( 12 ) United States Patent
`Yancopoulos
`
`US 10,828,345 B2
`( 10 ) Patent No .:
`( 45 ) Date of Patent :
`* Nov . 10 , 2020
`
`US010828345B2
`
`( 54 ) USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`( 71 ) Applicant : REGENERON
`PHARMACEUTICALS , INC . ,
`Tarrytown , NY ( US )
`( 72 ) Inventor : George D. Yancopoulos , Yorktown
`Heights , NY ( US )
`( 73 ) Assignee : REGENERON
`PHARMACEUTICALS , INC . ,
`Tarrytown , NY ( US )
`Subject to any disclaimer , the term of this
`patent is extended or adjusted under 35
`U.S.C. 154 ( b ) by 0 days .
`This patent is subject to a terminal dis
`claimer .
`( 21 ) Appl . No .: 16 / 159,282
`( 22 )
`Oct. 12 , 2018
`Filed :
`( 65 )
`Prior Publication Data
`US 2019/0046609 A1
`Feb. 14 , 2019
`Related U.S. Application Data
`( 63 ) Continuation of application No. 15 / 471,506 , filed on
`Mar. 28 , 2017 , now Pat . No. 10,130,681 , which is a
`continuation of application No. 14 / 972,560 , filed on
`Dec. 17 , 2015 , now Pat . No. 9,669,069 , which is a
`continuation of application No. 13 / 940,370 , filed on
`Jul . 12 , 2013 , now Pat . No. 9,254,338 , which is a
`continuation - in - part
`of
`application
`No.
`PCT / US2012 / 020855 , filed on Jan. 11 , 2012 .
`( 60 ) Provisional application No. 61 / 432,245 , filed on Jan.
`13 , 2011 , provisional application No. 61 / 434,836 ,
`filed on Jan. 21 , 2011 , provisional application No.
`61 / 561,957 , filed on Nov. 21 , 2011 .
`( 51 ) Int . Ci .
`A61K 38/17
`A61K 38/18
`COOK 14/71
`COZK 16/22
`A61K 9/00
`A61K 39/00
`( 52 ) U.S. CI .
`A61K 38/179 ( 2013.01 ) ; A61K 9/0048
`CPC
`( 2013.01 ) ; C07K 14/71 ( 2013.01 ) ; CO7K 16/22
`( 2013.01 ) ; A61K 2039/505 ( 2013.01 ) ; CO7K
`2319/30 ( 2013.01 ) ; C07K 2319/32 ( 2013.01 )
`( 58 ) Field of Classification Search
`None
`See application file for complete search history .
`References Cited
`U.S. PATENT DOCUMENTS
`7/2006 Papadopoulos
`7,070,959 B1
`12/2007 Wiegand
`7,303,746 B2
`
`( 2006.01 )
`( 2006.01 )
`( 2006.01 )
`( 2006.01 )
`( 2006.01 )
`( 2006.01 )
`
`( * ) Notice :
`
`( 56 )
`
`7,303,748 B2
`7,306,799 B2
`7,396,664 B2
`8,092,803 B2
`9,254,338 B2
`9,669,069 B2
`10,130,681 B2
`10,406,226 B2
`10,464,992 B2
`2003/0171320 Al
`2005/0163798 A1
`2005/0260203 A1
`2006/0058234 Al
`2006/0172944 Al
`2007/0190058 Al
`2008/0220004 Al
`2019/0290725 Al
`2019/0388539 A1
`2020/0017572 Al
`
`12/2007 Wiegand
`12/2007 Wiegand
`7/2008 Daly et al .
`1/2012 Furfine et al .
`2/2016 Yancopoulos
`6/2017 Yancopoulos
`11/2018 Yancopoulos
`9/2019 Dix et al .
`11/2019 Furfine et al .
`9/2003 Guyer
`7/2005 Papadopoulos et al .
`11/2005 Wiegand et al .
`3/2006 Daly et al .
`8/2006 Wiegand et al .
`8/2007 Shams
`9/2008 Wiegand et al .
`9/2019 Vitti et al .
`12/2019 Dix et al .
`1/2020 Furfine et al .
`
`FOREIGN PATENT DOCUMENTS
`2010-509369
`3/2010
`12/2000
`WO 2000/75319
`12/2004
`WO 2004/106378 A2
`1/2005
`WO 2005/000895 A2
`3/2006
`WO 2006/047325
`2/2007
`WO 2007/022101 A2
`WO 2008/063932
`5/2008
`7/2012
`WO 2012/097019
`
`JP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`OTHER PUBLICATIONS
`Anonymous “ Lucentis ( rangibizymab injection ) Intravitreal Injec
`tion ” pp . 103 ( Jun . 2006 ) .
`Information from ClinicalTrials.gov archive View of NCT00637377
`“ Vascular Endothelial Growth Factor ( VEGF ) Trap - Eye : Investiga
`tion of Efficacy and Safety in Wet Age - Related Macular Degenera
`tion ( AMD ) ( View 2 ) " Clinical Trials.gov . Web . Nov. 30 , 2010 .
`Center for Drug Evaluation and Research Application No. 21-756
`Medical Review ( s ) ( Dec. 17 , 2004 ) < URL : https : //www.accessdata .
`fda.gov/drugsatfda_docs/nda/2004/21-756_Macugen_medr.pdf > .
`Center for Drug Evaluation and Research BLA Application No.
`125156 Medical Review , ( Jun . 2006 ) < URL : https : //www.accessdata .
`fda.gov/drugsatfda_docs/nda/2006/1251568000_Lucentis_MedR .
`pdf > .
`
`( Continued )
`Primary Examiner Christine J Saoud
`Assistant Examiner - Jon M Lockard
`( 74 ) Attorney , Agent , or Firm — Thomas Triolo ; Karl
`Bozicevic
`
`( 57 )
`ABSTRACT
`The present invention provides methods for treating angio
`genic eye disorders by sequentially administering multiple
`doses of a VEGF antagonist to a patient . The methods of the
`present invention include the administration of multiple
`doses of a VEGF antagonist to a patient at a frequency of
`once every 8 or more weeks . The methods of the present
`invention are useful for the treatment of angiogenic eye
`disorders such as age related macular degeneration , diabetic
`retinopathy , diabetic macular edema , central retinal vein
`occlusion , branch retinal vein occlusion , and corneal neo
`vascularization .
`11 Claims , 1 Drawing Sheet
`Specification includes a Sequence Listing .
`
`Mylan Exhibit 1133
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`

`

`US 10,828,345 B2
`Page 2
`
`( 56 )
`
`References Cited
`
`OTHER PUBLICATIONS
`Charles , Steve ( Guest Lecturer ) “ VEGF Trap Has Positive DME
`Data ” Tenth Annual Retina Fellows Forum Jan. 29 and 30 , Chicago ,
`Article Date Mar. 1 , 2010 .
`Dixon et al . , “ VEGF Trap - Eye for the treatment of neobascular
`age - related macular degeneration ” Expert Opin . Investig . Drugs
`( 2009 ) 18 ( 10 ) : 1-8 .
`Do et al . , " An exploratory study of the safety , tolerability and
`bioactivity of a single intravitreal injection of vascular endothelial
`growth factor Trap - Eye in patients with diabetic macular oedema ”
`Br J Opthamol . 93 ( 2 ) : 144-1449 ( Feb. 2009 ) .
`Do et al . “ The DA VINCI Study : phase 2 primary results of VEGF
`Trap - Eye in patients with diabetic macular edema ” Opthamology
`118 ( 9 ) : 1819-1826 ( Sep. 2011 ) .
`The Eyetech Study Group , “ Anti - Vascular Endothelial Growth
`Factor Therapy for Subfoveal Choroidal Neovascularization Sec
`ondary to Age - related Macular Degeneration ” American Academy
`of Ophthamology , 110 ( 5 ) : 979-986 ( May 2003 ) .
`HEIERet al . , “ rhuFab V2 ( anti - VEGF Antibody ) for Treatment of
`Exudative AMD ” Symposium 8 : Experimental and Emerging Treat
`ments for Choroidal Neovascularization , 10 pp ( 2002 ) .
`Heier et al . ,
`“ RhuFab V2 in Wet AMD - 6 Month Continued
`Improvement Following Multiple Intravitreal Injections ” Invest
`Ophthalmol Vis Sci , 44 : E - Abstract 972 ( 2003 ) .
`Heier et al . , “ Intravitreal Aflibercept ( VEGF Trap - Eye ) in Wet
`Age - related macular Degeneration , ” Ophthalmology , 119 : 2537
`2548 ( 2012 )
`Information from Clinical Trials.gov archive on the VIEW 2 study
`( NCT00637377 ) “ VEGF Trap - Eye : Investigation of Efficacy and
`Safety in Wet AMD ( VIEW 2 ) ” version available and updated on
`Mar. 17 , 2008 .
`Information from ClinicalTrials.gov archive on the view of
`NCT00509795 " Vascular Endothelial Growth Factor ( VEGF ) Trap
`Eye : Investigation of Efficacy and Safety in Wet Age - Related
`Macular Degeneration ( AMD ) ” ( Dec. 1 , 2009 ) .
`Information from ClinicalTrials.gov archive on the view of
`NCT00789477 “ DME and VEGF Trap - Eye : Investigation of Clini
`cal Impact ” ( Nov. 18 , 2010 ) .
`Information from ClinicalTrials.gov archive on the view of
`NCT00509795 “ Vascular Endothelial Growth Factor ( VEGF ) Trap
`Eye : Investigation of Efficacy and Safety in Wet Age - Related
`Macular Degeneration ( AMD ) " ( Jan. 7 , 2011 ) .
`Krzystolik et al . ,
`“ Prevention of Experimental Choroidal
`NEovascularization With Intravitreal Anti - Vascular Endothelial Growth
`Factor Antibody Fragment ” Arch Ophthamol . , 120 : 338-346 ( Mar.
`2002 ) .
`Mitra et al . ,
`“ Review of anti - vascular endothelial growth factor
`therapy in macular edema secondary to central retinal vein occlu
`sions ” Expert Review in Ophthalmo , Taylor & Francis , GB ( Jan. 1 ,
`2011 ) 6 ( 6 ) : 623-629 .
`Mousa and Mousa , “ Current Status of Vascular Endothelial Growth
`Factor Inhibition in Age - Related Macular Degeneration ” Biodrugs
`2010 ; 24 ( 3 ) ; 183-194 .
`Nguyen et al . , “ A Phase I Study of Intravitreal Vascular Endothelial
`Growth Factor Trap - Eye in Patients with Neovascular Age - Related
`Macular Degeneration ” Opthamology , J.B. Lippincott Co. , Phila
`delphia , PA , US , 116 ( 11 ) : 2141-2148 ( Nov. 1 , 2009 ) 116 ( 11 ) : 2141
`2148 ( Nov. 1 , 2009 ) .
`Nguyen et al . , “ A phase I trial of an IV - administered vascular
`endothelial growth factor trap for treatment in patients with choroidal
`neovascularization due to age - related macular degeneration ” Oph
`thalmology ( Sep. 2006 ) 113 ( 9 ) : 1522e1-1522e14 ( epub Jul . 28 ,
`2006 ) .
`Nichols , Earl R. ,
`“ AAO : Ranibizumab ( rhuRab ) May Improve
`Vision in Age - Related Macular Degeneration ” Doctor's Guide
`Global Edition , www.pslgroup.com/dg/23f2aa.htm , pp . 1-2 ( Nov.
`24 , 20013 ) .
`
`Olivera et al . , “ VEGF Trap R1 R2 suppresses experimental corneal
`angiogenesis ” European Journal of Ophthalmology ( Jan. 1 , 2010 )
`20 ( 1 ) : 48-54 .
`Pai et al . , “ Current concepts in intravitreal drug therapy for diabetic
`retinopathy ” Saudi Journal of Opthamology 24 ( 4 ) : 143-149 ( Jun . 30 ,
`2010 ) .
`Regeneron Pharmaceuticals , Inc. Form 10 - Q , published on Nov. 7 ,
`2007 for the period ending Sep. 30 , 2007 .
`Regeneron , Press release “ Regeneron Reports First Quarter 2008
`Financial and Operating Results ” , May 1 , 2008 .
`Regeneron Press Release “ Bayer and Regeneron Report Positive
`Top - Line Results of Two Phase 3 Studies with VEGF Trap - Eye in
`Wet Age - related Macular Degeneration ” Nov. 22 , 2010 .
`Regeneron Press Release “ Regeneron and Bayer Report Positive
`Results for VEGF Trap - Eye in Phase 3 Study in Central Retinal Vein
`Occlusion ( CRVO ) and in Phase 2 Study in Diabetic Macular
`Edema ( DME ) " Dec. 20 , 2010 .
`Regeneron Pharmaceuticals Inc. , “ VEGF Trap - Eye Final Phase 2
`Results in Age - related Macular Degeneration Presented at 2008
`Retina Society Meeting ” ( Sep. 28 , 2008 ) ( XP - 002770952 ) .
`Simo and Hernandez , " Advances in Medical Treatment of Diabetic
`Retinopathy ” Diabetes Care , vol . 32 , No. 8 , Aug. 2009 .
`Slides for the 2008 Retina Society Meeting " VEGF Trap - Eye in Wet
`AMD CLEAR - IT 2 : Summary of One - Year Key Results ” , Sep. 28 ,
`2008 .
`Stewart , “ THe expanding role of vascular endothelial growth factor
`inhibitors in opthamology " Mayo Clin Proc . 87 ( 1 ) : 77-88 ( Jan.
`2012 ) .
`Thomas Reuters Integrity “ VEGF Trap - Eye final phase II results in
`age - related macular degeneration presented at 2008 Retina Society
`Meeting ” ( Sep. 28 , 2008 ) .
`WHO Drug Information , “ International Nonproprietary Names for
`Pharmaceutical Substances ( INN ) ” vol . 20 , No. 2 , 2006 , pp . 115
`119 .
`Barbazetto , “ Dosing Regimen and the Frequency of Macular Hem
`orrhages in Neovascular Age - Related Macular Degeneration Treated
`With Ranibizumab . " Retina , 30 : 9 , 1376-85 , 2010 .
`Bayer Investor News , “ Bayer and Regeneron Start additional Phase
`3 Study for VEGF Trap = Eye in Wet Age - related Macular Degen
`eration . ” May 8 , 2008 .
`Boyer , “ A Phase IIIb Study to Evaluate the Safety of Ranibizumab
`in Subjects with Neovascular Age - related Macular Degeneration . ”
`Opthalmology , 116 : 9 , 1731-39 , Sep. 2009 .
`Brown , “ Ranibizumab versus Verteporfin for Neovascular Age
`Related Macular Degeneration . ” N Engl J Med 355 : 14 , 1432-44 ,
`Oct. 5 , 2006 .
`Brown , “ Primary Endpoint Results of a Phase II Study of Vascular
`Endothelial Growth Factor Trap - Eye in Wet Age - related Macular
`Degeneration . ” Ophthalmology , 118 : 6 , 1089-97 , Jun . 2011 .
`Brown , “ Long - term Outcomes of Ranibizumab Therapy for Dia
`betic Macular Edema : The 36 - Month Results from Two phase III
`Trials . ” Ophthalmology , 2013 .
`Campochiaro , “ Ranibizumab for Macular Edema following Branch
`Retinal Vein Occlusion . ” Ophthalmology , 2010 .
`Campochiaro , “ Sustained Benefits from Ranibizumab for Macular
`Edema following Central Retinal Vein Occlusion : Twelve - Month
`Outcomes of a phase III Study . ” Ophthalmology , 188 : 10 , 2041-49 ,
`Oct. 2011 .
`Csaky , “ Safety Implications of Vascular Endothelial Growh Factor
`Blockade for Subjects Receiving Intravitreal Anti - Vascular Endothelial
`Growth Factor Therapies . ” Am . J. Opthalmology , 148 : 5 , 647-56 ,
`Nov. 2009 .
`Do ,
`“ One - Year Outcomes of the DA VINCI Study of VEGF
`Trap - Eye in Eyes with Diabetic Macular Edema . ” Ophthalmology ,
`2012 .
`Engelbert , “ The ‘ Treat and Extend ' Dosing Regimen of Intravitreal
`Anti - Vascular Endothelial Growth Factor Therapy for Neovascular
`Age - Related Macular Degeneration . ” Ophthalmology Manage
`ment , Jun . 2010 , available at http : //www.visioncareprofessional .
`com / emails / amdupdate / index.asp ? issue = 42 .
`Engelbert , “ Long - Term Follow - Up for Type 1 ( Subretinal Pigment
`Epithelium ) Neovascularization Using a Modified ‘ Treat and Extend '
`
`Mylan Exhibit 1133
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`

`

`US 10,828,345 B2
`Page 3
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`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`Dosing Regiment of Intravitreal Antivascular Endothelial Growth
`Factor Therapy . " Retina , 30 : 9 , 1368-75 , 2010 .
`Engelbert , “ Treat and Extend ' Dosing of Intravitreal Antivascular
`Endothelial Growth Factor Therapy for Type 3 Neovascularization /
`Retinal Angiomatous Proliferation . " Retina , 29:10 , 1424-31 , 2009 .
`Eylea® , Highlights of Prescribing Information , Revised Aug. 2018 .
`Fung , “ An Optical Coherence Tomography - Guided , Variable Dos
`ing Regiment with Intravitreal Ranibizumab ( Lucentis ) for Neovascular
`Age - related Macular Degeneration . ” Am J Ophthalmology 143 : 4 ,
`566-83 , Apr. 2007 .
`Gale , “ Complementary and Coordinated Roles of the VEGFs and
`Angiopoietins during Normal and Pathologic Vascular Formation . "
`Cold Spring Harbor Symposia on Quantitative Biology , vol . LXVIL ,
`pp . 267-73 , 2002 .
`Garcia - Quintanilla , “ Pharmacokinetics of Intravitreal Anti - VEGF
`Drugs in Age - Related Macular Degeneration . ” Pharmaceutics , 11 : 365 ,
`2019 .
`Gomez - Manzano , “ VEGF Trap induces antiglioma effect at differ
`ent stages of disease . ” Society for Neuro - Oncology , Dec. 2008 .
`Gragoudas , “ Pegaptanib for Neovascular Age - Related Macular Degen
`eration . ” N Engl J Med 351 : 27 , 2805-16 , Dec. 30 , 2004 .
`Heier , “ Intravitreal Aflibercept for Diabetic Macular Edema . ” Oph
`thalmology , 2016 .
`Ho et al . , Slides entitled CLEAR IT 2 One - Year Key Results , Retina
`Society 2008 .
`Korobelnik , “ Intravitreal Aflibercept for Diabetic Macular Edema . ”
`Ophthalmology , 121 : 11 , 2247-54 , Nov. 2014 .
`Lalwani , “ All About PrONTO : Study Yielded Good Results in
`AMD With Treatment Guided by OCT . ” Retina Today , May 2007 .
`Lalwani , A Variable - dosing Regimen with Intravitreal Ranibizumab
`for Neovascular Age - related Macular Degeneration : Year 2 of the
`PrONTO Study . Am J Ophthalmology , 148 : 1 , 43-58 , Jul . 2009 .
`Levine , “ Macular Hemorrhage in Neovascular Age - Related Macular
`Degeneration After Stabilization With Antiangiogenic Therapy . "
`Retina , 29 : 8 , 1074-79 , 2009 .
`Margolis , “ Hemorrhagic Recurrence of Neovascular Age - Related
`Macular Degeneration Not Predicted by Spectral Domain Optical
`Coherence Tomography . ” Retinal Cases & Brief Reports , 4 : 1 , 2010 .
`Massin , " Safety and Efficacy of Ranibizumab in Diabetic Macular
`Edema ( RESOLVE Study * ) . ” Diabetes Care , 33:11 , 2399-405 , Nov.
`2010 .
`Mitchell , “ The RESTORE Study , Ranibizumab Monotherapy or
`Combined with Laser versus Laser Monotherapy for Diabetic
`Macular Edema . ” Ophthalmology , 188 : 4 , 615-25 , Apr. 2011 .
`Nguyen , “ Ranibizumab for Diabetic Macular Edema , Results from
`2 Phase III Randomized Trials : RISE and RIDE . ” Ophthalmology ,
`119 : 4 , 789-801 , Apr. 2012 .
`Regeneron Press Release , “ Bayer and Regeneron Dose First Patient
`in Second Phase 3 Study for VEGF Trap - Eye in Wet Age - Related
`Macular Degeneration . ” May 8 , 2008 .
`Regeneron Press Release , “ VEGF Trap - Eye Shows Positive Results
`in a Phase 2 Study in Patients with Diabetic Macular Edema . ” Feb.
`18 , 2010 .
`Rosenfeld , “ Ranibizumab for Neovascular Age - Related Macular
`Degeneration . ” N Engl J Med , 355 : 14 , 1419-31 , Oct. 5 , 2006 .
`Rosenfeld , “ Lessons Learned From Avastin and OCT - The Great , the
`Good , the Bad , and the Ugly : The LXXV Edward Jackson Memo
`rial Lecture . " Am . J. Ophthalmology , 204 : 26-45 , Aug. 2019 .
`Schmidt - Erfurth , “ Efficacy and Safety of Monthly versus Quarterly
`Ranibizumab Treatment in Neovascular Age - related Macular Degen
`eration . ” Ophthalmology , 2010 .
`Schmidt - Erfurth , “ Three - Year Outcomes of Individualized Ranibizumab
`Treatment in Patients with Diabetic Macular Edema . ” Ophthalmol
`ogy , 121 : 5 , 1045-53 , May 2014 .
`Spaide , “ Ranibizumab According to Need : A Treatment for Age
`related Macular Degeneration . ” Am J Ophthalmology , Apr. 2007 .
`Wolfson , “ Regeneron Focuses on Age - Related Macular Degenera
`tion . ” Chemistry & Biology 15 : 303-304 , Apr. 2008 .
`
`Yancopoulos , “ Vascular - specific growth factors and blood vessel
`formation . ” Nature 407 : 242-48 , Sep. 14 , 2000 .
`Yancopoulos , “ Clinical Application of Therapies Targeting VEGF . ”
`Cell 143 , Oct. 1 , 2010 .
`Yung , “ moving Toward the Next Steps in Angiogenesis Therapy ? ”
`Society for Neuro - Oncology , 10 : 939 , 2008 .
`Browning et al . “ Aflibercept for age - related macular degeneration :
`a game - changer or quiet addition ? ” American Journal of Ophthal
`mology , vol . 154 ( 2 ) : 222-226 ( Aug. 1 , 2012 ) .
`Campochiaro et al .
`“ Ranibizumab for Macular Edema Due to
`Retinal Vein Occlusions Implication of VEGF as a Critical Stimu
`lator ” Molecular Therapy , 16 ( 4 ) : 791-799 ( 2008 ) .
`Cao ,
`“ A Subretinal Matrigel Rat Choroidal Neovascularization
`( CNV ) Model and Inhibition of CNV and Associated Inflammation
`and Fibrosis by VEGF Trap ” Investigative Ophthalmology & Visual
`Science , 51 ( 11 ) : 6009-6017 ( Nov. 2010 ) .
`Eichten ,
`“ Rapid decrease in tumor perfusion following VEGF
`blockade predicts long - term tumor growth inhibition in preclinical
`tumor models ” Angiogenesis , 16 : 429-441 ( 2013 ) .
`Ho , “ VEGF Trap - Eye in Wet AMD CLEAR - IT 2 : One - Year OCT
`and FA Outcomes " CLEAR - IT 2 Study Group , pp . 1-24 ( Sep. 28 ,
`2008 ) .
`Holash ,
`“ VEGF - Trap : A VEGF blocker with potent antitumor
`effects ” PNAS 99 ( 17 ) 11393-11398 ( Aug. 20 , 2002 ) .
`Holash , “ Inhibitors of growth factor receptors , signaling pathways
`and angiogenesis as therapeutic molecular agents . ” Cancer Metas
`tasis 25 : 243-252 ( 2006 ) .
`Karia , Niral , “ Retinal vein occlusion : pathophysiology and treat
`ment options " Clinical Ophthalmology , 4 : 809-816 ( 2010 ) .
`Kuo , “ Comparative evaluation of the antitumor activity of antiangiogenic
`proteins delivered by gene transfer ” PNAS 98 ( 8 ) : 4605-4610 ( Apr.
`10 , 2001 ) .
`Lucentis Label Title , 7 pages , Jun . 30 , 2010 [ Cited in Third Party
`Observations filed in parent U.S. Appl . No. 16 / 055,847 ] .
`Ohr , “ Aflibercept in wet age - related macular degeneration : a per
`spective review ” Ther . Adv . Chronic Dis . , 3 ( 4 ) : 153-161 ( 2012 ) .
`Papadppoulos , “ Binding and neutralization of vascular endothelial
`growth factor ( VEGF ) and related ligands by VEGF Trap , ranibizumab
`and bevacizumab ” Angiogenesis , 15 : 171-185 ( 2012 ) .
`Regillo et al . ,
`“ Randomized , Double - Masked , Sham - Controlled
`Trial of Ranibizumab for Neovascular Age - related Macular Degen
`eration : OIER Study Year 1 ” American Journal of Ophthalmology ,
`145 ( 2 ) : 239-248 ( 2008 ) .
`Schnichels , “ Comparative toxicity and proliferation testing of aflibercept ,
`bevacizumab and ranibizumab on different ocular cells . ” Br . J.
`Opthalmol . ( May 17 , 2013 ) .
`Sharma and S. and Kaiser , P. K. , Update on VEGF TRAP - Eye
`Clinical Trials and Retinal . Physician , Nov./Dec . 2010 , p . 1-6 ,
`< URL : https://www.retinalphysician.com/issues/2010/nov-dec/update
`on - vegf - trap - eye - clinical - trials > .
`Stewart et al . ,
`“ Predicted biological activity of intravitreal VEGF
`Trap ” British Journal of Ophthalmology , 2008 , vol . 92 , No. 5 , p .
`667-668 .
`Stewart , " Aflibercept ” Nature Reviews : Drug Discovery 11 : 269
`270 ( Apr. 1 , 2012 ) .
`Thurston , “ Vascular endothelial growth factor and other signaling
`pathways in developmental and pathologic angiogenesis . ” Interna
`tional Journal of Hematology 80 : 7-20 ( 2004 ) .
`Wachsberger , “ VEGF trap in combination with radiotherapy improves
`tumor control in u87 glioblastoma . ” Int . J. Radiation Oncology Biol
`Phys . 67 ( 5 ) : 1526-1537 ( 2007 ) .
`ADSIS R & D Profile “ Aflibercept : AVE 0005 , AVE 005 , AVE0005 ,
`VEGF Trap Regeneron , VEGF Trap ( R1R2 ) , VEGF Trap - Eye . ”
`Drugs R D , 9 ( 4 ) : 261-269 ( 2008 ) .
`N / A “ Materials from Jun . 2011 FDA Committee Mtg ” ( Jun . 17 ,
`2011 ) .
`N / A “ Materials from Dec. 2011 FDA Committee Mtg ” ( Dec. 1 ,
`2011 ) .
`Vascular Endothelial Growth Factor Trap & # 8208 ; Eye Investiga
`tion of Efficacy and Safety in Central Retinal Vein Occlusion title ,
`8 pages , Nov. 12 , 2009 , US [ Cited in Third Party Observations filed
`in parent U.S. Appl . No. 16 / 055,847 ] .
`
`Mylan Exhibit 1133
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`

`

`US 10,828,345 B2
`Page 4
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`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`U.S. Appl . No. 16 / 055,847 — Third Party Submissions dated May 1 ,
`2019 .
`Brown , “ Long - term Outcomes of Ranibizumab Therapy for Dia
`betic Macular Edema : The 36 - Month Results from Two phase III
`Trials . ” Ophthalmology , 120 ( 10 ) : 2013-22 ( Oct. 2013 ) .
`Campochiaro , “ Ranibizumab for Macular Edema following Branch
`Retinal Vein Occlusion : six - month primary end point results of a
`phase III study . ” Ophthalmology , 117 ( 6 ) : 1102-1112 ( Jun . 2010 ) .
`Dixon et al . , “ VEGF Trap - Eye for the treatment of neovascular
`age - related macular degeneration ” Expert Opin . Investig . Drugs ,
`18 ( 10 ) : 1573-1580 ( 2009 ) .
`Do ,
`“ One - Year Outcomes of the DA VINCI Study of VEGF
`Trap - Eye in Eyes with Diabetic Macular Edema . ” Ophthalmology ,
`119 ( 8 ) : 1658-65 ( 2012 ) .
`Engelbert , “ The ‘ Treat and Extend ’ Dosing Regimen of Intravitreal
`Anti - Vascular Endothelial Growth Factor Therapy for Neovascular
`Age - Related Macular Degeneration . ” Ophthalmology Manage
`ment , Issue 42 , ( Jun . 2010 ) available at http : // visioncareprofessional .
`com / emails / amdupdate / index.asp ? issue = 42 .
`Gomez - Manzano , " VEGF Trap induces antiglioma effect at differ
`ent stages of disease . ” Neuro - Oncology , 10 : 940-945 ( Dec. 2008 ) .
`Heier , “ Intravitreal Aflibercept for Diabetic Macular Edema : 148
`Week Results from the VISTA and VIVID Studies . ” Ophthalmol
`ogy , 123 ( 11 ) : 2376-2385 ( Nov. 2016 ) .
`Information from ClinicalTrials.gov archive on the view of
`NCT01012973 Vascular Endothelial Growth Factor ( VEGF ) Trap
`Eye : Investigation of Efficacy and Safety in Central Retinal Vein
`Occlusion ( CRVO ) ( GALILEO ) 7 pages , first posted Nov. 13 , 2009 ;
`results first posted Nov. 22 , 2012 ; last update posted Nov. 3 , 2014 ;
`printed Dec. 4 , 2019 ( https://clinicaltrials.gov/ct2/show/study/
`NCT01012973 ) ( Note : May correspond to " Vascular Endothelial
`Growth Factor Trap & # 8208 ; Eye Investigation of Efficacy and
`Safety in Central Retinal Vein Occlusion title , 8 pages , Nov. 12 ,
`2009 , US ( Cited in Third Party Observations filed in parent U.S.
`Appl . No. 16 / 055,847 ] ” which was cited in the Third Party Obser
`vations dated May 1 , 2019 ) .
`Kaiser , “ Vascular endothelial growth factor Trap - Eye for diabetic
`macular oedema . ” Br . J. Ophthalmol . 93 ( 2 ) : 135-36 ( Feb. 2009 ) .
`Margolis , “ Hemorrhagic Recurrence of Neovascular Age - Related
`Macular Degeneration Not Predicted by Spectral Domain Optical
`Coherence Tomography . " Retinal Cases & Brief Reports , 4 : 1-4
`( 2010 ) .
`Nichols , Earl R. ,
`" AAO : Ranibizumab ( rhuRab ) May Improve
`Vision in Age - Related Macular Degeneration ” Doctor's Guide
`Global Edition , www.pslgroup.com/dg/23f2aa.htm , pp . 1-2 ( Nov.
`24 , 2003 ) .
`Schmidt - Erfurth , “ Efficacy and Safety of Monthly versus Quarterly
`Ranibizumab Treatment in Neovascular Age - related Macular Degen
`eration : The EXCIE Study ” Ophthalmology , 118 ( 5 ) 831-839 ( 2010 ) .
`Schnichels , “ Comparative toxicity and proliferation testing of aflibercept ,
`bevacizumab and ranibizumab on different ocular cells . ” Br . J.
`Ophthalmol . , 97 : 917-923 ( 2013 ) .
`Simo and Hernandez , “ Advances in Medical Treatment of Diabetic
`Retinopathy ” Diabetes Care , 32 ( 8 ) : 1556-1562 ( Aug. 2009 ) .
`Spaide , “ Ranibizumab According to Need : A Treatment for Age
`related Macular Degeneration . ” Am J Ophthalmology , 143 ( 4 ) : 679
`680 ( Apr. 2007 ) .
`Vascular Endothelial Growth Factor Trap & # 8208 ; Eye Investiga
`tion of Efficacy and Safety in Central Retinal Vein Occlusion title ,
`pages , Nov. 12 , 2009 , US [ Cited in Third Party Observations filed
`8
`in parent U.S. Appl . No. 16 / 055,847 ] Note : May correspond to
`Information from ClinicalTrials.gov archive on the view of
`NCT01012973 “ Vascular Endothelial Growth Factor ( VEGF ) Trap
`Eye : Investigation of Efficacy and Safety in Central Retinal Vein
`Occlusion ( CRVO ) ( GALILEO ) 7 pages , first posted Nov. 13 , 2009 ;
`results first posted Nov. 22 , 2012 ; last update posted Nov. 3 , 2014 ;
`printed Dec. 4 , 2019 ( https://clinicaltrials.gov/ct2/show/study/
`NCT01012973 ) ” Office Action dated Dec. 10 , 2019 in U.S. Appl .
`No. 16 / 055,847 .
`
`Yancopoulos , “ Clinical Application of Therapies Targeting VEGF . ”
`Cell 143 : 13-16 ( Oct. 1 , 2010 ) .
`Gutierrez et al . , “ Intravitreal bevacizumab ( Avastin ) in the treatment
`of macular edema secondary to retinal vein occlusion ” Clin .
`Ophthalmol . , 2 ( 4 ) : 787,791 ( 2008 ) .
`Updated Information from Clinical Trials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 38 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_01182013_27424.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 10 pages ,
`Latest version submitted Oct. 27 , 2014 on ClinicalTrials .
`gov ( NCT01012973_01252011_27433.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 11 pages ,
`Latest version submitted Oct. 27 , 2014 on ClinicalTrials .
`gov ( NCT01012973_01262012_27428.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 38 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_01302013_27423.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 12 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_02092010_27442.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 11 pages ,
`Latest version submitted Oct. 27 , 2014 on ClinicalTrials.gov
`( NCT01012973_02202012_27427.1 ) .
`Updated Information from Clinical Trials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 12 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_03162010_27441.1 ) .
`Updated Information from Clinical Trials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 10 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_04082011_27432.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 12 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_04162010_27440.1 ) .
`Updated Information from Clinical Trials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 10 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_06232011_27431.1 ) .
`Updated Information from Clinical Trials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 12 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_07222010_27439.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`
`Mylan Exhibit 1133
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`

`

`US 10,828,345 B2
`Page 5
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 12 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_08252010_27438.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 10 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_08262010_27437.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 10 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_09082010_27436.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 10 pages ,
`Latest version submitted Oct. 27 , 2014 on Clinical Trials.gov
`( NCT01012973_09192011_27430.1 ) .
`Updated Information from Clinical Trials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 10 pages ,
`Latest version submitted Oct. 27 , 2014 on ClinicalTrials.gov
`( NCT01012973_10042010_27435.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 38 pages ,
`Latest version submitted Oct. 27 , 2014 on ClinicalTrials.gov
`( NCT01012973_10232012_27426.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 38 pages ,
`Latest version submitted Oct. 27 , 2014 on ClinicalTrials.gov
`( NCT01012973_10272013_27422.1 ) .
`Updated Information from ClinicalTrials.gov archive History of
`Changes for Study : NCT01012973 Vascular Endothelial Growth
`Factor ( VEGF ) Trap - Eye : Investigation of Efficacy and Safety in
`Central Retinal Vein Occlusion ( CRVO ) ( GALILEO ) 10 pages ,
`Latest version submitted