10, 2024, 13 pages.
[cited by applicant]
Oba, M., et al., “Stereoselective Deuterium-labelling of Diastereotopic Methyl and Methylene Protons of L-leucine, ” Tetrahedron Letters 39:1595-1598, Elsevier, Netherlands (Mar. 1998).
[cited by applicant]
Oba, M., et al., “Synthesis of (13)C/D Doubly Labeled L-leucines: Probes for Conformational Analysis of the Leucine Side-chain,” The Journal of Organic Chemistry 66(17):5919-5922, American Chemical Society, United State…
[cited by applicant]
Oba, M., et al., “Synthesis of L-threo- and L-erythro-[1-
[cited by applicant]
Olichney, J.M., et al., “Anosmia is Very Common in the Lewy Body Variant of Alzheimer's Disease,” Journal of Neurology, Neurosurgery, and Psychiatry 76(10):1342-1347, BMJ Publishing Group, United Kingdom (Oct. 2005).
[cited by applicant]
Orasji, S.S.S., et al., “Olfactory Dysfunction in Behavioral Variant Frontotemporal Dementia,” Clinical Neurology and Neurosurgery 141:106-110, Elsevier, Netherlands (Feb. 2016).
[cited by applicant]
Pankiv, S., et al., “P62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy,” The Journal of Biological Chemistry 282(33):24131-24145, American Society for Bioch…
[cited by applicant]
Patterson, M., et al., “Niemann-Pick Disease Type C,” in GeneReviews® [Internet], Adam, M.P., et al., eds., 2 pages, University of Washington, Seattle, United States (Dec. 10, 2020).
[cited by applicant]
Patterson, M.C., et al., “Disease and Patient Characteristics in NP-C Patients: Findings From an International Disease Registry,” Orphanet Journal of Rare Diseases 8:12, 10 pages, BioMed Central, United Kingdom (Jan. 20…
[cited by applicant]
Patterson, M.C., et al., “Long-term Miglustat Therapy in Children With Niemann-Pick Disease Type C,” Journal of Child Neurology 25(3): 300-305, Sage Publications, United States (Mar. 2010).
[cited by applicant]
Patterson, M.C., et al., “Miglustat for treatment of Niemann-Pick C disease: a Randomised Controlled Study,” The Lancet. Neurology 6(9):765-772, Lancet Pub. Group, United Kingdom (Sep. 2007).
[cited by applicant]
Patterson, M.C., et al., “Recommendations for the Detection and Diagnosis of Niemann-Pick Disease Type C: An update,” Neurology: Clinical Practice 7:499-511, Lippincott Williams and Wilkins, United States (Dec. 2017).
[cited by applicant]
Patterson, M.C., et al., “Recommendations for the Diagnosis and Management of Niemann-Pick Disease Type C: An update,” Molecular Genetics and Metabolism 106(3):330-344, Academic Press, United States (Jul. 2012).
[cited by applicant]
Wang, G., et al., “Intestinal OCTN2- and MCT1-targeted drug delivery to improve oral bioavailability,” Asian J Pharm Sci 15(2):158-173, Shenyang Pharmaceutical University, China (Mar. 2020).
[cited by applicant]
Vanier, M.T., et al., “Niemann-Pick disease type C,” Orphanet Journal of Rare Diseases 5:16, pp. 1-18, BioMed Central, United Kingdom (Jun. 2010).
[cited by applicant]
Pelz, J.O., et al., “Failure to Confirm Benefit of Acetyl-dl-leucine in Degenerative Cerebellar Ataxia: A Case Series,” Journal of Neurology 262(5):1373-1375, Springer-Verlag, Germany (2015).
[cited by applicant]
Pentchev, P.G., et al., “A Lysosomal Storage Disorder in Mice Characterized by a Dual Deficiency of Sphingomyelinase and Glucocerebrosidase,” Biochimica Et Biophysica Acta 619(3):669-679, Elsevier Pub. Co, Netherlands (…
[cited by applicant]
Pineda, M., et al., “Miglustat in Patients with Niemann-Pick Disease Type C (NP-C): a Multicenter Observational Retrospective Cohort Study,” Molecular Genetics and Metabolism 98(3):243-249, Academic Press, United States…
[cited by applicant]
Platt, F., and Strupp, M., “An Anecdotal Report by an Oxford Basic Neuroscientist: Effects of Acetyl-DL-leucine on Cognitive Function and Mobility in the Elderly,” Journal of Neurology 263(6):1239-1240, Springer-Verlag,…
[cited by applicant]
Platt, F.M., “Emptying the Stores: Lysosomal Diseases and Therapeutic Strategies,” Nature Reviews Drug Discovery 17(2):133-150, Nature Pub. Group, United Kingdom (Feb. 2018).
[cited by applicant]
Platt, F.M., et al., “The Cell Biology of Disease: Lysosomal Storage Disorders: the Cellular Impact of Lysosomal Dysfunction,” The Journal of Cell Biology 199(5):723-734, Rockefeller University Press, United States (Nov…
[cited by applicant]
Pliss, L., et al., “Cerebral Developmental Abnormalities in a Mouse With Systemic Pyruvate Dehydrogenase Deficiency,” PloS One 8(6):e67473, pp. 1-14, Public Library of Science, United States (Jun. 2013).
[cited by applicant]
Postuma, R.B., et al., “Advances in Markers of Prodromal Parkinson Disease,” Nature Reviews Neurology 12(11):622-634, Nature Publishing Group, United Kingdom (Oct. 2016).
[cited by applicant]
Pretegiani, E., and Optican, M.L., “Eye Movements in Parkinson's Disease and Inherited Parkinsonian Syndromes,” Frontiers in Neurology 8:592, 7 pages, Frontiers Research Foundation, Switzerland (Nov. 2017).
[cited by applicant]
Priestman, D.A., et al., “N-butyldeoxynojirimycin Causes Weight Loss as a Result of Appetite Suppression in Lean and Obese Mice,” Diabetes, Obesity and Metabolism 10(2):159-166, Wiley-Blackwell, United Kingdom (Feb. 200…
[cited by applicant]
Probert, F., et al., “NMR Analysis Reveals Significant Differences in the Plasma Metabolic Profiles of Niemann Pick C1 Patients, Heterozygous Carriers, and Healthy Controls,” Scientific Reports 7(1):6320, Nature Publish…
[cited by applicant]
Pubchem, “Acetylleucine,” CID 1995, accessed at https://pubchem.ncbi.nlm.nih.gov/compound/1995#section= 2D-Structure, 3 pages.
[cited by applicant]
Ray, K.K., “Interleukin-1 Revisited: Further Insights Into Its Role in Atherosclerosis and as a Potential Therapeutic Target for Treatment,” Journal of the American College of Cardiology 63(17):1735-1738, Elsevier Biome…
[cited by applicant]
Ren, K., and Torres, R., “Role of Interleukin-1beta during Pain and Inflammation,” Brain Research Reviews 60(1):57-64, Elsevier B.V., Netherlands (2009).
[cited by applicant]
Reunert, J., et al., “Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β, 5a, 6β-Triol and Further Insight into the Clinical Phenotype,” JIMD Reports 23:17-26, Wiley, United States (Mar. 2…
[cited by applicant]
Rose, J.E., et al., “Stereospecific Synthesis of a-Deuteriated a-Amino Acids: Regiospecific Deuteriation of Chiral 3-Isopropyl-2,5-Dimethoxy-3,6-Dihydropyrazines,” Journal of the Chemical Society 2:157-165, Royal Societ…
[cited by applicant]
Royall, D.R., et al., “CLOX: an Executive Clock Drawing Task,” Journal of Neurology, Neurosurgery, and Psychiatry 64(5):588-594, BMJ Publishing Group, United Kingdom (May 1998).
[cited by applicant]
Rozenbaum, H., “How to Evaluate the Risk-benefit Ratio of the Low-dose Hormone Replacement Therapy?” The Journal of Steroid Biochemistry and Molecular Biology 102(1-5):256-260, Pergamon, United Kingdom (Dec. 2006).
[cited by applicant]
Ruiz-Rodado, V., et al., “1h NMR-linked Metabolomics Analysis of Liver From a Mouse Model of NP-C1 Disease,” Journal of Proteome Research 15(10):3511-3527, American Chemical Society, United States (Oct. 2016).
[cited by applicant]
Sanchez-Cubillo, I., et al., “Construct Validity of the Trail Making Test: Role of Task-switching, Working Memory, Inhibition/interference Control, and Visuomotor Abilities,” Journal of the International Neuropsychologi…
[cited by applicant]
Sandhoff, L., and Harzer, K., “Gangliosides and Gangliosidoses: Principles of Molecular and Metabolic Pathogenesis,” The Journal of Neuroscience 33(25):10195-10208, Society for Neuroscience, United States (Jun. 2013).
[cited by applicant]
Sango, K., et al., “Mouse Models of Tay-sachs and Sandhoff Diseases Differ in Neurologic Phenotype and Ganglioside Metabolism,” Nature Genetics 11(2):170-176, Nature Pub. Co, United States (Oct. 1995).
[cited by applicant]
Sarkar, C., et al., “Impaired Autophagy Flux is Associated With Neuronal Cell Death After Traumatic Brain Injury,” Autophagy 10(12):2208-2222, Taylor & Francis, United States (2014).
[cited by applicant]
Sarkar, C., et al., “N-acetyl-L-leucine Treatment Attenuates Neuronal Cell Death and Suppresses Neuroinflammation After Traumatic Brain Injury in Mice,” bioRxiv, pp. 1-20, Retrieved from the Internet:[https://www.biorxi…
[cited by applicant]
Sarkar, C., et al., “PLA2G4A/cPLA2-Mediated Lysosomal Membrane Damage Leads to Inhibition of Autophagy and Neurodegeneration After Brain Trauma,” Autophagy 16(3):466-485, Taylor & Francis, United States (Mar. 2020).
[cited by applicant]
Scaglione, C., et al., “REM Sleep behaviour Disorder in Parkinson's Disease: A Questionnaire-based Study,” Neurological Sciences 25(6):316-321, Springer-Verlag Italia, Italy (Feb. 2005).
[cited by applicant]
Schneider, E., et al., “EyeSeeCam: An Eye Movement-Driven Head Camera for the Examination of Natural Visual Exploration,” Basic and Clinical Aspects of Vertigo and Dizziness: Annals of the New York Academy of Sciences, …
[cited by applicant]
Schneider, S., “Do Heterozygous Mutations of Niemann-Pick Type C Predispose to Late-onset Neurodegeneration: A Review of the Literature,” Journal of Neurology 268(6):2055-2064, Springer-Verlag, Germany (Jun. 2021).
[cited by applicant]
Wiederschain, G.Y., “The Metabolic and Molecular Bases of Inherited Disease,” Biochemistry (Moscow) 67(5):611-612, Pleiades Publishing, Ltd., Russia (May 2002).
[cited by applicant]
Sevin, M., et al., “The Adult Form of Niemann-Pick Disease Type C,” Brain 130:120-133, Oxford University Press, United Kingdom (Jan. 2007).
[cited by applicant]
Shah, S.A., et al., “Enantiomeric Conversion of Racemic Amino Acid Mixtures via an Oxidase-Aminotransferase Coupled System,” Tetrahedron Letters 35:29-32, Elsevier, United Kingdom (Jan. 1994).
[cited by applicant]
Shao, L., and Hewitt, M.C., “The Kinetic Isotope Effect in the Search for Deuterated Drugs,” Drug News & Perspectives 23(6)398-404, Thomson Reuters, United States (Jul.-Aug. 2010).
[cited by applicant]
Shibanuma, M., et al., “Inhibition by N-acetyl-L-cysteine of Interleukin-6 mRNA Induction and Activation of NF Kappa B by Tumor Necrosis Factor Alpha in a Mouse Fibroblastic Cell Line, Balb/3T3,” FEBS Letters 353(1):62-…
[cited by applicant]
Sidransky, E., et al., “Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease,” The New England Journal of Medicine 361(17):1651-1661, Massachusetts Medical Society, United States (Oct. 2009).
[cited by applicant]
Simonaro, C.M., “Lysosomes, Lysosomal Storage Diseases, and Inflammation,” Journal of Inborn Errors of Metabolism & Screening 4:1-8, Latin American Society of Inborn Errors of Metabolism and Newborn Screening, Uruguay (…
[cited by applicant]
Son, S.M., et al., “Leucine Signals to mTORC1 Via Its Metabolite Acetyl-Coenzyme A,” Cell Metabolism 29(1):192-201.e7, Cell Press, United States (Jan. 2019).
[cited by applicant]
Stein, L.R., and Imai, S-I., “The Dynamic Regulation of NAD Metabolism in Mitochondria,” Trends in Endocrinology and Metabolism 23(9):420-428, Elsevier Science Pub. Co, United States (Sep. 2012).
[cited by applicant]
Stiasny-Kolster, K., et al., “Diagnostic value of the REM sleep behavior disorder screening questionnaire in Parkinson's disease,” Sleep Medicine 16(1):186-189, Elsevier, Netherlands (Jan. 2015).
[cited by applicant]
Stiasny-Kolster, K., et al., “The REM Sleep Behavior Disorder Screening Questionnaire—A New Diagnostic Instrument,” Movement Disorders 22(16):2386-2393, Wiley, United States (Dec. 2007).
[cited by applicant]
Strupp, M., et al., “Effects of Acetyl-dl-leucine in Patients with Cerebellar Ataxia: A Case Series,” Journal of Neurology, 260(10):2556-2561, Springer-Verlag, Germany (2013).
[cited by applicant]
Te Vruchte, D., et al., “Relative Acidic Compartment Volume as a Lysosomal Storage Disorder-associated Biomarker,” The Journal of Clinical Investigation 124(3):1320-1328, American Society for Clinical Investigation, Uni…
[cited by applicant]
The Definition of “Disease Prevention”, accessed from Free Dictionary Web, Retrieved from Internet URL: https://web.archive.org/web/20150910204016/https://medical-dictionary.thefreedictionary.com/Prevention+(medical), 2…
[cited by applicant]
Tighilet, B., et al., “Comparative Analysis of Pharmacological Treatments With N-acetyl-dl-leucine (Tanganil) and Its Two Isomers (N-acetyl-L-leucine and N-acetyl-D-leucine) on Vestibular Compensation: Behavioral Invest…
[cited by applicant]
Timmins, G.S., “Deuterated Drugs: Where Are We Now?” Expert Opinion on Therapeutic Patents 24(10):1067-1075, Taylor & Francis, United Kingdom (Oct. 2014).
[cited by applicant]
Tuttolomondo, A., et al., “Studies of Selective TNF Inhibitors in the Treatment of Brain Injury from Stroke and Trauma: a Review of the Evidence to Date,” Drug Design, Development and Therapy 8:2221-2238, Dove Press Lim…
[cited by applicant]
Upson, D.A., and Hruby, V.J., “A General Method for the Preparation of Alpha-labeled Amino Acids,” The Journal of Organic Chemistry 42(13):2329-2330, American Chemical Society, United States (Jun. 1977).
[cited by applicant]
Van Tonder, E.C., et al., “Preparation and Physicochemical Characterization of 5 Niclosamide Solvates and 1 Hemisolvate,” AAPS PharmSciTech 5(1):E12, pp. 1-10, Springer, United States (Feb. 2004).
[cited by applicant]
Vibert, N., and Vidal, P.P., “In Vitro Effects of Acetyl-dl-leucine(Tanganil) on Central Vestibular Neurons and Vestibulo-ocular Networks of the Guinea-pig,” The European Journal of Neuroscience 13(4):735-748, Wiley-Bla…
[cited by applicant]
Williams, I.M., et al., “Improved Neuroprotection Using Miglustat, Curcumin and Ibuprofen as a Triple Combination Therapy in Niemann-pick Disease Type C1 Mice,” Neurobiology of Disease 67:9-17, Academic Press, United St…
[cited by applicant]
Written Opinion of International Preliminary Examining Authority of International Application No. PCT/IB2021/050236, European Patent Office, Netherlands, mailed on Dec. 17, 2021, 7 pages.
[cited by applicant]
Xu, H., and Ren, D., “Lysosomal Physiology,” Annual Review of Physiology 77:57-80, Annual Reviews, United States (2015).
[cited by applicant]
Yamauchi, N., and Endoh, S., “Improved Isotopic Deuterium Labeling at the Diastereotopic Methyl Group of Leucine: a Synthetic Route to (4S)- and (4R)-[5-
[cited by applicant]
Yanagisawa, H., et al., “L-leucine and SPNS1 Coordinately Ameliorate Dysfunction of Autophagy in Mouse and Human Niemann-Pick type C disease,” Scientific Reports 7(1):15944, Nature Publishing Group, United Kingdom (Nov.…
[cited by applicant]
Yanjanin, N.M., et al., “Linear Clinical Progression, Independent of Age of Onset, in Niemann-pick Disease, Type C,” American Journal of Medical Genetics Neuropsychiatric Genetics 153B(1):132-140, Wiley-Blackwell, Unite…
[cited by applicant]
Yu, W., et al., “Neurodegeneration in Heterozygous Niemann-Pick type Cl (NPC1) Mouse: Implication of Heterozygous NPC1 Mutations Being a Risk for Tauopathy,” The Journal of Biological Chemistry 280(29): 27296-27302, Ame…
[cited by applicant]
Yuan, S.S., and Ajami, A.M., “Trideuteromethyl Labeled Leucine and Valine,” Hua Xue—Chemistry 49(4):257-260, Zhonggguo Huaxuehui, Taiwan (Dec. 1991).
[cited by applicant]
Yudkoff, M., “Brain Metabolism of Branched-chain Amino Acids,” Glia 21(1):92-98, Wiley-Liss, United States (Sep. 1997).
[cited by applicant]
European Medicines Agency, “Zavesca,” European Public Assessment Report—Product Information, accessed at ec.europa.eu/health/documents/community-register/2010/2010060278532/anx_78532_en.pdf, accessed on Apr. 16, 2025, 2…
[cited by applicant]
Zech, M., et al., “Niemann-Pick C Disease Gene Mutations and Age-Related Neurodegenerative Disorders,” PLoS One 8(12):e82879, Public Library of Science, United States (Dec. 2013).
[cited by applicant]
Zwergal A., et al., “Sequential [(18)F]FDG μPET Whole-brain Imaging of Central Vestibular Compensation: A Model of Deafferentation-induced Brain Plasticity,” Brain Structure and Function 221(1):159-170, Springer-Verlag,…
[cited by applicant]
Armstrong, C., “AAN/AHS Update Recommendations for Migraine Prevention in Adults,” American Family Physician 87(8):584-585, American Academy of General Practice, United States (2013).
[cited by applicant]
Bartleson, J.D. and Cutrer F. M., “Migraine Update Diagnosis and Treatment,” Minnesota Medicine 93(5):36-41, Minnesota Medical Assn, United States (May 2010).
[cited by applicant]
Buchfuhrer, M.J., “Strategies for the Treatment of Restless Legs Syndrome,” Neurotherapeutics 9(4):776-790, Springer, United States (Oct. 2012).
[cited by applicant]
Bose, P. and Goadsby, P.J., “The Migraine Postdrome,” Current Opinion in Neurology 29(3):299-301, Lippincott Williams & Wilkins, United Kingdom (Jun. 2016).
[cited by applicant]
Buzzi, M.G., et al., “Prodromes and the Early Phase of the Migraine Attack: Therapeutic Relevance,” Functional neurology 20(4):179-183, CIC Edizioni Internazionali, Italy (Oct.-Dec. 2005).
[cited by applicant]
Colman, I., et al., “Parenteral Dexamethasonefor Acute Severe Migraine Headache: Meta-analysis of Randomised Controlled Trials for Preventing Recurrence,” BMJ (Clinical research ed.) 336(7657):1359-1361, British Medical…
[cited by applicant]
Derry, S., et al., “Diclofenac with or without an Antiemetic for Acute Migraine Headaches in Adults,” The Cochrane Database of Systematic Reviews 2013(4):CD008783, Wiley, United Kingdom (Apr. 2013), 43 Pages.
[cited by applicant]
Ferber-Viart, C., et al., “Effects of Acetyl-dl-leucine in Vestibular Patients: A Clinical Study Following Neurotomy and Labyrinthectomy,” Audiology and Neuro-otology 14(1):17-25, Karger, Switzerland (2009).
[cited by applicant]
Gilmore, B. and Michael, M., “Treatment of Acute Migraine Headache,” American family physician, 83(3):271-280, American Academy of General Practice, United States (2011).
[cited by applicant]
Headache Classification Subcommittee of the International Headache Society,
[cited by applicant]
Kelman, L., “The Postdrome of the Acute Migraine Attack,” Cephalalgia: An International Journal of Headache 26(2):214-220, Blackwell Publishing Ltd, United Kingdom (Feb. 2006).
[cited by applicant]
Kirthi, V., et al., “Aspirin with or without an Antiemetic For Acute Migraine Headaches in Adults,” The Cochrane database of systematic reviews 2013(4):CD008041, Wiley, United Kingdom (2010).
[cited by applicant]
Lempert, T., et al., “Vestibular Migraine: Diagnostic Criteria,” Journal of Vestibular Research: Equilibrium & Orientation 22(4):167-172, SAGE Publications, United States (2012).
[cited by applicant]
Ory, D.S., et al., “Intrathecal 2-hydroxypropyl-β-cyclodextrin Decreases Neurological Disease Progression in Niemann-Pick Disease, Type C1: a Non-randomised, Open-label, Phase 1-2 Trial,” Lancet 390(10104):1758-1768, El…
[cited by applicant]
Rabbie, R., et al., “Ibuprofen with or without an Antiemetic for Acute Migraine Headaches in Adults,” The Cochrane database of systematic reviews 6:(10):CD008039, Wiley, United Kingdom (Oct. 2010).
[cited by applicant]
Rae-Grant., [edited by] Lynn, J.D., et al., “The 5-Minute Neurology Consult, 2nd Edition,” Lippincott Williams & Wilkins, Philadelphia, p. 26 (2004).
[cited by applicant]
Rossi, P., et al., “Prodromes and Predictors of Migraine Attack,” Functional Neurology 20(4):185-191, CIC Edizioni Internazionali, Italy (Oct.-Dec. 2005).
[cited by applicant]
Wheeler, S., and Sillence, D.J., “Niemann-Pick type C Disease: Cellular Pathology and Pharmacotherapy,” Journal of Neurochemistry 153(6):674-692, Wiley on behalf of the International Society for Neurochemistry, United K…
[cited by applicant]
Tepper, S.J. and Tepper D.E., “Breaking the Cycle of Medication Overuse Headache,” Cleveland Clinic Journal of Medicine, 77(4):236-242, Cleveland Clinic Educational Foundation, United States (2010).
[cited by applicant]
Domitrz, I., et al., “Changes in Serum Amino Acids in Migraine Patients without and with Aura and their Possible Usefulness in the Study of Migraine Pathogenesis,” CNS and Neurological Disorders Drug Targets, 14(3):345-…
[cited by applicant]
Salzman, B., et al., “Gait and Balance Disorders in Older Adults,” American Family Physician 82(1):61-68, American Academy of General Practice, United States (Jul. 2010).
[cited by applicant]
Jahn, K., et al., “Dizziness and Unstable Gait in Old Age: Etiology, Diagnosis and Treatment,” German Medical Journal International 112(23):387-393, German Doctors Publishing House, Germany (Jun. 2015).
[cited by applicant]
Abe, et al., “Medium-Chain Triglycerides in Combination with Leucine and Vitamin D Increase Muscle Strength and Function in Frail Elderly Adults in a Randomized Controlled Trial” The Journal of Nutrition 146(5):1017-102…
[cited by applicant]
Iwasaki, S., and Yamasobaet, T., “Dizziness and Imbalance in the Elderly: Age-related Decline in the Vestibular System,” Aging and Disease 6(1):38-47, JKL International, United States (Feb. 2014).
[cited by applicant]
Davis, O.B., et al., “NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C,” Developmental Cell 56(3):260-276, Cell Press, United States (Feb. 202…
[cited by applicant]
Churchill, G.C., et al., “Acetylation Turns Leucine Into a Drug by Membrane Transporter Switching,” Scientific Reports 11(1):15812, pp. 1-10, Nature Publishing Group, United Kingdom (Aug. 2021).
[cited by applicant]
Auer, I.A., et al., “Paired Helical Filament Tau (PHFtau) in Niemann-pick Type C Disease is Similar to PHFtau in Alzheimer's Disease,” Acta Neuropathologica 90(6):547-551, Springer Verlag, Germany (1995).
[cited by applicant]
Nixon, R.A., “Niemann-Pick Type C Disease and Alzheimer's Disease: The APP-endosome Connection Fattens Up,” The American Journal of Pathology 164(3):757-761, Elsevier, United States (Mar. 2004).
[cited by applicant]
Castellano, B.M., et al., “Lysosomal Cholesterol Activates Mtorc1 via an Slc38a9-niemann-pick C1 Signaling Complex,” Science 355(6331):1306-1311, American Association for the Advancement of Science, United States (Mar. …
[cited by applicant]
English Translation of Decision of Refusal issued in related Japanese Application No. 2021-164793, dated Apr. 25, 2023, 3 pages.
[cited by applicant]
English Translation of Notice of Reason for Refusal issued in related Japanese Application No. 2021-164793, dated Sep. 29, 2022, 4 pages.
[cited by applicant]
English Translation of Notice of Final Rejection issued in related Korean Application No. KR 10-2022-7021012, dated Apr. 3, 2023, 4 pages.
[cited by applicant]
Communication from the European Patent Office issued in related EP Application No. 19174007.5, mailed Nov. 26, 2019, 5 pages.
[cited by applicant]
English Translation of The Second Office Action issued in related Chinese Application No. CN 201780059708.6, dated Dec. 15, 2021, 4 pages.
[cited by applicant]
English Translation of The First Office Action issued in related Chinese Application No. CN 201780059708.6, dated Jul. 29, 2021, 5 pages.
[cited by applicant]
English Translation of Search Report issued by the Registered Search Organization in related Japanese Application No. JP 2019-507819, dated Apr. 2, 2021, 14 pages.
[cited by applicant]
English Translation of Written Opinion issued in related Japanese Application No. JP 2019-507819, dated Aug. 11, 2021, 5 pages.
[cited by applicant]
English Translation of Notice of Reasons for Refusal issued in related Application No. JP 2019-507819, dated Apr. 27, 2021, 4 pages.
[cited by applicant]
Lukas, J., et al., “Enzyme Enhancers for the Treatment of Fabry and Pompe Disease,” Molecular Therapy 23(3):456-464, Cell Press, United States (Mar. 2015).
[cited by applicant]
Reagan-Shaw, S., et al., “Dose translation from animal to human studies revisited,” FASEB journal 22(3):659-661, Federation of American Societies for Experimental Biology, United States (Mar. 2008).
[cited by applicant]
Bremova, T., “Niemann-pick Type C: Effects of a Therapy With Acetyl-dl-leucine and Vestibular Function,” Disseration for Graduate School Systemic Neurosciences Der Ludwig-maximilians-universitat Munchen. Presented Orall…
[cited by applicant]
English Translation of Japanese Office Action in Counterpart Application No. 2019-507811 dated Apr. 27, 2021, 4 pages.
[cited by applicant]
English Translation of Search Report in Chinese Application No. 201780062740X, dated Aug. 14, 2021, 1 page.
[cited by applicant]
Search Report in Russian Application No. 2019106493, dated Oct. 26, 2020 with English Translation.
[cited by applicant]
Olesen, J., et al., “The International Classification of Headache Disorders, 3rd Edition (Beta Version),” Cephalalgia 33(9):629-808, Sage, United Kingdom (Jul. 2013).
[cited by applicant]
English language Translation of Pertinent Portion of Office Action for Japanese Patent Application No. 2020-519196, dated Apr. 26, 2022, 5 pages.
[cited by applicant]
Dos Santos, A.B., et al., “Treatment of Sleeping Disorders Should Be Considered in Clinical Management of Parkinson's Disease,” Frontiers in Aging Neuroscience 6:273, Frontiers Research Foundation, Switzerland (Oct. 201…
[cited by applicant]
Murofushi, T., “Migraine Associated Vertigo,” Equilibrium Research 70(3): 172-175, Japan Society for Equilibrium Research, Japan (2011).
[cited by applicant]
Kurokawa, K., et al., “Migraine and Vertigo: Introduction to Migrainous Vertigo,” Journal of Clinical and Experimental Medicine 255(7):757-761, Springer, Switzerland (2015).
[cited by applicant]
Fernandez, M., et al., “Pharmacological agents for the prevention of vestibular migraine,” The Cochrane Database of Systematic Reviews 2015(6):CD010600, Wiley, United Kingdom (Jun. 2015).
[cited by applicant]
Velazquez-Perez, L., et al., “Lisuride Reduces Involuntary Periodic Leg Movements in Spinocerebellar Ataxia Type 2 Patients,” Cerebellum (London, England) 11(4):1051-1056, Springer, United States (Dec. 2012).
[cited by applicant]
Porter, V.R., et al., “Sleep, Cognition and Dementia,” Current Psychiatry Reports 17(12):1-11, Current Science, United States (Oct. 2015).
[cited by applicant]
Suzuki, K., et al., “Sleep Disturbances in Neurodegenerative Diseases,” Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 106(2):309-318, Nihon Naika Gakkai, Japan (Feb. 2017).
[cited by applicant]
English Translation of Office Action for Japanese Patent Application No. 2020-521938, mailed on Apr. 1, 2022, 3 Pages.
[cited by applicant]