Granted Patent
B2
US 12,397,039 · App. 17/431,059 · Granted Aug 26, 2025
Compositions and methods for the treatment of ocular neovascularization
Assignee:
NOVALIQ GMBH
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The present invention relates to a non-aqueous ophthalmic composition comprising particles of a protein powder preparation suspended in a liquid vehicle comprising a semifluorinated alkane, wherein the particles of the protein powder preparation comprise an anti-VEGF protein selected from aflibercept or a sequence having at least 90% sequence identity to SEQ ID NO: 1. The composition is particularly suitable for the treatment of ocular neovascularization.
Claims (14)
1. A method of treatment of corneal neovascularization and/or corneal angiogenesis, comprising administering a non-aqueous topical ophthalmic composition topically to the eye or an ophthalmic tissue of a subject in need thereof, wherein the composition comprises particles of a protein powder preparation suspended in a liquid vehicle comprising a semifluorinated alkane, wherein the particles of the protein powder preparation comprise aflibercept.
2. The method according to claim 1 , wherein the particles of the protein powder preparation are obtained by spray-drying or lyophilization of an aqueous composition comprising the aflibercept.
3. The method according to claim 1 , wherein the particles of the protein powder preparation further comprise one or more protein stabilizing agents selected from polyols, sugars, amino acids, amines and salting out salts, polymers, surfactants, and arginine.
4. The method according to claim 1 , wherein the concentration of the aflibercept in the composition is between about 1 to 60 mg/ml, or about 5 mg/ml.
5. The method according to claim 1 , wherein the size of 90% of the suspended particles of the protein powder preparation is between 1 to 100 μm, as measured by laser diffraction.
6. The method according to claim 1 , wherein the semifluorinated alkane is selected from F4H4, F4H5, F4H6, F6H4, F6H6, F6H8, and F8H8.
7. The method according to claim 1 , wherein the method is for the treatment of ocular neovascularization.
8. The method according to claim 1 , wherein the method provides inhibition of growth of blood vessels and/or lymphatic vessels.
9. The method according to claim 1 , wherein the method is for the treatment of and/or corneal angiogenesis.
10. The method according to claim 1 , wherein the subject is undergoing corneal transplantation.
11. The method according to claim 1 , wherein the particles of the protein powder preparation further comprise one or more protein stabilizing agents selected from sugars.
12. The method according to claim 11 , wherein the sugar is sucrose.
13. The method according to claim 1 , wherein the semifluorinated alkane is F6H8.
14. The method according to claim 1 , wherein the concentration of the aflibercept in the composition is between about 1 to 25 mg/ml, the semifluorinated alkane is F6H8, and wherein the particles of the protein powder preparation further comprise one or more protein stabilizing agents comprising sucrose.
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 24, 2022
From: WITT, MADLEN
To: NOVALIQ GMBH
Reel/Frame 058743/0996 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 24, 2022
From: CURSIEFEN, CLAUS; BOCK, FELIX
To: UNIVERSITÄT ZU KÖLN
Reel/Frame 058744/0023 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 24, 2022
From: UNIVERSITÄT ZU KÖLN
To: NOVALIQ GMBH
Reel/Frame 058744/0054 →
Priority Claims (2)
EP 19156934
· Feb 13, 2019
· regional
EP 19171487
· Apr 29, 2019
· regional
Continuity (1)
References Cited (340)
US 2616927A
· Kauck et al.
· 1952
[cited by applicant]
US 4452818A
· Haidt
· 1984
[cited by applicant]
US 5077036A
· Long, Jr.
· 1991
[cited by applicant]
US 5152997A
· Ebert et al.
· 1992
[cited by applicant]
US 5254338A
· Sakai et al.
· 1993
[cited by applicant]
US 5326566A
· Parab
· 1994
[cited by applicant]
US 5336175A
· Mames
· 1994
[cited by applicant]
US 5370313A
· Beard
· 1994
[cited by applicant]
US 5518731A
· Meadows
· 1996
[cited by applicant]
US 5667809A
· Trevino
· 1997
[cited by applicant]
US 5851544A
· Penska et al.
· 1998
[cited by applicant]
US 5874469A
· Maniar et al.
· 1999
[cited by applicant]
US 5874481A
· Weers
· 1999
[cited by applicant]
US 5904933A
· Riess et al.
· 1999
[cited by applicant]
US 5980936A
· Krafft et al.
· 1999
[cited by applicant]
US 5981607A
· Ding
· 1999
[cited by applicant]
US 6042845A
· Sun et al.
· 2000
[cited by applicant]
US 6060085A
· Osborne
· 2000
[cited by applicant]
US 6113919A
· Cronelus
· 2000
[cited by applicant]
US 6140374A
· May et al.
· 2000
[cited by applicant]
US 6159977A
· Reeves
· 2000
[cited by applicant]
US 6177477B1
· George et al.
· 2001
[cited by applicant]
US 6197323B1
· Georgieff
· 2001
[cited by applicant]
US 6224887B1
· Samour et al.
· 2001
[cited by applicant]
US 6262126B1
· Meinert
· 2001
[cited by applicant]
US 6264990B1
· Knepp et al.
· 2001
[cited by applicant]
US 6294563B1
· Garst
· 2001
[cited by applicant]
US 6335335B2
· Higashiyama
· 2002
[cited by applicant]
US 6372243B2
· Kobuch et al.
· 2002
[cited by applicant]
US 6391879B1
· Reeves
· 2002
[cited by applicant]
US 6399087B1
· Zhang et al.
· 2002
[cited by applicant]
US 6458376B1
· Meadows
· 2002
[cited by applicant]
US 6486212B2
· Meinert
· 2002
[cited by applicant]
US 6489367B1
· Meinert
· 2002
[cited by applicant]
US 6528086B2
· Zhang
· 2003
[cited by applicant]
US 6730328B2
· Maskiewicz
· 2004
[cited by applicant]
US 7001607B1
· Menz
· 2006
[cited by applicant]
US 7026359B1
· Gross
· 2006
[cited by applicant]
US 7087237B2
· Peyman
· 2006
[cited by applicant]
US 7258869B1
· Berry
· 2007
[cited by applicant]
US 7608261B2
· Furfine et al.
· 2009
[cited by applicant]
US 7687455B2
· Bonnet et al.
· 2010
[cited by applicant]
US 7740875B2
· Dechow
· 2010
[cited by applicant]
US 8029977B2
· Meinert et al.
· 2011
[cited by applicant]
US 8222292B2
· Goskonda et al.
· 2012
[cited by applicant]
US 8470873B2
· Chen
· 2013
[cited by applicant]
US 8614178B2
· Theisinger et al.
· 2013
[cited by applicant]
US 8759281B2
· Bonnet et al.
· 2014
[cited by applicant]
US 8796340B2
· Theisinger et al.
· 2014
[cited by applicant]
US 8865131B2
· Hagedorn et al.
· 2014
[cited by applicant]
US 8916157B2
· Krause et al.
· 2014
[cited by applicant]
US 8916158B2
· Krause et al.
· 2014
[cited by applicant]
US 8986738B2
· Meinert
· 2015
[cited by applicant]
US 9000048B2
· Mecozzi et al.
· 2015
[cited by applicant]
US 9072668B2
· Dai et al.
· 2015
[cited by applicant]
US 9241900B2
· Wilson
· 2016
[cited by applicant]
US 9308262B2
· Wilson
· 2016
[cited by applicant]
US 9446026B2
· Bingaman et al.
· 2016
[cited by applicant]
US 9757459B2
· Theisinger et al.
· 2017
[cited by applicant]
US 9757460B2
· Günther et al.
· 2017
[cited by applicant]
US 9770508B2
· Günther et al.
· 2017
[cited by applicant]
US 9968678B2
· Theisinger et al.
· 2018
[cited by applicant]
US 9982032B2
· Park et al.
· 2018
[cited by applicant]
US RE50060E
· Graf et al.
· 2024
[cited by applicant]
US 20020004063A1
· Zhang
· 2002
[cited by applicant]
US 20020198266A1
· Meinert
· 2002
[cited by applicant]
US 20030018044A1
· Peyman
· 2003
[cited by applicant]
US 20030027833A1
· Cleary et al.
· 2003
[cited by applicant]
US 20030170194A1
· Piotrowiak
· 2003
[cited by applicant]
US 20040044045A1
· Burk
· 2004
[cited by applicant]
US 20040101551A1
· Selzer
· 2004
[cited by applicant]
US 20040265362A1
· Susilo
· 2004
[cited by applicant]
US 20050075407A1
· Tamarkin et al.
· 2005
[cited by applicant]
US 20050079210A1
· Gupta
· 2005
[cited by applicant]
US 20050175541A1
· Lanza et al.
· 2005
[cited by applicant]
US 20050288196A1
· Horn
· 2005
[cited by applicant]
US 20060009522A1
· Dana et al.
· 2006
[cited by applicant]
US 20060078580A1
· Dechow
· 2006
[cited by applicant]
US 20080019926A1
· Krafft et al.
· 2008
[cited by applicant]
US 20080050335A1
· Faour et al.
· 2008
[cited by applicant]
US 20080089923A1
· Burkstrand et al.
· 2008
[cited by applicant]
US 20080112895A1
· Kottayil et al.
· 2008
[cited by applicant]
US 20080207537A1
· Turner et al.
· 2008
[cited by applicant]
US 20080254106A1
· Bell
· 2008
[cited by applicant]
US 20080260656A1
· Mallard
· 2008
[cited by applicant]
US 20090136430A1
· Dugger
· 2009
[cited by applicant]
US 20100006600A1
· Dascanio
· 2010
[cited by applicant]
US 20100189765A1
· Erickson et al.
· 2010
[cited by applicant]
US 20110223208A1
· Hill et al.
· 2011
[cited by applicant]
US 20110269704A1
· Seigfried
· 2011
[cited by applicant]
US 20130309226A1
· Armstrong et al.
· 2013
[cited by applicant]
US 20140004197A1
· Theisinger et al.
· 2014
[cited by applicant]
US 20140186350A1
· Ghosh et al.
· 2014
[cited by applicant]
US 20150174096A1
· Bottger et al.
· 2015
[cited by applicant]
US 20160000941A1
· Keller et al.
· 2016
[cited by applicant]
US 20170087100A1
· Scherer et al.
· 2017
[cited by applicant]
US 20170348285A1
· Hellstron
· 2017
[cited by applicant]
US 20180360908A1
· Beier et al.
· 2018
[cited by applicant]
US 20190256591A1
· Günther et al.
· 2019
[cited by applicant]
US 20190328717A1
· Günther et al.
· 2019
[cited by applicant]
US 20190343793A1
· Günther et al.
· 2019
[cited by applicant]
US 20210121471A1
· Löscher et al.
· 2021
[cited by applicant]
US 20210315832A1
· Scherer et al.
· 2021
[cited by applicant]
US 20210346313A1
· Beier et al.
· 2021
[cited by applicant]
US 20220008397A1
· Xu et al.
· 2022
[cited by applicant]
US 20220031844A1
· Mauden et al.
· 2022
[cited by applicant]
US 20220079925A1
· Günther et al.
· 2022
[cited by applicant]
US 20220354786A1
· Friess et al.
· 2022
[cited by applicant]
US 20220354926A1
· Löscher et al.
· 2022
[cited by applicant]
US 20220362382A1
· Loscher et al.
· 2022
[cited by applicant]
US 20230139672A1
· Theisinger et al.
· 2023
[cited by applicant]
US 20230330056A1
· Günther et al.
· 2023
[cited by applicant]
US 20230398065A1
· Günther et al.
· 2023
[cited by applicant]
CN 200977281Y
· 2007
[cited by applicant]
CN 202136470U
· 2012
[cited by applicant]
CN 103096934A
· 2013
[cited by applicant]
CN 203524843U
· 2014
[cited by applicant]
EP 0670159
· 1995
[cited by applicant]
EP 1152749
· 2001
[cited by applicant]
EP 2708228A1
· 2014
[cited by applicant]
EP 2730291A1
· 2014
[cited by applicant]
JP S6452722
· 1989
[cited by applicant]
JP 2001158734
· 2001
[cited by applicant]
JP 2011006348
· 2011
[cited by applicant]
JP 2011024841
· 2011
[cited by applicant]
WO WO9300991
· 1993
[cited by applicant]
WO WO1998005301
· 1998
[cited by applicant]
WO WO0054588
· 2000
[cited by applicant]
WO WO2003099258
· 2003
[cited by applicant]
WO WO2007149334
· 2007
[cited by applicant]
WO WO2010146536
· 2010
[cited by applicant]
WO WO2011112669A1
· 2011
[cited by applicant]
WO WO2012097019
· 2012
[cited by applicant]
WO WO2015011199A1
· 2015
[cited by examiner]
WO WO2016082644A1
· 2016
[cited by applicant]
WO WO2016208989
· 2016
[cited by applicant]
WO WO2016208989A1
· 2016
[cited by examiner]
WO WO2017120601A1
· 2017
[cited by applicant]
WO WO2017220625A1
· 2017
[cited by examiner]
WO WO2018094316A1
· 2018
[cited by examiner]
The Diabetic Retinopathy Clinical Research Network, New Engl. J. Med. 372:1193-1203 (2015) (Year: 2015).
[cited by examiner]
Meinert, Eur J Ophthalmol. 2000; 10(3):189-197, Abstract (Year: 2000).
[cited by examiner]
Agarwal et al., Int J Pharm. Mar. 1, 2018;538(1-2):119-129 (Year: 2018).
[cited by examiner]
“EvoTears, Product Description” Accessed Online: Dec. 21, 2023. https://evotears.com/at/das-produkt/ (Year: 2017).
[cited by applicant]
“EvoTears—Gebrauchsanweisung,” May 2015, retrieved from the Internet, date retrieved: Jun. 26, 2018, 2 pages, URL: http://video.apo-rot.de/docs/11213615.pdf.
[cited by applicant]
“Novaliq Announces Positive Topline Results of Phase 2 Clinical Trial Evaluating CyclASol® in Adults with Moderate to Severe Dry Eye Disease,” Businesswire, Jan. 5, 2017, URL: < https://www.businesswire.com/news/home/20…
[cited by applicant]
“Novaliq begins Phase 2 trial of Cyclasol for dry eye disease,” Optometry Times, vol. 8, No. 3, (2016), p. 24.
[cited by applicant]
“Semifluorinated alkane technology brings advantages for topical therapy,” Ophthalmology Times, 2016, pp. 1-2.
[cited by applicant]
“Topical drug dosage forms for eye conditions,” The Pharmaceutical Journal, (Pharmaceutical Press, May 31, 2017), available at https://pharmaceutical-journal.com/article/ld/topical-drug-dosage-forms-for-eye-conditions.
[cited by applicant]
Ahmed, S. et al., “Ocular Drug Delivery: a Comprehensive Review,” AAPS PharmSciTech, vol. 24, No. 66, pp. 1-29, (2023).
[cited by applicant]
Chen, M. et al., “Persistent Inflammation Subverts Thrombospondin-1-Induced Regulation of Retinal Angiogenesis and Is Driven by CCR2 Litigation,” The American Journal of Pathology, vol. 180, pp. 235-245, (2012).
[cited by applicant]
Eva M. del Amo, “Topical ophthalmic administration: Can a drug instilled onto the ocular surface exert an effect at the back of the eye?” Frontiers in Drug Discovery 2:954771 (Sep. 8, 2022), available at https://www.fro…
[cited by applicant]
Kumar, S. et al., “Reduction in drop size of ophthalmic topical drop preparations and the impact of treatment,” J. Adv. Pharm. Tech. Res., vol. 2, No. 3, (2011).
[cited by applicant]
Messmer, E. et al., “Semifluorinated Alkanes as a Therapy for Meibomian Gland Dysfunction Results of a prospective, multi-centered observational study,” Presentation, DOG-Kongress, Sep. 29, 2016-Oct. 2, 2016, Berlin DOG…
[cited by applicant]
Sheppard, J. et al., “A Water-free 0.1% Cyclosporine A Solution for Treatment of Dry Eye Disease: Results of the Randomized Phase 2B/3 Essence Study,” Cornea, vol. 40, No. 10, pp. 1290-1297, (2021).
[cited by applicant]
Steven, P. et al., “Semifluorinated Alkane Eye Drops for Treatment of Dry Eye Disease—A Prospective, Multicenter Noninterventional Study” Investigative Ophthalmology & Visual Science, vol. 56, No. 4493, 1 page, (2015), …
[cited by applicant]
Torkildsen, G. et al., “A Clinical Phase 2 Study to Assess Safety, Efficacy, and Tolerability of CyclASol for the Treatment of Dry Eye Disease,” Poster Presentation at American Academy of Ophthalmology (AAO), New Orlean…
[cited by applicant]
Wu, Y. et al., “Tetramethylpyrazine (TMP) ameliorates corneal neovascularization via regulating cell infiltration into cornea after alkali burn,” Biomedicine and Pharmacotherapy, vol. 109, pp. 1041-1051, (2018).
[cited by applicant]
Guirakhoo et al., “Cloning, expression and functional activities of a single chain antibody fragment directed to fusion protein of respiratory syncytial virus,” Immunotechnology 2(3): 219-228 (1996), Abstract only.
[cited by applicant]
He et al., “High-throughput dynamic light scattering method for measuring viscosity of concentrated protein solutions,” Analytical Biochemistry, 399(1): 141-143 (2010), Abstract only.
[cited by applicant]
Kerns et al., Drug-Like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization, 2008, Elsevier, Chapter 10, Section 10.4.3, 133, 2008, 2 parts.
[cited by applicant]
Yaoxue Zhuanye Zhishi II (Editor: Jin Xiangqun), Military Medical Science Press, 1
[cited by applicant]
Yaoxue Zhuanye Zhishi II (Editor: Jin Xiangqun), Military Medical Science Press, 1
[cited by applicant]
Agarwal, P. et al., “Semifluorinated alkane based systems for enhanced corneal penetration of poorly soluble drugs,” International Journal of Pharmaceutics, vol. 538, No. 1-2, pp. 119-129, (2018).
[cited by applicant]
Augustin, A. et al., “Treatment of neovascular age-related macular degeneration: Current therapies,” Clinical Ophthalmology, vol. 3, pp. 175-182, (2009).
[cited by applicant]
Pensyl, D., “Chapter 14: Preparations for Dry Eye and Ocular Surface Disease,” Clinical Ocular Pharmacology, Fifth Edition, pp. 263-278, 18 pages, (2008).
[cited by applicant]
Schmitt, M., “Chapter 10: Design and Development of Ocular Formulations for Preclinical and Clinical Trials,” Innovative Dosage Forms: Design and Development at Early Stage, pp. 331-365, 35 pages, (2020).
[cited by applicant]
Turgut, B. et al., “The Impact of Tacrolimus on Vascular Endothelial Growth Factor in Experimental Corneal Neovascularization,” Current Eye Research, vol. 36, No. 1, pp. 34-40, (2011).
[cited by applicant]
Agarwal et al., “Modern Approaches to the Ocular Delivery of Cyclosporine A,” Drug Discovery Today, vol. 21, No. 6, pp. 977-988, (2016); doi: 10.1016/j.drudis.2016.04.002.
[cited by applicant]
Agrahari, et al., “A comprehensive insight on ocular pharmacokinetics,” Drug Delivery and Translational Research, 6(6):735-754 (2016).
[cited by applicant]
Ahmed, et al., “Disposition of Timolol and Inulin in the Rabbit Eye Following Corneal Versus Non-Corneal Absorption,” International Journal of Pharmaceutics, 1987, 38:9-21.
[cited by applicant]
Al-Amri, et al., “Long-term use of 0.003% tacrolimus suspension for treatment of vernal keratoconjunctivitis,” Oman Journal of Ophthalmology, 10(3):145-149, (2017).
[cited by applicant]
Astellas Pharma US, Inc. (2019). PROGRAF(R); Highlights of Prescribing Information. Northbrook, IL: Astellas Pharma US, Inc.
[cited by applicant]
Baerdemaeker, “Pharmacokinetics in Obese Patients,” Continuing Education in Anesthesia, Critical Care & Pain, 2004, 4:152-155.
[cited by applicant]
Barata-Vallejo et al., “(Me
[cited by applicant]
Bardin et al., “Long-Range Nanometer-Scale Organization of Semifluorinated Alkane Monolayers at the Air/Water Interface,” Langmuir, 2011, 27:13497-13505.
[cited by applicant]
Bertilla et al., “Semifluorinated Alkanes as Stabilizing Agents of Fluorocarbon Emulsions,” Springer, Tokyo, 2005, International Symposia for Life Sciences and Medicine, vol. 12, pp. 237-251.
[cited by applicant]
Blackie et al., “MGD: Getting to the Root Cause of Dry Eye,” Review of Optometry, 2012, pp. 1-12.
[cited by applicant]
Broniatowski, M. et al., “Langmuir Monolayers Characteristics of (Perfluorodecyl)-Alkanes,” Journal of Physical Chemistry B, 2004, 108:13403-13411.
[cited by applicant]
Cabral et al., “Retinal and choroidal angiogenesis: a review of new targets,” International Journal of Retina and Vitreous, 2017, 3:31.
[cited by applicant]
Chaglasian et al., “Recycling Cyclosporine,” Review of Cornea & Contact Lenses, 5 pages, (2016).
[cited by applicant]
Chao, W. et al., “Report of the Inaugural Meeting of the TFOS i2 = initiating innovation Series: Targeting the Unmet Need for Dry Eye Treatment,” (London, United Kingdom, Mar. 21, 2015) Accepted Manuscript, Accepted Dat…
[cited by applicant]
Chemical Book, 5-Fluorouracil, available at <http://www.chemicalbook.com/ChemicalProductProperty_EN_CB8162744.htm>, accessed Mar. 7, 2014, 1 page.
[cited by applicant]
Chhadva et al., “Meibomian Gland Disease The Role of Gland Dysfunction in Drye Eye Disease,” Ophthalmology (2017) 124(11 Supplement): S20-S26.
[cited by applicant]
Costa Gomes et al., “Solubility of dioxygen in seven fluorinated liquids,” Journal of Fluorine Chemistry, 2004, 125:1325-1329.
[cited by applicant]
Davies, “Biopharmaceutical Considerations in Topical Ocular Drug Delivery,” Clin. Exper. Pharmacol. Physiol., 2000, 27:558-562.
[cited by applicant]
Dembinski et al., Semi-fluorinated Alkanes as Carriers for Drug Targeting in Acute Respiratory Failure, Experimental Lung Research, 2010, 36(8):499-507.
[cited by applicant]
Dias et al., “Solubility of oxygen in liquid perfluorocarbons,” Fluid Phase Equilibria, 2004, 222-223:325-330.
[cited by applicant]
Dutescu et al., “Semifluorinated alkanes as a liquid drug carrier system for topical ocular drug delivery,” European Journal of Pharmaceutics and Biopharmaceutics, 2014, 88(1):123-128, Abstract Only (2 pages).
[cited by applicant]
Elkeeb, R. et al., “Transungual Drug Delivery: Current Status,” International Journal of Pharmaceutics, 2010, 384:1-8.
[cited by applicant]
English-language machine translation of EP0670159 (A1) issued in U.S. Appl. No. 14/122,025 on Apr. 1, 2015, 10 pages.
[cited by applicant]
Freiburger Dokumentenserver (FreiDok), Albert-Ludwigs, Unversitat Feiburg im Breisgau, retrieved from the Internet, date accessed: Feb. 5, 2014, 2 pages URL: <http://www.freidok.uni-freiburg.de/volltexte/5682>.
[cited by applicant]
Garritty, James, “Blepharitis-17. Eye Diseases-MSD Manual Professional Edition,” 3 pages, (2016); https://www.msdmanuals.com/ja-jp//.
[cited by applicant]
Gayton, J., “Etiology, Prevalence, and Treatment of Dry Eye Disease,” Clinical Ophthalmology, 2009, 3:405-412.
[cited by applicant]
Gehlsen et al., “A semifluorinated alkane (F4H5) as novel carrier for cyclosporine A: a promising therapeutic and prophylactic option for topical treatment of dry eye,” Graefe's Arch. Clin. Exp. Ophthalmol., (2017) 255(…
[cited by applicant]
Gehlsen. U., et al., “Cyclosporine A using F4H5 as liquid drug carrier is effective in treating experimental dry-eye disease,” Investigative Ophthalmology & Visual Science, 2015, 56(7):319, Abstract Only (2 pages).
[cited by applicant]
Gehlsen, U., et al., “Omega-3 Fatty Acids Using F6H8-Carrier as Topical Therapy in Experimental Dry-Eye Disease,” Investigative Ophthalmology & Visual Science, 2016, 57:417, Abstract Only (1 page).
[cited by applicant]
Gerdenitsch, “Emulsions—established and promising drug carriers for parenteral administration,” retrieved from Internet, date accessed: Jun. 20, 2016, 2 pages URL: <http:/ipimediaworld.com/wp-content/uploads/2012/05/Pag…
[cited by applicant]
German, E.J., et al., “Reality of drop size from multi-dose eye drop bottles: is it cause for concern?” Eye, 1999, 13:93-100.
[cited by applicant]
Gopal et al., “Use of intravitreal injection of triamcinolone acetonide in the treatment of age-related macular degeneration,” Indian J Ophthalmol., 2007, 55(6):431-435, (8 pages).
[cited by applicant]
Griffin, W., “Classification of Surface-Active Agnets by ‘HLB’,” Journal of the Society of Cosmetic Chemists, 1949, 1:311-326.
[cited by applicant]
Hardung, H., “Semifluorierte und perfluorierte Vergindungen zur topischen und parenteralen Anwendung,” 2008, 188 pages, retrieved from Internet, date accessed: Oct. 10, 2011, URL: <http://www.freidok.uni-freiburg.de/vol…
[cited by applicant]
Hardung, H., “Semifluorierte und perfluorierte Verbindungen zur topischen und parenteralen Anwendung,” 2008, English Language Abstract, 2 pages, retrieved from https://freidok.uni-freiburg.de/data/5682 (retrieved on Jul…
[cited by applicant]
Hoerauf et al., “Combined Use of Partially Fluorinated Alkanes, Perfluorocarbon Liquids and Silicone Oil: An Experimental Study,” Graefe's Archive For Clinical And Experimental Ophthalmology, 2001, 239(5):373-381.
[cited by applicant]
Holm, R. et al., “A novel excipient, 1-perfluorohexyloctane shows limited utility for the oral delivery of poorly water-soluble drugs,” European Journal of Pharmaceutical Sciences, 2011, 42: 416-422.
[cited by applicant]
Ishizaki et al., “Treatment of Diabetic Retinopathy,” Forum: Complication, Practice, 2009, 26(5):474-476 (3 pages).
[cited by applicant]
Jonas et al., “Intravitreal triamcinolone acetonide for exudative age-related macular degeneration,” Br J Ophthalmol, 2003, 87:462-468.
[cited by applicant]
Joussen et al., “The concept of heavy tamponades—chances and limitations,” Graefes Arch Exp Ophthalmol, 2008, 246:1217-1224.
[cited by applicant]
JPS6452722, English Machine Translation of the Abstract, Description, and Claims, Espacenet, Date Accessed: Feb. 10, 2016, 4 pages.
[cited by applicant]
Kaercher et al., “NovaTears® as new Therapy in Dry Eye Results from three prospective, multicenter, non-interventional studies in different patient populations,” TFOS Conference (Tear Film & Ocular Surface), Sep. 7-10, …
[cited by applicant]
Kheirkhah, A., et al., “Topical 0.005% tacrolimus eye drop for refractory vernal keratoconjunctivitis,” Eye (London, England), 25(7):872-880, (2011).
[cited by applicant]
Knepp et al., “Stability of Nonaqueous Suspension Formulations of Plasma Derived Factor IX and Recombinant Human Alpha Interferon at Elevated Temperatures,” Pharmaceutical Research, 1998, 15(7):1090-1095.
[cited by applicant]
Kociok, N., “Influence on Membrane-Mediated Cell Activation by Vesicles of Silicone Oil or Perfluorohexyloctane,” Graefe's Archive for Clinical and Experimental Ophthalmology, 2005, 243, 345-358.
[cited by applicant]
Lallemand et al., “Cyclosporine A delivery to the eye: a pharmaceutical challenge,” European Journal of Pharmaceutics and Biopharmaceutics, 2003, 56(3):307-318, Abstract Only (1 page).
[cited by applicant]
Lemp, M., “Management of Dry Eye Disease,” The American Journal of Managed Care, 2008, 14(3):S88-S101.
[cited by applicant]
Lin, H. et al., “Dry eye disease: A review of diagnostic approaches and treatments,” Saudi Journal of Ophthalmology, 2014, 28:173-181.
[cited by applicant]
Mackiewicz, J. et al., “In Vivo Retinal Tolerance of Various Heavy Silicone Oils,” Investigative Ophthalmology & Visual Science, 2007, 48 (4):1873-1883.
[cited by applicant]
Matteucci et al., “Biocompatibility assessment of liquid artificial vitreous replacements: relevance of in vitro studies,” Survey of Ophthalmology, 2007, 52(3):289-299, Abstract Only (1 page).
[cited by applicant]
Meinert, H. et al., “The Use of Semifluorinated Alkanes in Blood-Substitutes,” Biomaterials, Artificial Cells, and Immobilization Biotechnology, 1993, 21 (5):583-595.
[cited by applicant]
Meinert, H. et al., “Semifluorinated Alkanes—A New Class of Compounds with Outstanding Properties for Use in Ophthalmology,” European Journal of Ophthalmology, 2000, 10 (3), 189-197.
[cited by applicant]
Messmer, E.M., “The Pathophysiology, Diagnosis, and Treatment of Dry Eye Disease,” (2015) Deutsches Arzteblatt International, 112(5):71-82.
[cited by applicant]
Messmer et al., “Semifluorierte Alkane als Therapie bei Meibomdrüsen-Dysfunktion Ergebnisse einer prospektiven, multizentrischen Beobachtungsstudie”, Presentation, DOG-Kongress, Sep. 29-Oct. 2, 2016, Berlin DOG (Deutsch…
[cited by applicant]
Messmer et al., “Semifluorinated Alkanes as a Therapy for Meibomian Gland Dysfunction Results of a prospective, multi-centered observational study”, Presentation, DOG-Kongress, Sep. 29, 2016-Oct. 2, 2016, Berlin DOG (De…
[cited by applicant]
Moscovici, et al., “Clinical treatment of dry eye using 0.03% tacrolimus eye drops,” Cornea, 31(8):945-949, (2012).
[cited by applicant]
Murdan, S., “Enhancing the Nail Permeability of Topically Appied Drugs,” Expert Opinion on Drug Delivery, 2008, 5 (11):1267-1282.
[cited by applicant]
Neely, K. et al., “Ocular Neovascularization: Clarifying Complex Interactions,” American Journal of Pathology, 1998, vol. 153, No. 3.
[cited by applicant]
Novaliq GmbH Begins Phase II Clinical Trial of Cyclasol for the Treatment of Moderate to Severe Dry Eye Disease, (online), 5 pages, (2016); retrieved on Jan. 8, 2021 from the Internet: https://www.biospace.com/article/r…
[cited by applicant]
Ohashi, et al., “A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1% in severe allergic conjunctivitis,” Journal of ocular pharmacology and therapeutics, 26(2):165-174 (2010).
[cited by applicant]
O'Rourke, M. et al., “Enhancing Delivery of Topical Ocular Drops,” Cataract & Refractive Surgery Today Europe, 2016, 2 pages.
[cited by applicant]
Park et al., “Inhibitory Effect of Topical Aflibercept on Corneal Neovascularization in Rabbits,” Cornea, 2015, 34(10):1303-7.
[cited by applicant]
Perry, “Dry Eye Disease: Pathophysiology, Classification, and Diagnosis,” The American Journal of Managed Care, 2008, 14(3):S79-S87.
[cited by applicant]
Pflugfelder et al., “Treatment of Blepharitis: Recent Clinical Trials,” 2014, 12(4):273-284, Abstract Only (2 pages).
[cited by applicant]
Pflugfelder et al., “The Pathophysiology of Dry Eye Disease What We Know and Future Directions for Research,” Ophthalmology (2017) 124(11 Supplement): S4-S13.
[cited by applicant]
Pinarci, E. et al., “Intraocular Gas Application in the Diagnosis and Treatment of Valsalva Retiopathy in Case with Premacular Hemorrhage,” XP002625604, Retina Vitreus, 2009, 17 (2):153-155, 1 page, abstract only.
[cited by applicant]
Plassmann, M. et al., “Trace Analytical Methods for Semifluorinated n-Alkanes in Snow, Soil, and Air,” Analytical Chemistry, 2010, 82(11):4551-4557.
[cited by applicant]
Plassmann, M. et al., “Theoretical and Experimental Simulation of the Fate of Semifluorinated n-Alkanes During Snowmelt,” Environmental Science & Technology, 2010, 44(17):6692-6697.
[cited by applicant]
Rosca-Casian, O. et al., “Antifungal Activity of Aloe vera Leaves,” Fitoterapia, 2007, 28, 219-222.
[cited by applicant]
Rosenberg, A., “Effects of Protein Aggregates: An Immunologic Perspective,” The AAPS Journal, 2006, 8 (3), E501-E507.
[cited by applicant]
Sall, K. et al. “Two Multicenter, Randomized Studies of the Efficacy and Safety of Cyclosporine Ophthalmic Emulsion in Moderate to Severe Dry Eye Disease,” Ophthalmology, 2000, 107(4):631-639.
[cited by applicant]
Sato et al., “Vitrectomy and Intraocular Lens Implantation for Cytomegalovirus Retinitis in a Patient with Acquired Immunodeficiency Syndrome,” Presented by Medical Online, New Ophthalmology, 1999, 16(7): 995-998 (4 pag…
[cited by applicant]
Sella et al., “Efficacy of topical aflibercept versus topical bevacizumab for the prevention of corneal neovascularization in a rat model,” Experimental Eye Research, 2016, 146:224-32.
[cited by applicant]
Scherer et al., “Eyesol: A Novel Topical Ocular Drug Delivery System for Poorly Soluble Drugs,” Drug Development & Delivery, vol. 13, No. 1, pp. 40-44, (2013).
[cited by applicant]
Schmutz et al., “Fluorinated Vesicles Made from Combinations of Phospholipids and Semifluorinated Alkanes. Direct Experimental Evidence of the Location of the Semifluorinated Alkane within the Bilayer,” Langmuir, 2003, …
[cited by applicant]
Schnetler et al., “Lipid composition of human meibum: a review,” S Afr Optom, 2013, 72(2), 86-93.
[cited by applicant]
Spöler et al., “Towards a New in vitro Model of Dry Eye: The ex vivo Eye Irritation Test,” Developments in Ophthalmology, 2010, 45, 93-107.
[cited by applicant]
Steven, P. et al. “Semifluorinated Alkane Eye Drops for Treatment of Dry Eye Disease—A Prospective, Multicenter Noninterventional Study” Journal of Ocular Pharmacology and Therapeutics, 2015, 31(8):498-503.
[cited by applicant]
Steven et al., “Semifluorinated Alkane Eye Drops for Treatment of Dry Eye Disease Due to Meibomian Gland Disease,” Journal of Ocular Pharmacology and Therapeutics, 2017, 33(9):1-8.
[cited by applicant]
Stevenson, C., “Characterization of Protein and Peptide Stability and Solubility in Non-Aqueous Solvents,” Current Pharmaceutical Biotechnology, 2000, 1, 165-182.
[cited by applicant]
Tamura et al., “Tacrolimus is a class II low-solubility high-permeability drug: The effect of P- glycoprotein efflux on regional permeability of tacrolimus in rats,” Journal of Pharmaceutical Sciences, 2002, 91(3):719-7…
[cited by applicant]
Tiffany, J.M., “Individual Variations in Human Meibomian Composition,” Exp. Eye Res., 1978, 27, 289-300.
[cited by applicant]
Tobe, T. et al., “Targeted Disruption of the FGF2 Gene Does Not Prevent Choroidal Neovascularization in the Murine Model,” American Journal of Pathology., 1998, 153(5): 1641-1646.
[cited by applicant]
Toma, H. S., “Improved assessment of laser-induced choroidal neovascularization,” Microvasc. Res., 2010, 80(3): 295-302.
[cited by applicant]
Troiano et al., “Effect of Hypotonic .4% Hyaluronic Acid Drops in Dry Eye Patients: A Cross-Study,” Cornea 27(10): 1126-1130, 1 page (Abstract Only). 2008.
[cited by applicant]
Wang, W., “Lyophilization and Development of Solid Protein Pharmaceuticals,” International Journal of Pharmaceutics, 2000, 203, 1-60.
[cited by applicant]
Wegewitz et al., “Novel Approaches in the Treatment of Angiogenic Eye Disease,” Current Pharmaceutical Design, 2005; 11(18):2311-30 (Abstract Only).
[cited by applicant]
“What is retinal vitrectomy?” Presented by: Medical Online, Obesity and Diabetes Mellitus, 2005, 4(2): 284-286 (3 pages).
[cited by applicant]
Wirta, David L. et al., “A Clinical Phase II Study to Assess Efficacy, Safety and Tolerability of Waterfree Cyclosporine Formulation for the Treatment of Dry Eye Disease,” Ophthalmology 126:792-800 (2019).
[cited by applicant]
Wong et al., “Perfluorocarbons and Semifluorinated Alkanes,” Seminars in Ophthalmology; vol. 15 (1), 2000, p. 25-35.
[cited by applicant]
Wu et al., “Physicochemical characterization and aerosol dispersion performance of organic solution advanced spray-dried cyclosporine A multifunctional particles for dry powder inhalation aerosol delivery,” Internationa…
[cited by applicant]
Wu, Y. et al., “Tetramethylpyrazine (TMP) ameliorates corneal neovascularization via regulating cell infiltration into cornea after alkali burn,” Biomedicine and Pharmacotherapy, 2018, vol. 109, pp. 1041-1051.
[cited by applicant]
Xalatan, Latanoprost Ophthalmic Solution, 50 μg/mL Prostaglandin F
[cited by applicant]
Yazu, et al., “The efficacy of 0.1% tacrolimus ophthalmic suspension in the treatment of severe atopic keratoconjunctivitis,” Annals of allergy, asthma & immunology, 122(4), 387-392 (2019).
[cited by applicant]
Zhang et al., “Surface micelles of semifluorinated alkanes in Langmuir-Blodgett monolayers,” Phys. Chem. Chem. Phys., 2004, 6:1566-1569.
[cited by applicant]