Granted Patent
B2
US 12,629,360 · App. 18/539,823 · Granted May 19, 2026
Ophthalmic composition
Inventors:
Gregory I. Ostrow (San Diego, CA); Kenneth J. Widder (Rancho Santa Fe, CA); David S. Baker (Carlsbad, CA)
Assignee:
SYDNEXIS, INC.
View Patent ↗
Loading inventors, assignments & file history…
Abstract
Provided herein is an ophthalmic composition. In some embodiments, the ophthalmic composition includes a low concentration of an ophthalmic agent for treatment of an ophthalmic disorder or condition; and an ophthalmically acceptable carrier, wherein the ophthalmic agent is distributed with substantial uniformity throughout the ophthalmically acceptable carrier. Further disclosed herein include an ophthalmic composition including a low concentration of an ophthalmic agent and deuterated water. Also disclosed herein are methods of arresting or preventing myopia development by administering to an eye of an individual in need thereof an effective amount of an ophthalmic composition as described herein.
Claims (20)
1 . A stabilized ophthalmic composition for treating pre-myopia, myopia, or progression of myopia, comprising from about 0.001 wt % to about 0.05 wt % of atropine or atropine sulfate, deuterated water, and a buffering agent, wherein the buffering agent has a concentration from about 0.01 w/v % to about 0.08 w/v %.
2 . The stabilized ophthalmic composition of claim 1 , wherein the buffering agent has a buffering capacity sufficient to provide a pD of the solution from about 5.2 to about 7.2.
3 . The stabilized ophthalmic composition of claim 1 , further comprising noratropine, atropine-N-oxide, tropine, tropic acid, hyoscine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof.
4 . The stabilized ophthalmic composition of claim 1 , wherein the atropine or atropine sulfate is present in the composition at a concentration of from about 0.001 wt % to about 0.03 wt %.
5 . The stabilized ophthalmic composition of claim 1 , wherein the atropine or atropine sulfate is present in the composition at a concentration of from about 0.001 wt % to about 0.02 wt %.
6 . The stabilized ophthalmic composition of claim 1 , wherein the buffering agent has a concentration of from about 0.04 w/v % to 0.08 w/v %.
7 . The stabilized ophthalmic composition of claim 1 , wherein the buffering agent comprises an acetate buffering agent, a citrate buffering agent, a carbonate buffering agent, an organic buffering agent, an amino acid buffering agent, or a combination thereof.
8 . The stabilized ophthalmic composition of claim 1 , wherein the buffering agent comprises an acetate buffering agent, a citrate buffering agent, or a combination thereof.
9 . The stabilized ophthalmic composition of claim 1 , wherein the stabilized ophthalmic composition further comprises a tonicity adjusting agent.
10 . The stabilized ophthalmic composition of claim 9 , wherein the tonicity adjusting agent comprises a halide salt of a monovalent cation.
11 . The stabilized ophthalmic composition of claim 1 , further comprising an ophthalmically acceptable viscosity agent.
12 . The stabilized ophthalmic composition of claim 11 , wherein the ophthalmically acceptable viscosity agent comprises hydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxypropylmethyl-cellulose (HPMC).
13 . The stabilized ophthalmic composition of claim 1 , further comprising a preservative.
14 . The stabilized ophthalmic composition of claim 13 , wherein a concentration of the preservative is from about 0.0001% to about 1%.
15 . The stabilized ophthalmic composition of claim 13 , wherein the preservative is selected from benzalkonium chloride, certrimonium, sodium perborate, stabilized oxychloro complex, polyquaternium-1, chlorobutanol, edetate disodium, polydexamethylene biguanide, or combinations thereof.
16 . The stabilized ophthalmic composition of claim 1 , wherein the stabilized ophthalmic composition is essentially free of procaine and benactyzine, or pharmaceutically acceptable salts thereof.
17 . A method of treating the pre-myopia, myopia or progression of myopia in an individual in need thereof, comprising administering to an eye of the individual an effective amount of a stabilized ophthalmic composition comprising from about 0.001 wt % to about 0.05 wt % of atropine or atropine sulfate, deuterated water, and a buffering agent, wherein the buffering agent has a concentration of from about 0.01 w/v % to about 0.08 w/v %.
18 . The method of claim 17 , wherein the stabilized ophthalmic composition is administered topically.
19 . The method of claim 17 , wherein the stabilized ophthalmic composition is administered by instillation.
20 . The method of claim 17 , wherein the stabilized ophthalmic composition is administered through an eye drop bottle containing the stabilized ophthalmic composition.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Dec 28, 2023
From: OSTROW, GREGORY I.; WIDDER, KENNETH J.; BAKER, DAVID S.
To: SYDNEXIS, INC.
Reel/Frame 065975/0717 →
Continuity (11)
Provisional Application
62151926
· Apr 23, 2015
Provisional Application
62096433
· Dec 23, 2014
Provisional Application
62016502
· Jun 24, 2014
References Cited (400)
US 3863633A
· Ryde et al.
· 1975
[cited by applicant]
US 4014335A
· Arnold
· 1977
[cited by applicant]
US 4255415A
· Chrai et al.
· 1981
[cited by applicant]
US 4382124A
· Meitzner et al.
· 1983
[cited by applicant]
US 4474751A
· Haslam et al.
· 1984
[cited by applicant]
US 4852582A
· Pell
· 1989
[cited by applicant]
US 4938763A
· Dunn et al.
· 1990
[cited by applicant]
US 4952586A
· Morris et al.
· 1990
[cited by applicant]
US 4968302A
· Schluter et al.
· 1990
[cited by applicant]
US 5033252A
· Carter
· 1991
[cited by applicant]
US 5052558A
· Carter
· 1991
[cited by applicant]
US 5147647A
· Darougar
· 1992
[cited by applicant]
US 5185372A
· Ushio et al.
· 1993
[cited by applicant]
US 5249712A
· Lontrade et al.
· 1993
[cited by applicant]
US 5259998A
· Reich et al.
· 1993
[cited by applicant]
US 5260000A
· Nandu et al.
· 1993
[cited by applicant]
US 5323907A
· Kalvelage
· 1994
[cited by applicant]
US 5324519A
· Dunn et al.
· 1994
[cited by applicant]
US 5490938A
· Sawan et al.
· 1996
[cited by applicant]
US 5492689A
· Gwaltney, Jr.
· 1996
[cited by applicant]
US 5496471A
· Heyl et al.
· 1996
[cited by applicant]
US 5702716A
· Dunn et al.
· 1997
[cited by applicant]
US 5710182A
· Reunamaki et al.
· 1998
[cited by applicant]
US 5716952A
· Woldemussie et al.
· 1998
[cited by applicant]
US 5744153A
· Yewey et al.
· 1998
[cited by applicant]
US 5840770A
· Hill
· 1998
[cited by applicant]
US 5858375A
· Furminger et al.
· 1999
[cited by applicant]
US 5900360A
· Welch et al.
· 1999
[cited by applicant]
US 5976499A
· Rubenstein et al.
· 1999
[cited by applicant]
US 5990194A
· Dunn et al.
· 1999
[cited by applicant]
US 6139870A
· Verrecchia
· 2000
[cited by applicant]
US 6218428B1
· Chynn et al.
· 2001
[cited by applicant]
US 6270954B1
· Welch et al.
· 2001
[cited by applicant]
US 6410048B1
· Fotinos
· 2002
[cited by applicant]
US 6503497B2
· Chowhan et al.
· 2003
[cited by applicant]
US 6720001B2
· Chen et al.
· 2004
[cited by applicant]
US 7691099B2
· Berry
· 2010
[cited by applicant]
US 7858582B2
· Jin et al.
· 2010
[cited by applicant]
US 8333985B2
· Knaack et al.
· 2012
[cited by applicant]
US 8404271B2
· Byrne et al.
· 2013
[cited by applicant]
US 8414912B2
· Ciolino et al.
· 2013
[cited by applicant]
US 8623400B2
· Liu et al.
· 2014
[cited by applicant]
US 8863998B2
· Painchaud et al.
· 2014
[cited by applicant]
US 8980839B2
· Mitra et al.
· 2015
[cited by applicant]
US 8986266B2
· Painchaud et al.
· 2015
[cited by applicant]
US 9087145B2
· Ballou, Jr. et al.
· 2015
[cited by applicant]
US 9238003B2
· Byrne et al.
· 2016
[cited by applicant]
US 9421199B2
· Ostrow et al.
· 2016
[cited by applicant]
US 9463486B2
· Wilkerson et al.
· 2016
[cited by applicant]
US 9498035B2
· Luk et al.
· 2016
[cited by applicant]
US 9539604B2
· Wilkerson et al.
· 2017
[cited by applicant]
US 9770447B2
· Ostrow et al.
· 2017
[cited by applicant]
US 9827250B2
· Chehab et al.
· 2017
[cited by applicant]
US 20020151598A1
· Banerjee et al.
· 2002
[cited by applicant]
US 20020190079A1
· Hamamoto
· 2002
[cited by applicant]
US 20030157187A1
· Hunter
· 2003
[cited by applicant]
US 20030195179A1
· Sawa
· 2003
[cited by applicant]
US 20040136915A1
· Dugger, III et al.
· 2004
[cited by applicant]
US 20050249770A1
· Hunter
· 2005
[cited by applicant]
US 20050251254A1
· Brady et al.
· 2005
[cited by applicant]
US 20070207192A1
· Holl et al.
· 2007
[cited by applicant]
US 20070254914A1
· Wu et al.
· 2007
[cited by applicant]
US 20080021106A1
· Petit, II et al.
· 2008
[cited by applicant]
US 20080113035A1
· Hunter
· 2008
[cited by applicant]
US 20080153900A1
· Hunter
· 2008
[cited by applicant]
US 20100022495A1
· Hotamisligil et al.
· 2010
[cited by applicant]
US 20100120908A1
· Kimura et al.
· 2010
[cited by applicant]
US 20100196285A1
· Bayerl
· 2010
[cited by applicant]
US 20110076331A1
· Bayerl
· 2011
[cited by applicant]
US 20120028910A1
· Combal et al.
· 2012
[cited by applicant]
US 20120135084A1
· Bayerl
· 2012
[cited by applicant]
US 20120203161A1
· Herekar
· 2012
[cited by applicant]
US 20120225952A1
· Warner et al.
· 2012
[cited by applicant]
US 20120277694A1
· Odrich et al.
· 2012
[cited by applicant]
US 20130303627A1
· Miyano et al.
· 2013
[cited by applicant]
US 20140011761A1
· Hotamisligil et al.
· 2014
[cited by applicant]
US 20140088199A1
· Sharma
· 2014
[cited by applicant]
US 20140350049A1
· Hovnanian et al.
· 2014
[cited by applicant]
US 20150038473A1
· Stein et al.
· 2015
[cited by applicant]
US 20150076174A1
· Mersmann
· 2015
[cited by applicant]
US 20150297800A1
· Weikart et al.
· 2015
[cited by applicant]
US 20160009705A1
· Ostrow et al.
· 2016
[cited by applicant]
US 20160018671A1
· Waite et al.
· 2016
[cited by applicant]
US 20170304152A1
· Hernandez
· 2017
[cited by applicant]
US 20200306239A1
· Ostrow et al.
· 2020
[cited by applicant]
US 20200338060A1
· Ostrow et al.
· 2020
[cited by applicant]
US 20200345542A1
· Ostrow et al.
· 2020
[cited by applicant]
US 20220265631A1
· Ostrow et al.
· 2022
[cited by applicant]
US 20220265632A1
· Ostrow et al.
· 2022
[cited by applicant]
US 20220378775A1
· Ostrow et al.
· 2022
[cited by applicant]
US 20220409603A1
· Ostrow et al.
· 2022
[cited by applicant]
US 20220409604A1
· Ostrow et al.
· 2022
[cited by applicant]
US 20220409605A1
· Ostrow et al.
· 2022
[cited by applicant]
US 20230041788A1
· Ostrow et al.
· 2023
[cited by applicant]
US 20230381016A1
· Ostrow et al.
· 2023
[cited by applicant]
US 20240139166A1
· Ostrow et al.
· 2024
[cited by applicant]
US 20240398705A1
· Ostrow et al.
· 2024
[cited by applicant]
US 20250186251A1
· Ostrow et al.
· 2025
[cited by applicant]
US 20250255810A1
· Ostrow et al.
· 2025
[cited by applicant]
US 20250275983A1
· Ostrow et al.
· 2025
[cited by applicant]
CN 1323595A
· 2001
[cited by applicant]
CN 1456161A
· 2003
[cited by applicant]
CN 101049287A
· 2007
[cited by applicant]
CN 101327216A
· 2008
[cited by applicant]
CN 101468214A
· 2009
[cited by applicant]
DE 1182388B
· 1964
[cited by applicant]
DE 1518819B1
· 1969
[cited by applicant]
EP 0332826A1
· 1989
[cited by applicant]
EP 1998783B1
· 2014
[cited by applicant]
GB 2293100A
· 1996
[cited by applicant]
JP H01203320A
· 1989
[cited by applicant]
JP 2007308398A
· 2007
[cited by applicant]
JP 2012046513A
· 2012
[cited by applicant]
JP 2013189450A
· 2013
[cited by applicant]
JP 2013231067A
· 2013
[cited by applicant]
WO WO1993018764A2
· 1993
[cited by applicant]
WO WO9421298A1
· 1994
[cited by applicant]
WO WO9624331A1
· 1996
[cited by applicant]
WO WO9716192A1
· 1997
[cited by applicant]
WO WO0049990A2
· 2000
[cited by applicant]
WO WO02096418A1
· 2002
[cited by applicant]
WO WO2008005053A1
· 2008
[cited by applicant]
WO WO2008008330A2
· 2008
[cited by applicant]
WO WO2010083129A2
· 2010
[cited by applicant]
WO WO2011019940A2
· 2011
[cited by applicant]
WO WO2011098578A2
· 2011
[cited by applicant]
WO WO2011137449A2
· 2011
[cited by applicant]
WO WO2012111029A2
· 2012
[cited by applicant]
WO WO2012161655A1
· 2012
[cited by applicant]
WO WO2013166385A1
· 2013
[cited by applicant]
WO WO2013167865A1
· 2013
[cited by applicant]
WO WO2014140105A1
· 2014
[cited by applicant]
WO WO2014182620A1
· 2014
[cited by applicant]
WO WO2015200361A1
· 2015
[cited by applicant]
WO WO2016025560A1
· 2016
[cited by applicant]
WO WO2016172712A2
· 2016
[cited by applicant]
WO WO2016196367A1
· 2016
[cited by applicant]
WO WO2016205071A1
· 2016
[cited by applicant]
WO WO2017204262A1
· 2017
[cited by applicant]
WO WO2018154440A1
· 2018
[cited by applicant]
WO WO2018209051A1
· 2018
[cited by applicant]
WO WO2019104191A1
· 2019
[cited by applicant]
WO WO2020087021A1
· 2020
[cited by applicant]
WO WO2021126874A1
· 2021
[cited by applicant]
WO WO2022169959A1
· 2022
[cited by applicant]
WO WO2025212792A1
· 2025
[cited by applicant]
Abak. Pure technology in a bottle. The history of a technological revolution. Laboratoires Thea—12 Rue Louis Bleriot—63017 Clermont Ferrand—France Tel. Retrieved from the Internet: https://www.laboratoires-thea.com/medi…
[cited by applicant]
Abraham et al. Draize rabbit eye test compatibility with eye irritation thresholds in humans: a quantitative structure-activity relationship analysis. Toxicol Sci 76:384-391 (2003).
[cited by applicant]
Akorn Atropine Care™ (Atropine Sulfate Ophthalmic Solution, 1%), Product Label Rev. Jun. 2008.
[cited by applicant]
Akorn Atropine Care™ (atropine sulfate ophthalmic solution), Advertisement Rev. Aug. 2011.
[cited by applicant]
Akorn Atropine Care™ (atropine sulfate ophthalmic solution), NDA 206289 Product Label (Revised Jul. 2014).
[cited by applicant]
Anschel et al., Parenteral Formulation VI: Hydrolytic Degradation of Esters in Parenteral Solutions. Bulletin Of The Parenteral Drug Ass'n 26(6):271-289 (1972).
[cited by applicant]
Application No. 206289Orig1s000 Summary Review, U.S. FDA CTR. for Drug Evaluation & RES. (Jul. 18, 2014).
[cited by applicant]
Atropine sulfate injection 0.5 mg “Tanabe” Pharmaceutical Interview Form, 2007 (English/Machine Translation).
[cited by applicant]
Atropine Sulfate Ophthalmic Solution, Highlights of Prescribing Information, Revised Jul. 2014.
[cited by applicant]
Atropine Sulfate Ophthalmic Solution, Highlights of Prescribing Information, Revised Jul. 2014, Wayback Machine and Affidavit.
[cited by applicant]
Badaro et al. Retinal biocompatibility of brilliant Blue G with deuterated water for chromovitrectomy. J. Ophthalmic and Vision Research 9(2): 204-209 (2014).
[cited by applicant]
Bender et al., Deuterium Oxide Solvent Isotope Effects in the Nucleophilic Reactions of Phenyl Esters. J. Am. Chem. Soc. 84(4):595-599 (1962).
[cited by applicant]
Berton et al., Stability of Ophthalmic Atropine Solutions for Child Myopia Control. Pharmaceutics 12(8):781 (2020).
[cited by applicant]
Blake et al., Studies with Deuterated Drugs. J. Pharm. Sci. 64(3):367-391 (1975).
[cited by applicant]
Brown et al. The Preservation of Ophthalmic Preparations. J. Soc. Cosmetic Chemists 16:369-393 (1965).
[cited by applicant]
Certified English Translation of CN 101049287A.
[cited by applicant]
Chasin et al. Polyanhdrides for Controlled Drug Delivery. Biopharm pp. 33-46 (1988).
[cited by applicant]
Cheng et al. Water movement in the rabbit eye. Exp. Eye Res. 52:337-339 (1991).
[cited by applicant]
Cheng. Fate of water in the soft contact lens immediately after lens placement onto the cornea. Optometry and Vision Science 68(6):414-417 (1991).
[cited by applicant]
Chia et al., Atropine for the Treatment of Childhood Myopia: Changes after Stopping Atropine 0.01%, 0.1% and 0.5%. Am. J. Ophthalmology 157(2):451-457.e1 (2014).
[cited by applicant]
Chia et al., Atropine for the Treatment of Childhood Myopia: Safety and Efficacy of 0.5%, 0.1%, and 0.01% Doses (Atropine for the Treatment of Myopia 2). Ophthalmology 119(2):347-354 (2012).
[cited by applicant]
Chirieri et al. Investigations concerning the changes induced by deuterium for hydrogen substitution in bioelectric activity of the frog retina. Physiologie 14(2):119-123 (1977).
[cited by applicant]
Chowhan et al., Chapter 43: Ophthalmic Preparations, in Remington: The Science and Practice of Pharmacy 907-929 (22nd ed. 2013).
[cited by applicant]
Chua et al., Atropine for the Treatment of Childhood Myopia. Ophthalmology 113(12):2285-2291 (2006).
[cited by applicant]
Criado et al. Scavenging of photogenerated oxidative species by antimuscarinic drugs: atropine and derivatives. Redoc Rep 7(6):385-394 (2002).
[cited by applicant]
Declaration of Dr. Stephen Byrn, Ph. D., dated Feb. 2, 2021 (U.S. Pat. No. 9421199).
[cited by applicant]
Declaration of Dr. Stephen Byrn, Ph. D., dated Jan. 7, 2022 (U.S. Appl. No. 10/888,557).
[cited by applicant]
Declaration of Dr. Stephen Byrn, Ph. D., dated Jan. 7, 2022 (U.S. Appl. No. 10/940,145).
[cited by applicant]
Declaration of Dr. Stephen Byrn, Ph.D., dated Dec. 29, 2021 (U.S. Appl. No. 10/842,787).
[cited by applicant]
Dictionary of Chemistry (McGraw Hill 2nd ed.) (443 pgs) (2003).
[cited by applicant]
Donnelly et al. Physical Compatibility and Chemical Stability of a Concentrated Solution of Atropine Sulfate (2 mg/mL) for Use as an Antidote in Nerve Agent Casualties. Int'l J. Pharm. Compounding 12(6):550-552 (2008).
[cited by applicant]
Douglas et al. Nanoparticles in Drug Delivery. CRC Crit. Rev. Therap. Drug Carr Syst 3:233-261 (1987).
[cited by applicant]
Driver et al., The Stability of Atropine Sulfate Solutions Stored in Plastic Syringes in the Operating Room. Anesth. Analg. 89:1056-1058 (1999).
[cited by applicant]
Drug Repositioning Bringing New Life to Shelved Assets and Existing Drugs pp. 53-64, 291-343 (Michael J. Barratt & Donald E. Frail eds., 2012).
[cited by applicant]
Drugs@FDA: FDA-Approved Drugs: AKORN NDA 206289, U.S. FDA, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overvi ew.process&ApplNo=206289.
[cited by applicant]
Fang et al. Prevention of Myopia Onset with 0.025% Atropine in Premyopic Children. Journal of Ocular Pharmacology and Therapeutics 26(4):341-345 (2010).
[cited by applicant]
Filed Application of U.S. Pat. No. 9,421,199, May 29, 2015.
[cited by applicant]
Fletcher et al. The effect of solution tonicity on the eye. Clin. & Exp. Optom. 76.1:17-21 (1993).
[cited by applicant]
Florence. Chapter 3: Physicochemical properties of drugs in solution. Physiochemical Principles of Pharmacy pp. 56-92 (4th ed. 2006).
[cited by applicant]
Food Drug Administration Center for Drugs Evaluation Research Guidance For Industry: Drug Stability Guidelines (Dec. 9, 2008).
[cited by applicant]
Foster et al. Deuterium isotope effects in the metabolism of drugs and xenobiotics: implications for drug design. Adv Drug Res 14:1-36 (1985).
[cited by applicant]
Ganea. Heavy water effect on certain energetic processes in retina. Physiologie 6(1):59-62 (1979).
[cited by applicant]
Ganesan et al. Pharmaceutical intervention for myopia control. Expert Rev Ophthalmol 5(6):759-787 (2010).
[cited by applicant]
Gant. Using Deuterium in Drug Discovery: Leaving the Label in the Drug. J. Med. Chem. 57(9):3595-3611 (2014).
[cited by applicant]
Garcia-Valldecabres et al. pH Stability of ophthalmic solutions. Optometry 75(3):161-168 (2004).
[cited by applicant]
Garcia-Valldecabres et al. pH Stability of ophthalmic solutions. Optometry 75(3):161-168 (2004) (Abstract only).
[cited by applicant]
Gettings et al. A comparison of low vol. Draize and in vitro eye irritation test data. III. Surfactant-based formulations. Food Chem Toxicol 36(3):209-231 (1998).
[cited by applicant]
Glasoe et al. Use of glass electrodes to measure acidities in deuterium oxide. Journal of Physical Chemistry.64:188-190 (1960).
[cited by applicant]
Guidance for Industry: Q1A (R2) Stability Testing of New Drug Substances and Products. U.S. Department of Health and Human Services, Food and Drug Administration. Retrieved from the internet http://fda.gov/downloads/dru…
[cited by applicant]
Handbook of Pharmaceutical Excipients 5-7, 193-196, 281-284, 351-352, 741-742, 984-989 (Raymond C. Rowe et al. eds., 7th ed. 2012).
[cited by applicant]
Hanson et al., A Mechanistic and Kinetic Study of the E-Ring Hydrolysis and Lactonization of a Novel Phosphoryloxymethyl Prodrug of Camptothecin. Pharm. Research 20(7):1031-1038 (2003).
[cited by applicant]
HOWARD. Chapter 17: Special Solutions and Suspensions. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. p. 607 (Dec. 2013).
[cited by applicant]
Hui et al. In vitro release of two anti-muscarinic drugs from soft contact lenses. Clin Ophthalmol 11:1657-1665 (2017).
[cited by applicant]
Januschowski et al. Evaluating retinal toxicity of a new heavy intraocular dye, using a model of perfused and isolated retinal cultures of bovine and human origins. Graefes Arch Clin Exp Ophthalmol. 250:1013-1022 (2012).
[cited by applicant]
Jencks et al. General Base Catalysis of Ester Hydrolysis. J. Am. Chem. Soc. 83(7):1743-50 (1961).
[cited by applicant]
Jeong et al. Biodegradable block copolymers as injectable drug-delivery systems. Nature 388(6645):860-862 (1997).
[cited by applicant]
Jeong et al. Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers. J Control Release 63(1-2):155-163 (2000).
[cited by applicant]
Jeong et al. Thermosensitive sol-gel reversible hydrogels. Advanced Drug Delivery Reviews 54:37-51 (2002).
[cited by applicant]
Jiang Qiaoxi. Characteristics and Preparation of Dosage Forms of Ophthalmic Drugs. The Journal of Pharmacy 5(3-4):123-133 (1989).
[cited by applicant]
Kirchhoff et al., Analysis of atropine, its degradation products and related substances of natural origin by means of reversed-phase high-performance liquid chromatography. J. Chromatography A 1046:115-120 (2004).
[cited by applicant]
Kondritzer et al. Stability of Atropine in Aqueous Solution. J. Am. Pharm. Ass'n 46(9):531-535 (1957).
[cited by applicant]
Kresge. Solvent Isotope Effect in H2O-D2O Mixtures. Pure Appl. Chem. 8(3-4):243-258 (1964).
[cited by applicant]
Krezel et al. A formula for correlating pKa values determined in D2O and H2O. Journal of Inorganic Chemistry 98:161-166 (2008).
[cited by applicant]
Krumbiegel. Large deuterium isotope effects and their use: a historical review. Isotopes in Environmental and Health Studies 47(1):1-17 (2011).
[cited by applicant]
Kushner et al. Pharmacological uses and perspective of heavy water and deuterated compounds. Canadian Journal of Physiology and Pharmacology 77(2):79-88 (1999).
[cited by applicant]
Lachkar et al. Drug-induced acute angle closure glaucoma. Curr Opin Ophthalmol. 18(2):129-33 (2007).
[cited by applicant]
Lai et al. Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. PNAS USA 104(5):1482-1487 (2007).
[cited by applicant]
Lallemand et al., Successfully Improving Ocular Drug Delivery Using the Cationic Nanoemulsion. Novasorb. J. Drug Delivery 2012:1-16 (2012).
[cited by applicant]
Lee et al., Prevention of Myopia Progression with 0.05% Atropine Solution. J Ocul Pharmacol Ther. 22(1):41-46 (2006).
[cited by applicant]
Li. Preparation and Quality Control of 0.04% Atropine Sulfate Eye Drops. China Pharmacy 17(2):111-113 (2006) (English Translation).
[cited by applicant]
Lin et al., Formulation and stability of an extemporaneous 0.02% chlorhexidine digluconate ophthalmic solution. J. Formosan Med. Ass'n 114:1162-1169 (2015).
[cited by applicant]
Lund et al. The Kinetics of atropine and apoatropine in aqueous solutions. ACTA Chemica Scandinavica 22:3085-3097 (1968).
[cited by applicant]
Mair et al. The Detection of Atropine and Its Degradation Products by Thin-Layer Chromatography. J. Clin. Pharm. 2:101-104 (1977).
[cited by applicant]
Mcbrien et al., Point-Counterpoint. How does atropine exert its anti-myopia effects? Ophthalmic & Physiol Opt. 33:373-378 (2013).
[cited by applicant]
Mccall et al. Mechanisms of corneal tissue cross-linking in response to treatment with topical riboflavin and long-wavelength ultraviolet radiation (UVA). Investigative Ophthalmology & Visual Science 51(1):129-138 (2010…
[cited by applicant]
Minor et al. One-Proton Solvation Bridge in Intramolecular Carboxylate Catalysis of Ester Hydrolysis. J. Am. Chem. Soc. 95(7):2279-2281 (1973).
[cited by applicant]
Miyazaki. Eye-drop. Nihon, Nanzando Co., Ltd., Oct. 20, 1962.
[cited by applicant]
Mullins et al. Pharmaceutical Necessities and Ophthalmic Preparations, in Remington: The Science and Practice of Pharmacy, vol. II 1380-1416, 1563-1576 (Alfonso R. Gennaro ed., 19th ed. 1995).
[cited by applicant]
Mullins et al. Tonicity, Osmoticity, Osmolality and Osmolarity and Stability of Pharmaceutical Products, in Remington: The Science and Practice of Pharmacy, vol. I 613-627, 639-647 (Alfonso R. Gennaro ed., 19th ed. 1995…
[cited by applicant]
NCT02130167. Low Concentration atropine for Myopia Progression in school Children. ClinicalTrials.gov archive (3 pgs) (Jan. 29, 2018).
[cited by applicant]
Nee. The Use of Deuterium Oxide to Stabilize Pharmaceuticals Against Chemical Degradation. SlideServe—Theophilus Stavros. Retrieved from the Internet: URL:https://www.slideserve.com/theophilus-stavros/the-use-of-deuteri…
[cited by applicant]
Obata et al. Deuterium magnetic resonance imaging of rabbit eye in Vivo. Magnetic Resonance in Medicine.33(4):569-572 (1995).
[cited by applicant]
Obata et al. Deuterium MR in vivo imaging of the rat eye using 2H2O. Acta Radiologica,36:552-555 (1995).
[cited by applicant]
Obridge Koichi. Eyedrop New Insight, eyedrop—common send, common sense—General knowledge, Co. Ltd. Jul. 10, 1997 (pp. 9-14 and 166-121).
[cited by applicant]
O'Driscoll. Heavyweight drugs. Chem. & Indus. 24-26 (2009).
[cited by applicant]
Parmar et al. The solution, solid state stability and kinetic investigation in degradation studies of lercanidipine: study of excipients compatibility of lercanidipine. Pharm. Dev. Technol. 17(6):730-740 (2011).
[cited by applicant]
Patel et al., Ophthalmic Drug Delivery System: Challenges and Approaches. Systematic Reviews In Pharmacy 1(2):113-120 (2010).
[cited by applicant]
PCT/US2015/037249 International Search Report and Written Opinion dated Sep. 30, 2015.
[cited by applicant]
PCT/US2016/029222 International Search Report and Written Opinion dated Oct. 21, 2016.
[cited by applicant]
PCT/US2016/034823 International Search Report and Written Opinion dated Aug. 23, 2016.
[cited by applicant]
PCT/US2018/062279 International Search Report and Written Opinion dated Feb. 1, 2019.
[cited by applicant]
PCT/US2020/065149 International Search Report and Written Opinion dated Mar. 22, 2021.
[cited by applicant]
PCT/US2022/015092 International Search Report and Written Opinion dated May 30, 2022.
[cited by applicant]
Pfannkoch. Chapter 3: The Preparation of Buffers and Other Solutions: A Chemist's Perspective. Molecular Biology Problem Solver: A Laboratory Guide pp. 31-47 (Alan S. Gerstein ed., 2001).
[cited by applicant]
U.S. Appl. No. 60/016,502, filed Jun. 24, 2014.
[cited by applicant]
U.S. Appl. No. 62/096,433, filed Dec. 23, 2014.
[cited by applicant]
Rajpal et al., Bromfenac ophthalmic solution for the treatment of postoperative ocular pain and inflammation: safety, efficacy, and patient adherence. Patient Prefer Adherence 8:925-31 (2014).
[cited by applicant]
Richard et al. Effects of sterilizing-grade filters on the physico-chemical properties of onion-like vesicles. Int J Pharm 312(1-2):144-150 (2006).
[cited by applicant]
Rubinson. Practical corrections for p(H,D) measurements in mixed H2O/D2O biological buffers. Anal. Methods 9:2744-2750 (2017).
[cited by applicant]
Sadeghi-Hashjin et al. Effects of Selected Antimuscarinic Agents on the Intra-Ocular Pressure in Healthy Rabbits. Journal of Pharmacology and Toxicology 3(5):382-385 (2008).
[cited by applicant]
Sasuki et al. Medicine and dosage regimen in the ophthalmic region, Pharmaceutical Journal Co., Ltd., pp. 134-135 (2009).
[cited by applicant]
Schier et al., Preparing for Chemical Terrorism: Stability of Injectable Atropine Sulfate. Acad. Emerg. Med. 11(4):329-334 (2004).
[cited by applicant]
Schowen. Chapter 6: Solvent Hydrogen Isotope Effects, Transition States of Biochem Processes pp. 25-283 (Richard D. Gandour & Richard L. Schowen eds., 1978).
[cited by applicant]
Schubert et al., Sterility of Anesthetic Multiple-Dose Vials after Opening. Anesthesiology 62:634-636 (1985).
[cited by applicant]
Sen et al., Role of heavy water in biological sciences with an emphasis on thermostabilization of vaccines. Expert Rev. Vaccines 8(11):1587-1602 (2009).
[cited by applicant]
Sharma et al. A quantitative NMR protocol for the simultaneous analysis of atropine and obidoxime in parenteral injection devices. J Pharm Biomed Anal 49(4):1092-1096 (2009).
[cited by applicant]
Shih et al., An intervention trial on efficacy of atropine and multi-focal glasses in controlling myopic progression. Acta Ophthalmologica Scandinavica 79:233-236 (2001).
[cited by applicant]
Shih et al., Effects of Different Concentrations of Atropine on Controlling Myopia in Myopic Children. J Ocul Pharmacol Ther. 15(1):85-90 (1999).
[cited by applicant]
Shizhen Wang. Molecular Nuclear Medicine, Peking Union Medical College Press, the 1st Edition, Apr. 2004, p. 417, lines 9-10, published on Apr. 30, 2004.
[cited by applicant]
Siegel et al. Stability of procaine in deuterium oxide. J Pharm Sci 53:978-979 (1964).
[cited by applicant]
Sodium Phosphate Dibasic, Anhydrous Material Safety Data Sheet, Scholar Chem. (Jan. 23, 2009).
[cited by applicant]
Sodium phosphate monobasic Safety Data Sheet, Version 1.1, G-BIOSCIS. (Jan. 9, 2012).
[cited by applicant]
Stefanidis et al., General Base Catalysis of Ester Hydrolysis. J. Am. Chem. Soc. 115:6045-6050 (1993).
[cited by applicant]
Susina et al., Effect of Deuterium Oxide on Local Anesthetic Activity of Procaine. J. Pharm. Sci. 51(12):1166-1169 (1962).
[cited by applicant]
Taktak et al. Assay of Pyrogens by Interleukin-6 Release from Monocytic Cell Lines. J. Pharm. Pharmacol. 43:578-582 (1991).
[cited by applicant]
Taylor et al. A critical appraisal of drug stability testing methods. Pharm. Res. 4(3):177-80 (1987).
[cited by applicant]
The U. S. Food and Drug Administration has provided regulatory guidance in the publication: Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing. Available at: http://www.fda.gov/cder/guidance/588…
[cited by applicant]
Timmins. Deuterated drugs; where are we now? Expert Opin. Ther. Pat. 24(10):1067-1075 (2014).
[cited by applicant]
Unknown. Modern Physical Organic Chemistry. Notes Chapter 8 (2) Under the isotope effect. Available at https://www.zhihu.com/tardis/sogou/art/163777237 (Edited 2020).
[cited by applicant]
U.S. Pat. No. 10,076,515 Decision Denying Institution of Inter Partes Review dated Nov. 7, 2022 (Case No. IPR2022-00965).
[cited by applicant]
U.S. Pat. No. 10,076,515 File History.
[cited by applicant]
U.S. Pat. No. 10,076,515 Non-Final Rejection Nov. 24, 2017.
[cited by applicant]
U.S. Pat. No. 10,076,515 Notice of Allowance May 24, 2018.
[cited by applicant]
U.S. Pat. No. 10,076,515 Patent Owner's Preliminary Response dated Aug. 11, 2022 (Case No. IPR2022-00965).
[cited by applicant]
U.S. Pat. No. 10,076,515 Petition for Inter Partes Review dated Mar. 3, 2021 (Case No. IPR2021-00441).
[cited by applicant]
U.S. Pat. No. 10,076,515 Petition for Inter Partes Review dated May 3, 2022 (Case No. IPR2022-00965).
[cited by applicant]
U.S. Pat. No. 10,076,515 Terminal Disclaimer.
[cited by applicant]
U.S. Pat. No. 10,201,534 Decision Denying Institution of Inter Partes Review dated Nov. 7, 2022 (Case No. IPR2022-00966).
[cited by applicant]
U.S. Pat. No. 10,201,534 File History.
[cited by applicant]
U.S. Pat. No. 10,201,534, Non-Final Rejection, Aug. 8, 2018.
[cited by applicant]
U.S. Pat. No. 10,201,534, Notice of Allowance, Sep. 25, 2018.
[cited by applicant]
U.S. Pat. No. 10,201,534 Patent Owner's Preliminary Response dated Aug. 11, 2022 (Case No. IPR2022-00966).
[cited by applicant]
U.S. Pat. No. 10,201,534 Petition for Inter Partes Review dated Mar. 18, 2021 (Case No. IPR2021-00442).
[cited by applicant]
U.S. Pat. No. 10,201,534 Petition for Inter Partes Review dated May 3, 2022 (Case No. IPR2022-00966).
[cited by applicant]
U.S. Pat. No. 10,251,875 File History.
[cited by applicant]
U.S. Pat. No. 10,842,787 Decision dated Jul. 15, 2022 (Case No. IPR2022-00384).
[cited by applicant]
U.S. Pat. No. 10,842,787 File History.
[cited by applicant]
U.S. Pat. No. 10,842,787 Judgement—Final Written Decision Denying Patent Owner's Motion to Exclude Determining All Challenged Claims Unpatentable 35 USC § 318(a) dated Jul. 13, 2023 (Case No. IPR2022-00384) (Paper No. 3…
[cited by applicant]
U.S. Pat. No. 10,842,787 Petition for Inter Partes Review dated Dec. 29, 2021 (Case No. IPR2022-00384).
[cited by applicant]
U.S. Pat. No. 10,888,557 Decision dated Jul. 15, 2022 (Case No. IPR2022-00415).
[cited by applicant]
U.S. Pat. No. 10,888,557 File History.
[cited by applicant]
U.S. Pat. No. 10,888,557 Judgement—Final Written Decision Denying Patent Owner's Motion to Exclude Determining All Challenged Claims Unpatentable 35 USC § 318(a) dated Jul. 13, 2023 (Case No. IPR2022-00415) (Paper No. 3…
[cited by applicant]
U.S. Pat. No. 10,888,557 Petition for Inter Partes Review dated Jan. 7, 2022 (Case No. IPR2022-00415).
[cited by applicant]
U.S. Pat. No. 10,940,145 Decision dated Jul. 15, 2022 (Case No. IPR2022-00414).
[cited by applicant]
U.S. Pat. No. 10,940,145 File History.
[cited by applicant]
U.S. Pat. No. 10,940,145 Judgement—Final Written Decision Denying Patent Owner's Motion to Exclude Determining All Challenged Claims Unpatentable 35 USC § 318(a) dated Jul. 13, 2023 (Case No. IPR2022-00414) (Paper No. 3…
[cited by applicant]
U.S. Pat. No. 10,940,145 Petition for Inter Partes Review dated Jan. 7, 2022 (Case No. IPR2022-00414).
[cited by applicant]
U.S. Pat. No. 9,421,199 Decision Denying Institution of Inter Partes Review dated Nov. 8, 2022 (Case No. IPR2022-00963).
[cited by applicant]
U.S. Pat. No. 9,421,199 File History.
[cited by applicant]
U.S. Pat. No. 9,421,199, Interview Summary, Apr. 13, 2016.
[cited by applicant]
U.S. Pat. No. 9,421,199, Non-Final Rejection, Mar. 7, 2016.
[cited by applicant]
U.S. Pat. No. 9,421,199, Notice of Allowance, Jun. 13, 2016.
[cited by applicant]
U.S. Pat. No. 9,421,199 Patent Owner's Preliminary Response dated Aug. 11, 2022 (Case No. IPR2022-00963).
[cited by applicant]
U.S. Pat. No. 9,421,199 Petition for Inter Partes Review dated Feb. 3, 2021 (Case No. IPR2021-00439).
[cited by applicant]
U.S. Pat. No. 9,421,199 Petition for Inter Partes Review dated May 3, 2022 (Case No. IPR2022-00963).
[cited by applicant]
U.S. Pat. No. 9,421,199, Response to Non-Final Rejection, Apr. 5, 2016.
[cited by applicant]
U.S. Pat. No. 9,770,447, Advisory Action, Apr. 13, 2017.
[cited by applicant]
U.S. Pat. No. 9,770,447, AFCP2.0 Response to Final Office Action Dated and Advisory Action, Apr. 21, 2017.
[cited by applicant]
U.S. Pat. No. 9,770,447, Certificate of Correction.
[cited by applicant]
U.S. Pat. No. 9,770,447 Decision Denying Institution of Inter Partes Review dated Nov. 7, 2022 (Case No. IPR2022-00964).
[cited by applicant]
U.S. Pat. No. 9,770,447 File History.
[cited by applicant]
U.S. Pat. No. 9,770,447, Final Rejection, Jan. 25, 2017.
[cited by applicant]
U.S. Pat. No. 9,770,447, Information Disclosure Statement and International Search Report, Nov. 17, 2016.
[cited by applicant]
U.S. Pat. No. 9,770,447, Non-Final Office Action, Sep. 30, 2016.
[cited by applicant]
U.S. Pat. No. 9,770,447, Notice of Allowance, May 30, 2017.
[cited by applicant]
U.S. Pat. No. 9,770,447 Patent Owner's Preliminary Response dated Aug. 11, 2022 (Case No. IPR2022-00964).
[cited by applicant]
U.S. Pat. No. 9,770,447 Petition for Inter Partes Review dated Feb. 17, 2021 (Case No. IPR2021-00440).
[cited by applicant]
U.S. Pat. No. 9,770,447 Petition for Inter Partes Review dated May 3, 2022 (Case No. IPR2022-00964).
[cited by applicant]
U.S. Pat. No. 9,770,447, Preliminary Amendment and Response to Notice to File Missing Parts, Aug. 3, 2013.
[cited by applicant]
U.S. Pat. No. 9,770,447, Response to Final Office Action, Mar. 21, 2017.
[cited by applicant]
U.S. Appl. No. 14/859,042 Office Action dated May 18, 2017.
[cited by applicant]
U.S. Appl. No. 14/859,042 Office Action dated Oct. 25, 2016.
[cited by applicant]
U.S. Appl. No. 15/208,537 Office Action dated Jan. 25, 2017.
[cited by applicant]
U.S. Appl. No. 15/208,537 Office Action dated Sep. 30, 2016.
[cited by applicant]
U.S. Appl. No. 15/568,381 Office Action dated Apr. 16, 2020.
[cited by applicant]
U.S. Appl. No. 15/568,381 Office Action dated Apr. 3, 2019.
[cited by applicant]
U.S. Appl. No. 15/568,381 Office Action dated Nov. 22, 2019.
[cited by applicant]
U.S. Appl. No. 15/578,202 Office Action dated Jan. 3, 2020.
[cited by applicant]
U.S. Appl. No. 15/578,202 Office Action dated Jan. 7, 2021.
[cited by applicant]
U.S. Appl. No. 15/578,202 Office Action dated Jun. 1, 2020.
[cited by applicant]
U.S. Appl. No. 15/578,202 Office Action dated Jun. 28, 2019.
[cited by applicant]
U.S. Appl. No. 15/661,816 Office Action dated Nov. 24, 2017.
[cited by applicant]
U.S. Appl. No. 15/895,933 Office Action dated Aug. 9, 2018.
[cited by applicant]
U.S. Appl. No. 16/224,286 Ex Parte Quayle dated Jun. 24, 2020.
[cited by applicant]
U.S. Appl. No. 16/224,286 Office Action dated Dec. 23, 2019.
[cited by applicant]
U.S. Appl. No. 16/677,538 Office Action dated Jan. 13, 2020.
[cited by applicant]
U.S. Appl. No. 16/765,144 Office Action dated Feb. 2, 2023.
[cited by applicant]
U.S. Appl. No. 16/765,144 Office Action dated Mar. 29, 2022.
[cited by applicant]
U.S. Appl. No. 16/765,144 Office Action dated Sep. 2, 2022.
[cited by applicant]
U.S. Appl. No. 16/785,411 Office Action dated Dec. 14, 2020.
[cited by applicant]
U.S. Appl. No. 16/785,411 Office Action dated Jan. 24, 2022.
[cited by applicant]
U.S. Appl. No. 16/785,411 Office Action dated Jun. 23, 2020.
[cited by applicant]
U.S. Appl. No. 16/785,411 Office Action dated Jun. 28, 2021.
[cited by applicant]
U.S. Appl. No. 16/785,411 Office Action dated Mar. 28, 2023.
[cited by applicant]
U.S. Appl. No. 16/785,411 Office Action dated Sep. 9, 2022.
[cited by applicant]
U.S. Appl. No. 16/785,413 Office Action dated Aug. 3, 2020.
[cited by applicant]
U.S. Appl. No. 16/785,416 Office Action dated Aug. 3, 2020.
[cited by applicant]
U.S. Appl. No. 16/785,418 Office Action dated Aug. 3, 2020.
[cited by applicant]
U.S. Appl. No. 16/805,612, Information Disclosure Statement, Mar. 2, 2020.
[cited by applicant]
U.S. Appl. No. 16/805,612 Office Action dated May 15, 2020.
[cited by applicant]
U.S. Appl. No. 16/805,612 Office Action dated Nov. 23, 2020.
[cited by applicant]