Granted Patent
B2
US 12,297,502 · App. 17/708,909 · Granted May 13, 2025
Methods and compositions for detecting and diagnosing diseases and conditions
Assignee:
STEALTH BIOTHERAPEUTICS INC.
C12Q1/6883A61K38/06C12Q2600/106C12Q2600/118C12Q2600/158G01N33/92G01N2405/04G01N2560/00G01N2800/325G01N2800/52
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Abstract
The disclosure provides methods for detecting and diagnosing diseases and conditions associated with defects in cardiolipin remodeling. In some embodiments, the present technology relates to methods for detecting the presence or amount of cardiolipin isoforms and/or the presence or amount of enzymes involved in cardiolipin remodeling.
Claims (11)
1. A method for monitoring and treating a subject for heart failure, the method comprising:
(a) detecting levels of monolysocardiolipin acyltransferase (MLCL AT1) or acyl-CoA lysocardiolipin (ALCAT1) mRNA in a biological sample from the subject;
(b) selecting the subject for aromatic-cationic peptide treatment where the level of MLCL AT1 or ALCAT1 mRNA in the biological sample from the subject is elevated about 2.5-fold compared to a normal control sample; and
(c) administering to the subject a therapeutically effective amount of the aromatic-cationic peptide, wherein the aromatic-cationic peptide is D-Arg-2′6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof, wherein treatment increases the expression of TAZ1 in the myocardium of the subject.
2. The method of claim 1 , further comprising detecting levels of cardiolipin isoforms in a biological sample from the subject and comparing the levels of cardiolipin isoforms to those of a normal control subject, wherein the detecting levels of cardiolipin isoforms comprises chromatography, mass spectrometry, ELISA, Western blotting, immunodetection, or immunoprecipitation.
3. The method of claim 1 , wherein detecting the level of MLCL AT1 or ALCAT1 mRNA comprises RT-PCR, in situ hybridization, or Northern blotting.
4. The method of claim 1 , wherein the peptide is administered daily for 6 weeks or more.
5. The method of claim 1 , wherein the heart failure results from hypertension; ischemic heart disease; exposure to a cardiotoxic compound; myocarditis; thyroid disease; viral infection; gingivitis; drug abuse; alcohol abuse; pericarditis; atherosclerosis; vascular disease; hypertrophic cardiomyopathy; acute myocardial infarction; left ventricular systolic dysfunction; coronary bypass surgery; starvation; an eating disorder; or a genetic defect.
6. The method of claim 1 , wherein the peptide is administered orally, topically, systemically, intravenously, subcutaneously, intraperitoneally, or intramuscularly.
7. The method of claim 1 , further comprising separately, sequentially or simultaneously administering a cardiovascular agent to the subject, wherein the cardiovascular agent is selected from the group consisting of: an anti-arrhythmia agent, a vasodilator, an anti-anginal agent, a corticosteroid, a cardioglycoside, a diuretic, a sedative, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II antagonist, a thrombolytic agent, a calcium channel blocker, a throboxane receptor antagonist, a radical scavenger, an anti-platelet drug, a β-adrenaline receptor blocking drug, α-receptor blocking drug, a sympathetic nerve inhibitor, a digitalis formulation, an inotrope, and an antihyperlipidemic drug.
8. The method of claim 1 , wherein the biological sample comprises tissue, a cell, or a mitochondrion from the subject.
Assignments (5)
CHANGE OF ADDRESS
Recorded Apr 14, 2025
From: STEALTH BIOTHERAPEUTICS INC.
To: STEALTH BIOTHERAPEUTICS INC.
Reel/Frame 070830/0608 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 5, 2022
From: WILSON, D. TRAVIS
To: STEALTH PEPTIDES INTERNATIONAL, INC.
Reel/Frame 061316/0750 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 5, 2022
From: WILSON, D. TRAVIS
To: STEALTH PEPTIDES INTERNATIONAL, INC.
Reel/Frame 061607/0299 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 5, 2022
From: STEALTH BIOTHERAPEUTICS CORP
To: STEALTH BIOTHERAPEUTICS INC.
Reel/Frame 061607/0310 →
CHANGE OF NAME
Recorded Oct 5, 2022
From: STEALTH PEPTIDES INTERNATIONAL, INC.
To: STEALTH BIOTHERAPEUTICS CORP
Reel/Frame 061607/0342 →
Continuity (5)
Division
14392293
Provisional Application
61840760
· Jun 28, 2013
Provisional Application
61839753
· Jun 26, 2013
References Cited (236)
US 4522811A
· Eppstein et al.
· 1985
[cited by applicant]
US 5674534A
· Zale et al.
· 1997
[cited by applicant]
US 5716644A
· Zale et al.
· 1998
[cited by applicant]
US 6468798B1
· Debs et al.
· 2002
[cited by applicant]
US 7550439B2
· Szeto
· 2009
[cited by applicant]
US 7576061B2
· Szeto et al.
· 2009
[cited by applicant]
US 7718620B2
· Szeto et al.
· 2010
[cited by applicant]
US 7781405B2
· Szeto
· 2010
[cited by applicant]
US 8143219B2
· Szeto et al.
· 2012
[cited by applicant]
US 8404646B2
· Schiller et al.
· 2013
[cited by applicant]
US 8592373B2
· Szeto et al.
· 2013
[cited by applicant]
US 8618061B2
· Szeto
· 2013
[cited by applicant]
US 8940696B2
· Szeto et al.
· 2015
[cited by applicant]
US 8957030B2
· Szeto et al.
· 2015
[cited by applicant]
US 9241933B2
· Cohen et al.
· 2016
[cited by applicant]
US 9457057B2
· Tompkins et al.
· 2016
[cited by applicant]
US 9687519B2
· Wilson et al.
· 2017
[cited by applicant]
US 20070026090A1
· Tirosh et al.
· 2007
[cited by applicant]
US 20070135335A1
· Collier et al.
· 2007
[cited by applicant]
US 20070265216A1
· Gross et al.
· 2007
[cited by applicant]
US 20080318909A1
· Sparagna et al.
· 2008
[cited by applicant]
US 20090143279A1
· Mootha et al.
· 2009
[cited by applicant]
US 20090298848A1
· Stewart
· 2009
[cited by applicant]
US 20100158995A1
· Mill et al.
· 2010
[cited by applicant]
US 20100190718A1
· Schiller et al.
· 2010
[cited by applicant]
US 20100331265A1
· Tompkins et al.
· 2010
[cited by applicant]
US 20110039766A1
· Szeto
· 2011
[cited by applicant]
US 20110082084A1
· Szeto et al.
· 2011
[cited by applicant]
US 20110172312A1
· Miller et al.
· 2011
[cited by applicant]
US 20110197294A1
· Gottlieb et al.
· 2011
[cited by applicant]
US 20120046363A1
· Stanley
· 2012
[cited by applicant]
US 20120122957A1
· Dillin et al.
· 2012
[cited by applicant]
US 20130040901A1
· Szeto et al.
· 2013
[cited by applicant]
US 20130288985A1
· Jurkunas
· 2013
[cited by applicant]
US 20130345312A1
· Jankowski et al.
· 2013
[cited by applicant]
US 20140031432A1
· Jankowski et al.
· 2014
[cited by applicant]
US 20140349941A1
· Wilson et al.
· 2014
[cited by applicant]
US 20140378396A1
· Wilson et al.
· 2014
[cited by applicant]
US 20150018288A1
· Wilson et al.
· 2015
[cited by applicant]
US 20150246092A1
· Wilson et al.
· 2015
[cited by applicant]
US 20150266946A1
· Sinclair et al.
· 2015
[cited by applicant]
US 20150353602A1
· Szeto et al.
· 2015
[cited by applicant]
US 20150359838A1
· Szeto et al.
· 2015
[cited by applicant]
US 20160175380A1
· Jurkunas
· 2016
[cited by applicant]
US 20160361377A1
· Wilson et al.
· 2016
[cited by applicant]
CN 1787831A
· 2006
[cited by applicant]
JP 2013521231
· 2013
[cited by applicant]
JP 6918046B2
· 2021
[cited by applicant]
WO WO9640073A2
· 1996
[cited by applicant]
WO WO9915154A1
· 1999
[cited by applicant]
WO WO0038651A1
· 2000
[cited by applicant]
WO WO2004070054A2
· 2004
[cited by applicant]
WO WO2004070054A3
· 2005
[cited by applicant]
WO WO2005072295A2
· 2005
[cited by applicant]
WO WO2006122140
· 2006
[cited by applicant]
WO WO2010120431A2
· 2010
[cited by applicant]
WO WO2011082324A1
· 2011
[cited by applicant]
WO WO2011096398A1
· 2011
[cited by applicant]
WO WO2011106717A1
· 2011
[cited by applicant]
WO WO2011116007A1
· 2011
[cited by applicant]
WO WO2011139992A1
· 2011
[cited by applicant]
WO WO2012129427
· 2012
[cited by applicant]
WO WO2013049697
· 2013
[cited by applicant]
WO WO2014066419
· 2014
[cited by applicant]
Notification of Reexamination on CN Patent Application No. 201480022767.2 dated Sep. 1, 2022 (11 pages) (with English Translation).
[cited by applicant]
“The Voice of the Patient: Barth Syndrome” Presentation. Barth Syndrome Foundation, (2019).
[cited by applicant]
Acín-Pérez, et al., “Respiratory Active Mitochondrial Supercomplexes,” Molecular Cell,Nov. 21, 2008, vol. 32, No. 4, pp. 529-539.
[cited by applicant]
Aljabri, et al. “Lethal neonatal mitochondrial phenotype caused by a novel polymerase subunit gamma mutation,” Medicine, vol. 97, No. 40(e12591) (2018) (pp. 1-7).
[cited by applicant]
Amselem, et al., “A Large-Scale Method for the Preparation of Sterile and Nonpyrogenic Liposomal Formulations of Defined Size Distributions for Clinical Use.” Liposome Technology, 1993, vol. I, 2nd ed., CRC Press, pp. 5…
[cited by applicant]
Aprikyan et al. “Advances in the understanding of Barth syndrome,” British Journal of Haematology, vol. 161 (2013) (pp. 330-338).
[cited by applicant]
Ashley, et al., “Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations,” Hum. Mol. Gene., 2008, vol. 17, No. 16, pp. 2496-2506.
[cited by applicant]
Barth, et al. “An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes,” Journal of the Neurological Sciences, vol. 62 (1983) (pp. 327-355).
[cited by applicant]
Birk et al. “The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin,” Journal of the American Society of Nephrology, vol. 24 (2013) (pp. 1250-1261).
[cited by applicant]
Birk, et al., “Targeting cytochrome C for optimization of mitochondrial electron transport chain,” FASEB Journal, 2011, vol. 25, No. 1, Abstract.
[cited by applicant]
Blok, et al., “The unfolding clinical spectrum of POLG mutations,” J. Med. Genet., 2009, vol. 46, No. 22, pp. 776-785.
[cited by applicant]
CA Office Action on CA Patent Application No. 2916977 dated Mar. 8, 2022 (8 pages).
[cited by applicant]
Calvani et al. “Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy,” Biological Chemistry, vol. 394, No. 3 (2013) (pp. 393-414).
[cited by applicant]
Chinnery, Patrick F. “Mitochondrial Disorders Overview” GeneReviews (2000).
[cited by applicant]
Chonn, et al., “Recent Advances in Liposomal Drug-Delivery Systems,” Curr. Opin. Biotechnol., Dec. 1995, vol. 6, Issue 6, pp. 698-708.
[cited by applicant]
Colan, Steven D., “Classification of teh cardiomyopathies,” Progress in Pediatric Cardiology, vol. 23, (2007) (pp. 5-15).
[cited by applicant]
Dai et al. “Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease,” Antioxidants & Redox Signaling, vol. 16, No. 12 (2012) (pp. 1492-1526).
[cited by applicant]
Dai et al. “Mitochondria and Cardiovascular Aging,” Circulation Research, vol. 110 (2012) (pp. 1109-1124).
[cited by applicant]
Dai et al. “Mitochondrial oxidative stress mediates Angiotension II-induced cardiac hypertrophy and Gaq overexpression-induced heart failure,” Circulation Research, vol. 108, No. 7 (2011) (pp. 837-846).
[cited by applicant]
Dai, et al., “Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy,” Journal of the American College of Cardiology, 2011, vol. 38, No. 1, pp. 73-82.
[cited by applicant]
Decision of Rejection in CN Patent Application No. 201480022764.9 dated Mar. 19, 2019.
[cited by applicant]
Diaz, et al., Cytochrome c Oxidase Is Required for the Assembly/Stability of Respiratory Complex I in Mouse Fibroblasts, Mol. Cell. Bio., Jul. 2006, vol. 26, No. 13, pp. 4872-4881.
[cited by applicant]
Examination Report in EP Patent Application No. 14756991.7 mailed May 11, 2018.
[cited by applicant]
Extended European Search Report on EP Patent Application No. 19190165.1 dated Feb. 5, 2020 (11 pages).
[cited by applicant]
Extended Search Report in EP Patent Application 14757000 No. dated Jul. 16, 2016.
[cited by applicant]
Extended Search Report in EP Patent Application No. 14756991.7 mailed Jul. 19, 2016.
[cited by applicant]
Farina, et al, “MR Findings in Leigh Syndrome with COX deficiency and SURF-1 Mutations,” Am. J. Neuroradiol., 2002, vol. 23, pp. 1095-1100.
[cited by applicant]
Ferraris, et al., “Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1,” Arch. Neurol., 2008, vol. 65, pp. 125-131.
[cited by applicant]
Final Office Action in U.S. Appl. No. 14/771,411 dated Jan. 25, 2018.
[cited by applicant]
Final Office Action on U.S. Appl. No. 15/626,255 dated Nov. 26, 2018, 13 pages.
[cited by applicant]
Final Office Action on U.S. Appl. No. 16/101,078 dated Sep. 29, 2021 (7 pages).
[cited by applicant]
Final Office Action on U.S. Appl. No. 16/930,028 dated Sep. 17, 2021 (22 pages).
[cited by applicant]
Final Rejection in U.S. Appl. No. 16/929,370 dated Mar. 3, 2021 (7 pages).
[cited by applicant]
Final Rejection on JP Patent Application No. 2019-133638 dated Apr. 4, 2022 (4 pages).
[cited by applicant]
Foreign Action other than Search Report on EP 14757000.6 DTD Sep. 25, 2018.
[cited by applicant]
Foreign Action other than Search Report on JP 2015-560380 DTD Aug. 5, 2019.
[cited by applicant]
Gregoriadis, “Engineering Liposomes for Drug Delivery: Progress and Problems,” Trends in Biotechnology, Dec. 1995, vol. 13, No. 12, pp. 527-537.
[cited by applicant]
Han, et al., “Shotgun lipidomics of cardiolipin molecular species in lipid extracts of biological samples,” J Lipd Res, 2006, vol. 47, No. 4, pp. 864-879.
[cited by applicant]
He, et al., “Abstract 15771: Mitochondria Targeted Antioxidant Prevents Mitochondrial Dysfunction Induced by Cardiolipin Deficiency,” Circulation, Nov. 20, 2012, vol. 126, 2 pages.
[cited by applicant]
Houtkooper, et al., “The Enigmatic Role of Tafazzin in Cardiolipin Metabolism,” Biochimica et Biophysica Acta 1788, 2009, pp. 2003-2014.
[cited by applicant]
Houtkooper, et al., “Cardiolipin and monolysocardiolipin analysis in fibroblasts, lymphocytes, and tissues using high-performance liquid chromatography-mass spectrometry as a diagnostic tests for Barth syndrome,” Analyt…
[cited by applicant]
International Search Report and Written Opinion in International Patent Application No. PCT/US14/19622 dated Jun. 3, 2014 (11 pages).
[cited by applicant]
International Search Report and Written Opinion in International Patent Application No. PCT/US14/19645 dated Jun. 17, 2014 (11 pages).
[cited by applicant]
International Search Report and Written Opinion in International Patent Application No. PCT/US14/43711 dated Jan. 2, 2015 (10 pages).
[cited by applicant]
Jefferies, John L. “Barth Syndrome,” American Journal of Medical Genetics Part C (Seminars in Medical Genetics), vol. 163C (2013) (pp. 198-205).
[cited by applicant]
Jeffries, John Lynn. Letter to FDA.
[cited by applicant]
Karkucinska-Wieckowska, et al., “Left Ventricular Noncompaction (LVNC) and Low Mitochondrial Membrane Potential are Specific for Barth Syndrome” J. Inherit. Metab. Dis., Jan. 2013, vol. 36, pp. 929-937.
[cited by applicant]
Koshkin, et al., “Cardiolipin prevents rate-dependent uncoupling and provides osmotic stability in yeast mitochondria,” Biochem. J., 2002, vol. 364, pp. 317-322.
[cited by applicant]
Non-Final Office Action in U.S. Appl. No. 16/101,078 dated Mar. 24, 2021.
[cited by applicant]
Non-Final Office Action on U.S. Appl. No. 14/392,293 mailed Jun. 29, 2017.
[cited by applicant]
Non-Final Office Action on U.S. Appl. No. 15/626,255 mailed Apr. 16, 2018.
[cited by applicant]
Non-Final Rejection on U.S. Appl. No. 16/930,028 dated Feb. 25, 2021 (26 pages).
[cited by applicant]
Notice of Allowance in U.S. Appl. No. 14/392,293 dated Apr. 12, 2018.
[cited by applicant]
Notice of Allowance in U.S. Appl. No. 14/771,408 mailed Mar. 1, 2017.
[cited by applicant]
Notice of Allowance on U.S. Appl. No. 15/626,255 DTD May 28, 2021.
[cited by applicant]
Notice of Allowance on U.S. Appl. No. 16/101,078 dated Dec. 22, 2021.
[cited by applicant]
Notice of Refusal in JP Patent Application No. 2015-560380 dated Mar. 22, 2019 (with English translation) (6 pages).
[cited by applicant]
Nurminen et al. “Pathogenicity in POLG syndromes: DNA polymerase gamma pathogenicity prediction server and database,” BBA Clinical, vol. 7 (2017) (pp. 147-156).
[cited by applicant]
Office Action in CA Patent Application No. 2916880 dated Jan. 6, 2020.
[cited by applicant]
Office Action in CA Patent Application No. 2916977 dated May 27, 2020 (6 pages).
[cited by applicant]
Office Action in CN Patent Application No. 201480022767.2 dated Mar. 28, 2017 (with English translation).
[cited by applicant]
Office Action in CN Patent Application No. 201480022764.9 dated Jun. 17, 2017.
[cited by applicant]
Office Action in CN Patent Application No. 201480022764.9 dated May 16, 2018.
[cited by applicant]
Office Action in JP Patent Application No. 2015-560380 dated Dec. 25, 2017 (English translation not available).
[cited by applicant]
Office Action in JP Patent Application No. 2015-560380 dated Jun. 1, 2020 (with English translation) (8 pages).
[cited by applicant]
Office Action in JP Patent Application No. 2019-080101 dated Apr. 13, 2020 (with English translation) (7 pages).
[cited by applicant]
Office Action on CA Patent Application No. 2916977 dated Apr. 9, 2021.
[cited by applicant]
Office Action on JP Patent Application No. 2019-133638 dated Jun. 3, 2021 (with English translation) (4 pages).
[cited by applicant]
Palsdottir,et al., “Lipids in membrane protein structures,” Biochim Biophys Acta, Nov. 3, 2004, vol. 1666 (1-2), pp. 2-18.
[cited by applicant]
Phoon et al., “Tafazzin knockdown in mice leads to a developmental cardiomyopathy with early diastolic dysfunction preceding myocardial noncompaction,” J. Am Heart Assoc, Apr. 2012, vol. 1, No. 2, 13 pages.
[cited by applicant]
Picard, Martin. “Assessment of mitochondrial function in skeletal muscle during disease, disuse and normal aging,” Department of Kinesiology and Physical Education, McGill University, Montreal, Canada (2012).
[cited by applicant]
Puccio et al. “Friedreich ataxia: a paradigm for mitochondrial diseases,” Curr. Opin. Genetics Develop., 2002, vol. 12, pp. 272-277.
[cited by applicant]
Raja et al. “Barth syndrome: A life-threatening disorder caused by abnormal cardiolipin remodeling,” Journal of Rare Diseases Research & Treatment, vol. 2, No. 2 (2017) (pp. 58-62).
[cited by applicant]
Reddy, “Controlled-Release, Pegylation, Liposomal Formulations: New Mechanisms in the Delivery of Injectable Drugs,” Ann Pharmacother., Jul./Aug. 2000, vol. 34, pp. 915-923.
[cited by applicant]
Restriction Requirement on U.S. Appl. No. 14/392,293, mailed Oct. 13, 2016.
[cited by applicant]
Ristow et al., “Frataxin activates mitochondrial energy conversion and oxidative phosphorylation,” PNAS, Oct. 24, 2000, vol. 97, No. 22, pp. 12239-12243.
[cited by applicant]
Sabbah, Hani N. “Barth syndrome cardiomyopathy: targeting the mitochondria with elamipretide,” Heart Failure Reviews (2020) (pp. 1-17).
[cited by applicant]
Sabbah, Hani N. et al., “A canine model of chronic heart failure produced by multiple sequential coronary microembolizations,” Am J Physiol.—Heart and Circulatory Physiology, 1991, vol. 260, Issue 4, pp. H1379-H1384.
[cited by applicant]
Saini-Chohan et al. “Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure”, Journal of Lipid Research vol. 50 (2008) (pp. 1600-1608).
[cited by applicant]
Saneto, et al., “Aplers-Huttenlocher Syndrome,” Pediatric Neurol., 2013, vol. 48, pp. 167-178.
[cited by applicant]
Schlame, et al., “Barth syndrome, a human disorder of cardiolipin metabolism,” FEBS Letters, 2006, vol. 580, pp. 5450-5455.
[cited by applicant]
Schlame, et al., “The biosynthesis and functional role of cardiolipin,” Progress in Lipid Research, 2000, vol. 39, pp. 257-288.
[cited by applicant]
Schulte, et al., “Ataxia with Ophthalmoplegia or Sensory Neuropathy is Frequently caused by POLG Mutations,” Neurology, Sep. 15, 2009, vol. 73, No. 11, pp. 898-900.
[cited by applicant]
Second Office Action in CN Patent Application 201480022767.2, No. dated Nov. 9, 2017.
[cited by applicant]
Shoemaker, et al. “Clinically Meaningful Change Estimates for the Six-Minute Walk Test and Daily Activity in Individuals With Chronic Heart Failure,” Cardiopulmonary Physical Therapy Journal, vol. 24, No. 3 (2013) (pp. …
[cited by applicant]
Siegel, et al., “Reversal of Age-Related Mitochondrial Dysfunction in vivo by Treatment with the Mitochondrially Targeted therapeutic SS-31,” The FASEB Journal, Apr. 2012, vol. 26, No. 1, 1 page.
[cited by applicant]
Spinazzola, et al., “Clinical and molecular features of mitochondrial DNA depletion syndromes,” J. INhert. Metab. Dis., 2009, vol. 32, Issue 2, pp. 143-158.
[cited by applicant]
Stewart, et al., “Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children,” J. Med. Genet., Mar. 2009, vol. 46, No. 3, pp. 209-214.
[cited by applicant]
Supplentary Tables. Elamipretide (MPT-131 for SC Injection) (2018).
[cited by applicant]
Takeda, et al., “Barth syndrome diagnosed in the subclinical stage of heart failure based on the presence of lipid storage myopathy and isolated noncompaction of the ventricular myocardium,” Eur J Pediatr, 2011, vol. 17…
[cited by applicant]
Tarnavski, et al., “Mouse cardiac surgery: comprehensive techniques for the generation of mouse models of human diseases and their application for genomic studies,” Physiol. Genomics, 2004, vol. 16, Issue 3, pp. 349-360.
[cited by applicant]
The fact sheet of Ataxia Neuropathy Spectrum, retrieved from Genetics Home Reference website, published Feb. 26, 2019, 5 pages.
[cited by applicant]
The fact sheet of Leigh Syndrome, retrieved from the Genetics Home Reference website, published Feb. 21, 2017, 8 pages.
[cited by applicant]
The fact sheet of Progressive External Ophthalmoplegia, retrieved from Genetics Home Reference website, published Feb. 26, 2019, 7 pages.
[cited by applicant]
The factsheet of Alpers Syndrome from the website of Genetic and Rare Disease Information Center at NIH. (rarediseases.info.nih.gov/diseases/5783/alpers-syndrome), retrieved on Sep. 13, 2021.
[cited by applicant]
The Factsheet of ataxia-neuropathy-spectrum from the MedicinePlus website. (medlineplus.gov/download/genetics/condition/X ataxia-neuropathy-spectrum.pdf).
[cited by applicant]
The Factsheet of Kearns-sayre-syndrome from the NIH website. (rarediseases. info. ni h .gov/diseases/6817 /kearns-sayre-syndrome).
[cited by applicant]
The factsheet of POLG gene from MedicinePlus Website. (medlineplus.gov/download/genetics/gene/polg.pdf).
[cited by applicant]
The factsheet of progressive external ophthalmoplegia (PEO) from the website of Genetic and Rare Disease Information Center at NIH. (rarediseases.info.nih.gov/diseases/4503/chronic-progressive-external-ophthalmoplegia),…
[cited by applicant]
The factsheet of sensory ataxia-neuropathy with dysarthria and ophthalmoparesis (SANDO) from the website of Genetic and Rare w Disease Information Center at NIH. (rarediseases.info.nih.gov/diseases/9998/sensory-ataxic-n…
[cited by applicant]
Thompson, et al. “A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism,” G…
[cited by applicant]
Tiranti, et al., “Mutations of SURF-1 in Leigh Disease Associated with Cytochrome c Oxidase Deficiency,” Am. J. Hum. Genet., Dec. 1998, vol. 63, No. 6, pp. 1609-1621.
[cited by applicant]
US Notice of Allowance on U.S. Appl. No. 16/929,370 DTD May 25, 2021.
[cited by applicant]
US Office Action on U.S. Appl. No. 14/392,293 DTD Oct. 13, 2016.
[cited by applicant]
US Office Action on U.S. Appl. No. 16/929,370 DTD Mar. 3, 2021.
[cited by applicant]
Van Goethem, et al., “Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions,” Nature Genetics, Jul. 2001, vol. 28, No. 3, pp. 211-212.
[cited by applicant]
Voller, et al., “Enzyme immunoassays with special reference to ELISA techniques,” J. Clinical Pathology, 1978, vol. 31, Issue 6, pp. 507-520.
[cited by applicant]
Weiner, Alan L., “Liposomes for Protein Delivery: Selecting Manufacture and Development Processes,” Immunomethods, Jun. 1994, vol. 4, No. 3, pp. 201-209.
[cited by applicant]
Williams, et al., “Cytochrome c Oxidase Subassemblies in Fibroblast Cultures from Patients Carrying Mutations in COX10, SCO1, or SURF1,” J. Biol. Chem., 2004, vol. 279, No. 9, pp. 7462-7469.
[cited by applicant]
Wong, et al., “Molecular and Clinical Genetics of Mitochondrial Diseases Due to POLG Mutations,” Hum. Mutat., Sep. 200), vol. 29, No. 9, pp. E150-E172.
[cited by applicant]
Zhao et al., “Cell-permeable Peptide Antioxidants Targeted to Inner Mitochondrial Membrane inhibit Mitochondrial Swelling, Oxidative Cell Death, and Reperfusion Injury,” The Journal of Biological Chemistry, Aug. 13, 200…
[cited by applicant]
Zhao, et al., “Transcellular Transport of a Highly Polar 3+ Net Charge Opioid Tetrapeptide,” Journal of Pharmacology and Experimental Therapeutics, 2003, vol. 304, No. 1, pp. 425-432.
[cited by applicant]
Zhu, et al., “SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome,” Nature Genetics, Dec. 1998, vol. 20, pp. 337-343.
[cited by applicant]
Zou, et al., “An in vitro preliminary study of the radio-protective properties of antioxidant peptide SS31,” Journal of Radiation Research and Radiation Proceeding, Oct. 2012, vol. 30, Edition 5, pp. 291-296, (English a…
[cited by applicant]
First Office Action in CN Application No. CN201910589605.1, Dated Nov. 2, 2022, with English-language translation.
[cited by applicant]
Non-Final Office Action on U.S. Appl. No. 17/371,475 dated Jan. 26, 2023 (12 pages).
[cited by applicant]
Sabbah et al., “Acute Intravenous Infusion of Bendavia (MTP-131), A Novel Mitochondria-Targeting Peptide, Improves Left Ventricular Systolic Function in Dogs With Advanced Heart Failure”, American Heart Association, Abs…
[cited by applicant]
Communication pursuant to Article 94(3) EPC on EP Patent Application No. 19190165.1 dated May 9, 2023 (8 pages).
[cited by applicant]
Final Office Action on U.S. Appl. No. 17/371,475, filed May 23, 2023.
[cited by applicant]
Office Action on JP Patent Application No. 2022-077425 dated May 28, 2023 (4 pages) (with English Translation).
[cited by applicant]
Non-Final Office Action on U.S. Appl. No. 18/454,319 dated May 1, 2024.
[cited by applicant]
Office Action in EP 19190165.1, dated Jun. 25, 2024.
[cited by applicant]
Office Action on CA 2916977 dated Aug. 8, 2024.
[cited by applicant]
Nih, “Ataxia neuropathy spectrum,” 2021, Retrieved from medlineplus.gov/download/genetics/condition/ataxia-neuropathy-spectrum.pdf.
[cited by applicant]
Nih, “POLG Gene,” 2021, Mediline Plus, Retrieved from medlineplus.gov/download/genetics/gene/polg.pdf.
[cited by applicant]
Non-Final Office Action on U.S. Appl. No. 17/963,697 DTD Dec. 4, 2024.
[cited by applicant]
U.S. Appl. No. 18/890,079, filed Sep. 19, 2024, Wilson, T.
[cited by applicant]
Final Office Action on U.S. Appl. No. 18/454,319 DTD Nov. 15, 2024.
[cited by applicant]
Kozarich, et al., “Next generation therapeutics: Looking to the horizon: Editorial overview,” Curr. Opin. Chem. Biol., 1998, vol. 2, Issue 4, pp. 439-440.
[cited by applicant]
Lewis et al. “Biological Phenotypes of Heart Failure With Preserved Ejection Fraction,” Journal of the American College of Cardiology, vol. 70, No. 17 (2017) (pp. 2186-2200).
[cited by applicant]
Lichtenberg, et al., “Liposomes: Preparation, Characterization, and Preservation,” Methods Biochem. Anal., 1998, vol. 33, pp. 337-462.
[cited by applicant]
Liu, et al. “Novel cardiolipin therapeutic protects endothelial mitochondria during renal ischemia and mitigates microvascular rarefaction, inflammation, and fibrosis,” American Journal of Physiology-Renal Physiology, v…
[cited by applicant]
Ma, et al., “Superoxide Flashed Early Mitochondrial Signals for Oxidative Stress-Induced Apoptosis” The Journal of Biological Chemistry, 2011, vol. 286, No. 31, pp. 27573-27581.
[cited by applicant]
Ma, et al., “The Human TAZ Gene Complements Mitochondrial Dysfunction in the Yeast taz1? Mutant: Implications for Barth Syndrome,” 2004, vol. 279, No. 43, pp. 44394-44399.
[cited by applicant]
Makaryan, et al., “The Cellular and Molecular Mechanisms for Neutropenia in Barth Syndrome” European Journal of Haematology, 2011, vol. 88, pp. 195-209.
[cited by applicant]
Martin, et al., “Leigh syndrome associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFS1 gene,” Arch. Neurol., 2005, vol. 62, pp. 659-661.
[cited by applicant]
McHugh, et al., “Sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) in a sibling pair with a homozygous p. A467T POLG mutation,” Muscle Nerve, 2010, vol. 41, No. 2, pp. 265-269.
[cited by applicant]
Menezes, et al., “Peripheral neuropathy associated with mitochondrial disease in children,” Dev. Med. & Child Neurol. 2012, vol. 54, pp. 407-414.
[cited by applicant]
Mizuguchi, et al., “Intratumor administration of fusogenic liposomes containing fragment A of diphtheria toxin suppresses tumor growth.” Cancer Lett., Feb. 26, 1996, vol. 100, Issue 1, pp. 63-69.
[cited by applicant]
Moore et al. “Age-induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge,” Aging Cell, vol. 19 (2020) (pp. 1-18).
[cited by applicant]
Non-Final Office Action in U.S. Appl. No. 14/771,408 dated Aug. 10, 2016.
[cited by applicant]
Non-Final Office Action in U.S. Appl. No. 14/771,411 dated Apr. 27, 2017.
[cited by applicant]
Non-Final Office Action in U.S. Appl. No. 14/771,411 dated Mar. 8, 2019, 15 pages.
[cited by applicant]
Non-Final Office Action in U.S. Appl. No. 15/626,255 dated Jan. 23, 2020.
[cited by applicant]
Notice of Allowance on U.S. Appl. No. 18/454,319 DTD Feb. 28, 2025.
[cited by applicant]