IP Library › Granted Patent US 12,409,170
Granted Patent B2
US 12,409,170 · App. 18/394,155 · Granted Sep 9, 2025

Composition comprising combination of rapamycin and metformin and use thereof for treating neurodegenerative diseases

Inventor: Jeffrey M. Melin (Meadowbrook, PA)
Assignee: IMM Licensing LLC
A61K31/436A61K9/0014A61K9/0087A61K9/06A61K31/155A61K31/519A61K47/10A61K2300/00
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Quick Facts
Patent No.
US 12,409,170
App. No.
18/394,155
Granted
Sep 9, 2025
Kind
B2
Abstract

A formulation for treating neurodegenerative diseases comprising a combination of rapamycin and metformin in a molar ratio of about 20:1, 10:1, 5:1, 4:1, 3:1, or 1:1. A method of treating neurodegenerative diseases comprising administering the formulation comprising a combination of rapamycin and metformin in a molar ratio of about 20:1, 10:1, 5:1, 4:1, 3:1, or 1:1.

Claims (17)

1. A method of treating a neurodegenerative disease or disorder comprising administering an effective amount of a composition comprising a combination of rapamycin and metformin to a subject, wherein the molar ratio of rapamycin to metformin is in the range of about 20:1 to about 1:1.

2. The method of claim 1 , wherein the molar ratio of rapamycin to metformin is in the range of about 15:1 to about 3:1.

3. The method of claim 1 , wherein the molar ratio of rapamycin to metformin is in the range of about 10:1 to about 4:1.

4. The method of claim 1 , wherein the molar ratio of rapamycin to metformin is about 5:1 to about 3:1.

5. The method of claim 1 , wherein the molar ratio of rapamycin to metformin is about 5:1 to about 4:1.

6. The method of claim 1 , wherein the neurodegenerative disease or disorder is associated with mTORC1 hyperactivation, or an acquired neurodegenerative disease or disorder.

7. The method of claim 6 , wherein the neurodegenerative disease or disorder is Alzheimer's disease (AD), Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), Dementia with Lewy Bodies, Huntington's disease, amyloid associated vasculopathies, traumatic brain injury-related disease, or a tauopathy.

8. The method of claim 6 , wherein the neurodegenerative disease or disorder is associated with mTORC1 hyperactivation and is Alzheimer's disease, ALS, tauopathies, Parkinson's Disease, FTD, or Tuberous Sclerosis Complex, and Seizure Disorders.

9. The method of claim 1 , wherein the composition is formulated for oral administration.

10. The method of claim 1 , wherein the composition is formulated for topical administration.

11. The method of claim 1 , wherein the composition is formulated for parenteral administration.

12. The method of claim 9 , wherein the composition comprises a nanoparticle encapsulating at least the rapamycin, the metformin, or the combination of rapamycin and metformin.

13. A method of treating a neurodegenerative disease or disorder mediated by mTORC1 activation comprising administering an effective amount of a composition comprising a combination of rapamycin and metformin to a subject, wherein the molar ratio of rapamycin to metformin is in the range of about 20:1 to about 1:1.

14. The method of claim 13 , wherein the molar ratio of rapamycin to metformin is in the range of about 10:1 to about 4:1.

15. The method of claim 14 , wherein the composition comprises a nanoparticle encapsulating at least the rapamycin, the metformin, or the combination of rapamycin and metformin.

16. The method of claim 13 , wherein the neurodegenerative disease or disorder is AD.

17. The method of claim 13 , wherein the neurodegenerative disease or disorder occurs either sporadically or as part of TSC.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 8, 2024
From: MELIN, JEFFREY M.
To: JMM LICENSING LLC
Reel/Frame 066050/0665 →
Continuity (8)
Continuation 17392516 · Aug 3, 2021
Continuation 16931133 · Jul 16, 2020
Continuation 16040160 · Jul 19, 2018
Continuation 15828926 · Dec 1, 2017
Continuation 15241312 · Aug 19, 2016
Provisional Application 62318302 · Apr 5, 2016
Provisional Application 62259384 · Nov 24, 2015
Related Publication 20240261269A1 · Aug 8, 2024
References Cited (94)
US 5100899A · Calne · 1992 [cited by applicant]
US 5362718A · Skotnicki et al. · 1994 [cited by applicant]
US 5540931A · Hewitt et al. · 1996 [cited by applicant]
US 7169594B2 · Guan · 2007 [cited by applicant]
US 7799782B2 · Munson et al. · 2010 [cited by applicant]
US 8026276B2 · Rubino et al. · 2011 [cited by applicant]
US 8150592B2 · Song et al. · 2012 [cited by applicant]
US 8197804B2 · Sing et al. · 2012 [cited by applicant]
US 8299116B2 · Rubino et al. · 2012 [cited by applicant]
US 8455539B2 · Rubino et al. · 2013 [cited by applicant]
US RE44768E · Skotnicki et al. · 2014 [cited by applicant]
US 8722700B2 · Rubino · 2014 [cited by applicant]
US 8791097B2 · Dukart et al. · 2014 [cited by applicant]
US 8911768B2 · Whitcup et al. · 2014 [cited by applicant]
US 8911786B2 · Desai et al. · 2014 [cited by applicant]
US 9150592B2 · Cusack et al. · 2015 [cited by applicant]
US 9155801B2 · Weisbart · 2015 [cited by applicant]
US 10765665B2 · Melin · 2020 [cited by applicant]
US 10925862B2 · Melin · 2021 [cited by examiner]
US 10952994B2 · Melin · 2021 [cited by examiner]
US 11141409B2 · Melin · 2021 [cited by applicant]
US 11890274B2 · Melin · 2024 [cited by applicant]
US 20060286046A1 · Haber · 2006 [cited by applicant]
US 20110144143A1 · Sun et al. · 2011 [cited by applicant]
US 20110256130A1 · Schultz et al. · 2011 [cited by applicant]
US 20110275597A1 · Namdeo et al. · 2011 [cited by applicant]
US 20120022095A1 · Teng et al. · 2012 [cited by applicant]
US 20120283332A1 · Scarbrough et al. · 2012 [cited by applicant]
US 20140186306A1 · Plante · 2014 [cited by applicant]
US 20140301980A1 · Day · 2014 [cited by applicant]
US 20170143682A1 · Melin · 2017 [cited by applicant]
US 20180153864A1 · Melin · 2018 [cited by applicant]
US 20190000815A1 · Melin · 2019 [cited by applicant]
US 20200345703A1 · Melin · 2020 [cited by applicant]
US 20210361630A1 · Melin · 2021 [cited by applicant]
JP 2011529860A · 2011 [cited by applicant]
JP 2012514633A · 2012 [cited by applicant]
JP 2012131827 · 2012 [cited by applicant]
WO WO2008022256 · 2008 [cited by applicant]
WO WO2008110491 · 2008 [cited by applicant]
WO WO2010028596A1 · 2010 [cited by applicant]
WO WO2010073642A1 · 2010 [cited by applicant]
WO WO2014052640A1 · 2014 [cited by applicant]
WO WO2017034315A1 · 2017 [cited by applicant]
WO WO2017091454A1 · 2017 [cited by applicant]
Barrett, D. et al.; Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies; NIH Public Access Author Manuscript; Oct. 1, 2012; pp. 1-31; 14(5); Springer International Publishing. [cited by applicant]
Bhattaram, P. et al.; “Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast-Like Synoviocytes in Arthritic Disease,” Arthritis & Rheumatology, vol. 70, No. 3, Mar. 2018… [cited by applicant]
Bibee, K.P., ct al.; Rapamycin Nonoparticlcs Targct Dcfcctivc Autophagy in Muscular Dystrophy to Enhance Both Strength and Cardiac Function; The FASEB Journal—Research Communication; May 2014; pp. 2047-2061; vol. 28. [cited by applicant]
Bride, K. ct al.; Sirolimus is Effcctivc for Autoimmunc Cytopcnias; Blood First Edition Papcr; Oct. 26, 2015; pp. 1-35; American Society of Hematology. [cited by applicant]
Bruyere et al. “A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis—From evidence-based medicine… [cited by applicant]
Bruyn, G et al.; Everolimus in Patients with Rheumatoid Arthritis Receiving Concomitant Methotrexate: a 3-month, Double-blind, Randomised, Placebo-Controlled, Parallel-group, proof-of-concept Study; http://ard.bmj.com/c… [cited by applicant]
Bubna; Indian J. Pharmacol., 2016, vol. 48, No. 1, pp. 4-10 (Year: 2016). [cited by applicant]
Cejka, et al.; Arthritis & Rheumatism, 2010, vol. 62, No. 8, pp. 2294-2302 (Year: 2010). [cited by applicant]
Checkley, L.A. et al.; Metromin Inhibits Skin Tumor Promotion in Overweight and Obese Mice; Cancer Prevention Research; Nov. 6, 2013; pp. 54-65; 7(1); American Association for Cancer Research. [cited by applicant]
Checkley et al. “Metformin Inhibits Skin Tumor Promotion in Overweight and Obese Mice,” Cancer Prevention Research, vol. 7, No. 1, Nov. 6, 2013, pp. 54-64 XP055332804, United States. [cited by applicant]
Efe, et al. “Penetration of topical diclofenac sodium 4% spray gel into the synovial tissue and synovial fluid of the knee: a randomised clinical trial,” Knee Surg sports Traumatol Arthrosc (2014) 22:345-350, published … [cited by applicant]
Haemel, et al. “Topical Rapamycin; a Novel Approach to Facial Angiofibromas in Tuberous Sclerosis,” Arch Dermatol, vol. 146, No. 7, Jul. 2010, published by American Medical Association 2010. [cited by applicant]
Intravitreal Sirolimus as Therapeutic Approach to Uveitis—Full Text View—ClinicalTrials.gov (date unavailable). [cited by applicant]
Kloppenburg, et al. “2018 update of the EULAR recommendations for the management of hand osteoarthritis,” Ann Rheum Dis, 0:1-9, 2018, doi: 10.1136/annrheumdis-2018-213826. [cited by applicant]
Lai, Z. et al.; N-Acetylcysteine Reduces Disease Activity by Blocking MTOR in T Cells of Lupus Patients; NIH Public Access Author Manuscript; Sep. 2012; pp. 1-15; 64(9). [cited by applicant]
Lamming, D. et al.; Rapalogs and MTOR Inhibitors as Anti-aging Therapeutics; The Journal of Clinical Investigation; Mar. 2013; pp. 980-989; vol. 123, No. 3. [cited by applicant]
MacKcnzic, M.J. ct al., “A phasc I study of tcmsirolimus and mctformin in advanccd solid tumours,” Invest New Drugs, vol. 30; No. 2; 647-652 (2012). [cited by applicant]
Madke, Indian Dermatol. Online J. 2013, vol. 4, No. 1, pp. 54-57 (Year: 2013). [cited by applicant]
Mahalati, K. and Kahan, B.D., “Clinical Pharmacokinetics of Sirolimus,” Clin. Pharmacokinet., vol. 40; 573-585 (2001). [cited by applicant]
Marques et al. “Topical rapamycin combined with pulsed dye laser in the treatment of capillary vascular malformations in Sturge-Weber syndrome: Phase II, randomized, double-blind, intraindividual placebo-controlled clin… [cited by applicant]
Mayo Clinic, ClinicaiTrials.gov NCT01649960, posted Jul. 25, 2012 (Year: 2012). [cited by applicant]
Mayo Clinic; “Arthritis pain: Treatments absorbed through your skin”, https://www.mayoclinic.org/diseases-conditions/osteoarthritis/in-depth/pain-maedications/art-20045899, accessed Feb. 21, 2018. [cited by applicant]
Mekahli, D. et al., “Polycystin-1 but not polycystin-2 deficiency causes upregulation of the mTOR pathway and can be synergistically targeted with rapamycin and metformin”, Eur. J. Physiol., vol. 466, 1591-1604 (2014). [cited by applicant]
Metformin Dosage, Life Extension, Aug. 2003, https://www.lifeextension.com/Featured%20Articles/2003/8/Metformin%20Dosage/Page%2001 (Year: 2003). [cited by applicant]
Migata et al., Clin. Exp. Immunol., 1996, vol. 104, pp. 86-91 (Year: 1996). [cited by applicant]
Miyatake, S. et al.; “Randomized clinical comparisons of diclofenac concentration in the soft tissues and blood plasma between topical and oral applications,” British Journal of Clinical Pharmacology, 67:1, pp. 125-129 … [cited by applicant]
Naing, Exp. Op. Invest. Drugs, 2013, vol. 22, No. 6, pp. 679-685 (Year: 2013). [cited by applicant]
Oy, S.; Public Summary of Opinion on Orphan Designation Sirolimus for the Treatment of Chronic Non-infectious Uveitis; Sep. 20, 2011; pp. 1-4; European Medicines Agency; United Kingdom. [cited by applicant]
Phillips, B. et al.; A Retrospective Review of Oral Low-dose Sirolimus (rapamycin) for the Treatment of Active Uveitis; J Ophthal Inflamm Infect; 2011; pp. 29-34; 1; The Authors. [cited by applicant]
Rannou, et al. “Efficacy and safety of topical NSAIDs in the management of osteoarthritis: Evidence from real-life setting trials and surveys,” Seminars in Arthritis and Rheumatism, 2016, 4 pages, published by Elsevier … [cited by applicant]
Riaz, H. et al.; mTOR Inhibitors: A Novel Class of Anti-Cancer Agents; Infectious Agents and Cancer; 2012; pp. 1-2; 7:1; BioMed Central. [cited by applicant]
Saha, A. et al., “Effect of Metformin, Rapamycin, and their Combination on Growth and Progression of Prostate Tumors in HiMyc Mice,” Cancer Prevention Research, vol. 8, No. 7, 597-606 (2015). [cited by applicant]
Son et al. “Modulators of Inflammation,” 2014, Article ID 973986 (Year 2014). [cited by applicant]
Teachey, D. et al.; mTOR Inhibitors are Synergistic with Methotreazate; An Effective Combination to Treat Acute Lymphoblastic Leukemia; Bloodjournal.org; Sep. 1, 2008; pp. 2020-2024; vol. 112, No. 5; Blood. [cited by applicant]
Wee, J. S., et al.; Familial Multiple Discoid Fibromas: Unique Histological Features and Therapeutic Response to Toical Rapamycin; British Journal of Dermatology; 2013; pp. 177-180; The Authors and British Association o… [cited by applicant]
Yan, H. et al.; Suppression of Experimental Arthritis Through AMP-activated Protein Kinase Activation and Autophagy Modulation; HHS Public Access Author Manuscript; Feb. 28, 2015; pp. 1-18; 1(1): 5-. [cited by applicant]
You, S. et al.; “The Tumor-Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine,” Arthritis & Rheumatology; vol. 70, No. 5, May 2018, pp. 637-652. [cited by applicant]
Yu et al., J. Gerontal. A Bioi. Sci. Med. Sci., 2015, vol. 70, No. 4, pp. 410-420 (Year: 2015). [cited by applicant]
Yu, G. et al.; Metformin Potentiates Rapamycin and Cisplatin in Gastric Cancer in Mice; www.impactjournals.com/oncotarget/; Feb. 28, 2015; pp. 12748-12762; vol. 6, No. 14. [cited by applicant]
Extended European Search Report and Written Opinion received for EP Patent Application No. 21187553.9, mailed on Nov. 5, 2021, 11 pages. [cited by applicant]
International Preliminary Report on Patentability received for PCT Patent Application No. PCT/US16/62656, mailed on Jun. 7, 2018, 8 pages. [cited by applicant]
Examination Report issued by the European Patent Office for Patent Application No. 16 805 683.6-1109 dated May 17, 2021, 10 pages. [cited by applicant]
Examination Report issued by the European Patent Office for Patent Application No. 16 805 683.6-1109 dated Nov. 25, 2019, 11 pages. [cited by applicant]
International Search Report of the International Searching Authority for International Patent Application No. PCT/US2016/062656 dated Jan. 13, 2017, 5 pages. [cited by applicant]
Office Action/Notice of Reasons for Rejection issued by the Japanese Patent Office for Japanese Patent Application No. 2018-527959 dated Aug. 4, 2020, 8 pages. [cited by applicant]
Written Opinion of the International Searching Authority for International Patent Application No. PCT/US2016/062656 dated Jan. 13, 2017, 7 pages. [cited by applicant]
Non-Final Office Action for U.S. Appl. No. 17/392,516, mailed Jul. 26, 2023. [cited by applicant]
Notice of Allowance for U.S. Appl. No. 17/392,516, mailed Dec. 14, 2023. [cited by applicant]
International Search Report and Written Opinion received for PCT Patent Application No. PCT/US16/62656, mailed on Jan. 13, 2017, 10 pages. [cited by applicant]