( 12 ) United States Patent
`Yancopoulos
`
`US 11,253,572 B2
`( 10 ) Patent No .:
`( 45 ) Date of Patent :
`* Feb . 22 , 2022
`
`US011253572B2
`
`( 54 ) USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`( 71 ) Applicant : REGENERON
`PHARMACEUTICALS , INC . ,
`Tarrytown , NY ( US )
`( 72 ) Inventor : George 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 .: 17 / 352,892
`( 22 ) Filed :
`Jun . 21 , 2021
`( 65 )
`Prior Publication Data
`Oct. 7 , 2021
`US 2021/0308217 A1
`Related U.S. Application Data
`Continuation of application No. 17 / 350,958 , filed on
`Jun . 17 , 2021 , which is a continuation of application
`No. 17 / 112,404 , filed on Dec. 4 , 2020 , which is a
`continuation of application No. 17 / 072,417 , filed on
`Oct. 16 , 2020 , which is a continuation of application
`No. 16 / 055,847 , filed on Aug. 6 , 2018 , now Pat . No.
`10,857,205 , and a continuation of application No.
`16 / 397,267 , filed on Apr. 29 , 2019 , now Pat . No.
`10,888,601 , which is a continuation of application
`No. 16 / 159,282 , filed on Oct. 12 , 2018 , now Pat . No.
`10,828,345 , which is a 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.
`a
`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 .
`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 . Cl .
`( 2006.01 )
`A61K 38/17
`( 2006.01 )
`COZK 14/71
`( 2006.01 )
`COZK 19/00
`( 2006.01 )
`CO7K 16/22
`( 2006.01 )
`A61K 9/00
`( 2006.01 )
`A61K 39/00
`U.S. Cl .
`A61K 38/179 ( 2013.01 ) ; A61K 9/0048
`CPC
`( 2013.01 ) ; C07K 14/71 ( 2013.01 ) ; C07K 16/22
`
`( 63 )
`
`.
`
`( * ) Notice :
`
`( 60 )
`
`( 52 )
`
`( 2013.01 ) ; A61K 2039/505 ( 2013.01 ) ; COOK
`2319/30 ( 2013.01 ) ; CO7K 2319/32 ( 2013.01 )
`( 58 ) Field of Classification Search
`None
`See application file for complete search history .
`
`( 56 )
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`6,171,586 B1
`6,833,349 B2
`6,879,294 B2
`6,897,294 B2
`7,070,959 B1
`7,303,746 B2
`7,303,747 B2
`7,303,748 B2
`7,306,799 B2
`7,374,757 B2
`7,374,758 B2
`7,378,095 B2
`7,396,664 B2
`7,482,002 B2
`7,521,049 B2
`7,531,173 B2
`7,750,138 B2
`7,951,585 B2
`8,092,803 B2
`
`1/2001 Lam et al .
`12/2004 Xia et al .
`5/2005 Davis - Smyth et al .
`5/2005 Davis - Smyth et al .
`7/2006 Papadopoulos
`12/2007 Wiegand
`12/2007 Wiegand et al .
`12/2007 Wiegand
`12/2007 Wiegand
`5/2008 Papadopoulos et al .
`5/2008 Papadopoulos et al .
`5/2008 Cao et al .
`7/2008 Daly et al .
`1/2009 Cedarbaum
`4/2009 Wiegand et al .
`5/2009 Wiegand et al .
`7/2010 Fang et al .
`5/2011 Ke
`1/2012 Furfine et al .
`( Continued )
`FOREIGN PATENT DOCUMENTS
`
`CN
`CN
`
`3/2007
`1304427 C
`6/2009
`100502945 C
`( Continued )
`
`OTHER PUBLICATIONS
`U.S. Appl . No. 16 / 055,847 — Third Party Submissions dated May 1 ,
`2019 .
`
`( 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
`a
`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 .
`
`30 Claims , 1 Drawing Sheet
`Specification includes a Sequence Listing .
`
`Celltrion Exhibit 1001
`Page 1
`
`

`

`US 11,253,572 B2
`Page 2
`
`( 56 )
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`8,216,575 B2
`9,254,338 B2
`9,657,084 B2
`9,669,069 B2
`10,130,681 B2
`10,406,226 B2
`10,464,992 B2
`10,828,345 B2
`2003/0113316 A1
`2003/0138417 A1
`2003/0171320 A1
`2004/0197324 Al
`2004/0213787 Al
`2004/0266688 A1
`2005/0032699 A1
`2005/0163798 A1
`2005/0260203 Al
`2005/0281822 A1
`2006/0030000 Al
`2006/0058234 A1
`2006/0172944 Al
`2006/0217311 A1
`2007/0190058 A1
`2008/0220004 A1
`2009/0264358 A1
`2013/0295094 Al
`2016/0130337 A1
`2019/0290725 A1
`2019/0388539 Al
`2020/0017572 A1
`
`7/2012 Yu
`2/2016 Yancopoulos
`5/2017 Ke et al .
`6/2017 Yancopoulos
`11/2018 Yancopoulos
`9/2019 Dix et al .
`11/2019 Furfine et al .
`11/2020 Yancopoulos
`6/2003 Kaisheva et al .
`7/2003 Kaisheva et al .
`9/2003 Guyer
`10/2004 Liu et al .
`10/2004 Sleeman et al .
`12/2004 Nayak
`2/2005 Holash et al .
`7/2005 Papadopoulos et al .
`11/2005 Wiegand et al .
`12/2005 Cedarbaum et al .
`2/2006 Alitalo et al .
`3/2006 Daly et al .
`8/2006 Wiegand et al .
`9/2006 Dix et al .
`8/2007 Shams
`9/2008 Wiegand et al .
`10/2009 Yu
`11/2013 Yancopoulos
`5/2016 Gekkieva et al .
`9/2019 Vitti et al .
`12/2019 Dix et al .
`1/2020 Furfine et al .
`
`FOREIGN PATENT DOCUMENTS
`
`100567325 C
`102233132 B
`102380096 B
`103212075 B
`107115294 A
`2663325
`2010-509369
`97/04801
`WO 97/04801
`WO 2000/75319
`WO 2004/106378 A2
`WO 2005/000895 A2
`WO 2006/047325
`WO 2007/022101 A2
`WO 2008/063932
`WO 2012/097019
`
`# 22222
`
`CN
`EP
`JP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`12/2009
`10/2013
`4/2014
`6/2017
`9/2017
`11/2013
`3/2010
`2/1997
`2/1997
`12/2000
`12/2004
`1/2005
`3/2006
`2/2007
`5/2008
`7/2012
`
`OTHER PUBLICATIONS
`U.S. Appl . No. 16 / 159,282 — Third Party Submissions dated May
`31 , 2019 .
`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 ) .
`Anonymous “ Lucentis ( rangibizymab injection ) Intravitreal Injec
`tion ” pp . 103 ( Jun . 2006 ) .
`Anonymous “ Anti - VEGF 2019 : The State of the Art ” Review of
`Ophthalmology ( published Aug. 5 , 2019 ) .
`Barbazetto , “ Dosing Regimen And The Frequency Of Macular
`Hemorrhages 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 ) .
`Bayer Investor News ,
`“ VEGF Trap - Eye : New Data Confirm Suc
`cesses in the Treatment of Age - related Macular Degeneration ” ( Sep.
`28 , 2008 ) .
`Benz et al . “ CLEAR - IT - 2 : Interim Results Of The Phase II , Ran
`domized , Controlled Dose - and Interval - ranging Study Of Repeated
`
`Intravitreal VEGF Trap Administration In Patients With Neovascular
`Age - related Macular Degeneration ( AMD ) ” ARVO Annual Meeting
`Abstract ( May 2007 ) .
`Boyer , “ A Phase IIIb Study to Evaluate the Safety of Ranibizumab
`in Subjects with Neovascular Age - related Macular Degeneration . ”
`Ophthalmology , 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 , 120 ( 10 ) : 2013-22 ( Oct. 2013 ) .
`Browning et al . “ Aflibercept for age - related macular degeneration :
`a game - changer or quiet addition ? ” American Journal of Ophthal
`mology , 154 ( 2 ) : 222-226 ( Aug. 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 ) .
`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 ) .
`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 ) .
`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 ) .
`Center for Drug Evaluation and Research BLA Application No.
`125156 Medical Review , ( Jun . 2006 ) < URL : https : //www.accessdata .
`fda.gov/drugsatfda_docs/nda/2006/125156s000_Lucentis_MedR .
`pdf > .
`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 ) .
`Chatziralli et al . “ Intravitreal aflibercept for neovascular age - related
`macular degeneration in patients aged 90 years or older : 2 - year
`visual acuity outcomes ” Eye ( 2018 ) 32 : 1523-1529 .
`Chung et al . “ Ziv - aflibercept : A novel angiogenesis inhibitor for the
`treatment of metastatic colorectal cancer ” Am J Heath - Syst Pharm
`( Nov. 1 , 2013 ) 70 : 1887-1896 .
`Cooper et al . , “ Increased Renal Expression of Vascular Endothelial
`Growth Factor ( VEGF ) and Its Receptor VEGFR - 2 in Experimental
`Diabetes ” Diabetes ( 1999 ) 48 : 2229-2239 .
`Croll et al . , “ VEGF - mediated inflammation precedes angiogenesis
`in adult brain ” Experimental Neurology ( 2004 ) 187 : 388-402 .
`Csaky , “ Safety Implications of Vascular Endothelial Growth Factor
`Blockade for Subjects Receiving Intravitreal Anti - Vascular Endothelial
`Growth Factor Therapies . ” Am . J. Ophthalmology , 148 ( 5 ) : 647-56 ,
`( Nov. 2009 ) .
`DeVriese et al . , “ Antibodies against Vascular Endothelial Growth
`Factor Improve Early Renal Dysfunction in Experimental Diabetes ”
`J. Am . Soc . Nephrol ( 2001 ) 12 : 993-1000 .
`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 Ophthalmol . 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 ” Ophthalmology ,
`118 ( 9 ) : 1819-1826 ( Sep. 2011 ) .
`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 ) .
`Do et al . “ Results of a Phase 1 Study of Intravitreal VEGF Trap in
`Subjects with Diabetic Macular Edema : The CLEAR - IT DME
`Study " ARVO Annual Meeting Abstract ( May 2007 ) .
`
`Celltrion Exhibit 1001
`Page 2
`
`

`

`US 11,253,572 B2
`Page 3
`
`> >
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`Do et al . “ VEGF Trap - Eye Vision - specific Quality of Life through
`52 Weeks in Patients with Neovascular AMD in CLEAR - IT 2 : A
`Phase 2 Clinical Trial ” ARVO Annual Meeting Abstract ( Apr.
`2009 ) .
`Eichten ,
`“ Rapid decrease in tumor perfusion following VEGF
`blockade predicts long - term tumor growth inhibition in preclinical
`tumor models ” Angiogenesis , 16 : 429-441 ( 2013 ) .
`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 ) .
`Engelbert , “ Long - Term Follow - Up For Type 1 ( Subretinal Pigment
`Epithelium ) Neovascularization Using A Modified “ Treat And Extend '
`Dosing Regiment Of Intravitreal Antivascular Endothelial Growth
`Factor Therapy . ” Retina , 30 ( 9 ) : 1368-75 ( 2010 ) .
`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 : //www.visioncareprofes
`sional.com/emails/amdupdate/index.asp?issue=42 .
`Eremina et al . , " Glomerular - specific alterations of VEGF - A expres
`sion lead to distinct congenital and acquired renal diseases ” Journal
`of Clinical Investigation ( Mar. 2003 ) 111 ( 5 ) : 707-716 .
`Eriksson et al . , " Structure , Expression and Receptor - Binding Prop
`erties of Novel Vascular Endothelial Growth Factors ” Vascular
`Growth Factors and Angiogenesis , Springer ( 1999 ) pp . 41-57 .
`The Eyetech Study Group , “ Anti - Vascular Endothelial Growth
`Factor Therapy for Subfoveal Choroidal Neovascularization Sec
`ondary to Age - related Macular Degeneration ” American Academy
`of Ophthalmology , 110 ( 5 ) : 979-986 ( May 2003 ) .
`Eylea® , Highlights of Prescribing Information , Revised Aug. 2018 .
`Ferrara , N. “ Vascular Endothelial Growth Factor : Molecular and
`Biological Aspects ” Advances in Organ Biology ( 1999 ) pp . 1-30 .
`Ferrara et al . , “ Clinical applications of angiogenic growth factors
`and their inhibitors ” Nature Medicine ( Dec. 1999 ) 5 ( 12 ) : 1359-1364 .
`Flyvbjerg et al . , “ Amelioration of Long - Term Renal Changes in
`Obese Type 2 Diabetic Mice by a Neutralizing Vascular Endothelial
`Growth Factor Antibody ” Diabetes ( Oct. 2002 ) 51 : 3090-3094 .
`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 . 267-273 ( 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 . ” Neuro - Oncology , 10 : 940-945 ( Dec. 2008 ) .
`Gragoudas , “ Pegaptanib for Neovascular Age - Related Macular Degen
`eration . ” N Engl J Med , 351 ( 27 ) : 2805-16 , ( Dec. 30 , 2004 ) .
`Gutierrez et al . , “ Intravitreal bevacizumab ( Avastin ) in the treatment
`of macular edema secondary to retinal vein occlusion ” Clin .
`Ophthalmol . , 2 ( 4 ) : 787,791 ( 2008 ) .
`Haller et al . , “ VEGF Trap - Eye In CRVO : Primary Endpoint Results
`of the Phase 3 COPERNICUS Study ” ARVO Annual Meeting
`Abstract ( Apr. 2011 ) .
`Heier et al . , " CLEAR - IT 2 : Phase 2 , Randomized Controlled Dose
`and Interval - Ranging Study of Intravitreal VEFG Trap Eye in
`Patients with Neovascular Age - Related Macular Degeneration : Pre
`dictive Factors for Visual Acuity ” ARVO Annual Meeting Abstract
`( Apr. 2009 ) .
`Heier , J. , “ Intravitreal VEGF Trap for AMD : An Update , The
`CLEAR - IT 2 Extension Study ” Presented at the annual meeting of
`the Association for Research in Vision and Ophthalmology , Retina
`Today ( 2009 ) pp . 44-45 .
`
`Heier et 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 ) .
`Heier , “ Intravitreal Aflibercept for Diabetic Macular Edema : 148
`Week Results from the VISTA and VIVID Studies . ” Ophthalmol
`ogy , 123 ( 11 ) : 2376-2385 ( Nov. 2016 ) .
`Heier et al . , “ The 1 - year Results of CLEAR - IT 2 , a Phase 2 Study
`of Vascular Endothelial Growth Factor Trap - Eye Dosed As - needed
`After 12 - week Fixed Dosing ” Ophthalmology 2011 ; 118 : 1098-1106
`( Jun . 2011 ) .
`Heier et al . , “ The 1 - year Results of CLEAR - IT 2 , a Phase 2 Study
`of Vascular Endothelial Growth Factor Trap - Eye Dosed As - needed
`After 12 - week Fixed Dosing : Erratum ” Ophthalmology 2011 ; 118 : 1700
`( Sep. 2011 ) .
`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 ) .
`Ho et al . , Slides entitled CLEAR IT 2 One - Year Key Results , Retina
`Society ( 2008 ) .
`Holash et al . , “ Vessel Cooption , Regression , and Growth in Tumors
`Mediated by Angiopoietins and VEGF ” Science ( Jun . 18 , 1999 )
`284 ( 5422 ) : 1994-1998 .
`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 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00320775 “ Safety and Tolerability of Intravitreal Admin
`istration of VEGF Trap in Patients With Neovascular Age - Related
`Macular Degeneration ” 70 pages , Latest version submitted Jun . 8 ,
`2011 on ClinicalTrials.gov ( NCT00320775_2006-2011 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00320775 " Safety and Tolerability of Intravitreal Admin
`istration of VEGF Trap in Patients With Neovascular Age - Related
`Macular Degeneration " 10 pages , Latest version submitted Mar. 16 ,
`2015 on ClinicalTrials.gov ( NCT00320775_2015 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00320788 “ Safety and Efficacy of Repeated Intravitreal
`Administration of Vascular Endothelial Growth Factor ( VEGF )
`Trap in Patients With Wet Age - Related Macular Degeneration
`( AMD ) ” 71 pages , Latest version submitted Dec. 1 , 2011 on
`ClinicalTrials.gov ( NCT00320788_2006-2011 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00320788 “ Safety and Efficacy of Repeated Intravitreal
`Administration of Vascular Endothelial Growth Factor ( VEGF )
`Trap in Patients With Wet Age - Related Macular Degeneration
`( AMD ) ” 31 pages , Latest version submitted Jan. 27 , 2012 on
`ClinicalTrials.gov ( NCT00320788_2012 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00320814 “ Phase 1 Study of VEGF Trap in Patients
`With Diabetic Macular Edema ” 30 pages , Latest version submitted
`Jun . 8 , 2011 on Clinical Trials.gov ( NCT00320814_2006-2011 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00509795 “ Double - Masked Study of Efficacy and Safety
`of IVT VEGF Trap - Eye in Subjects With Wet AMD ( VIEW 1 ) ” 318
`pages , Latest version submitted Dec. 1 , 2011 on ClinicalTrials.gov
`( NCT00509795_2007-2011 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00509795 “ Double - Masked Study of Efficacy and Safety
`of IVT VEGF Trap - Eye in Subjects With Wet AMD ( VIEW 1 ) " 200
`pages , Latest version submitted Dec. 20 , 2012 on ClinicalTrials.gov
`( NCT00509795_2012 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00527423 “ Randomized , Single - Masked , Long - Term ,
`
`*
`
`Celltrion Exhibit 1001
`Page 3
`
`

`

`US 11,253,572 B2
`Page 4
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`Safety and Tolerability Study of VEGF Trap - Eye in AMD ” 64
`pages , Latest version submitted Nov. 1 , 2011 on Clinical Trials.gov
`( NCT00527423_2007-2011 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00527423 “ Randomized , Single - Masked , Long - Term ,
`Safety and Tolerability Study of VEGF Trap - Eye in AMD ” 42
`pages , Latest version submitted Jun . 10 , 2013 on Clinical Trials.gov
`( NCT00527423_2012-2013 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00637377 “ Vascular Endothelial Growth Factor ( VEGF )
`Trap - Eye : Investigation of Efficacy and Safety in Wet Age - Related
`Macular Degeneration ( AMD ) ( VIEW 2 ) ” 667 pages , Latest version
`submitted Dec. 16 , 2011 on ClinicalTrials.gov ( NCT00637377_
`2008-2011 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00637377 “ Vascular Endothelial Growth Factor ( VEGF )
`Trap - Eye : Investigation of Efficacy and Safety in Wet Age - Related
`Macular Degeneration ( AMD ) ( VIEW 2 ) ” 289 pages , Latest version
`submitted Nov. 28 , 2014 on ClinicalTrials.gov ( NCT00637377_
`2012-2014 ) .
`Information from Clinical Trials.gov archive History of Changes for
`Study : NCT00789477 “ DME And VEGF Trap - Eye [ Intravitreal
`Aflibercept Injection ( IAI ; EYLEA® ; BAY86-5321 ) ] INvestigation
`of Clinical Impact ( DA VINCI ) ” 135 pages , Latest version submit
`ted May 2 , 2011 on Clinical Trials.gov ( NCT00789477_2008-2011 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00789477 “ DME And VEGF Trap - Eye [ Intravitreal
`Aflibercept Injection ( IAI ; EYLEA® ; BAY86-5321 ) ] INvestigation
`of Clinical Impact ( DA VINCI ) " 53 pages , Latest version submitted
`Aug. 28 , 2014 on Clinical Trials.gov ( NCT00789477_2013-2014 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00943072 “ Vascular Endothelial Growth Factor ( VEGF )
`Trap - Eye : Investigation of Efficacy and Safety in Central Retinal
`Vein Occlusion ( CRVO ) ” 98 pages , Latest version submitted May
`9 , 2011 on ClinicalTrials.gov ( NCT00943072_2009-2011 ) .
`Information from ClinicalTrials.gov archive History of Changes for
`Study : NCT00943072 “ Vascular Endothelial Growth Factor ( VEGF )
`Trap - Eye : Investigation of Efficacy and Safety in Central Retinal
`Vein Occlusion ( CRVO ) ” 64 pages , Latest version submitted Apr.
`16 , 2013 on ClinicalTrials.gov ( NCT00943072_2012-2013 ) .
`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 ) " ClinicalTrials.gov . Web . ( Nov. 30 , 2010 ) .
`Information from ClinicalTrials.gov archive on the VIEW 2 study
`( NCT00637377 ) “ VEGF Trap - Eye : Investigation of Efficacy and
`Safety in Wet AMD ( VIEW 2 ) " version available ( 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 ) .
`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 appli
`
`cation U.S. Appl . No. 16 / 055,847 ] ” which was cited in the Third
`Party Observations dated May 1 , 2019 ) .
`Karia , Niral , “ Retinal vein occlusion : pathophysiology and treat
`ment options " Clinical Ophthalmology , 4 : 809-816 ( 2010 ) .
`Korobelnik et al . , “ Intravitreal Aflibercept Injection for Macular
`Edema Resulting from Central Retinal Vein Occlusion ” American
`Academy of Ophthalmology ( 2014 ) 121 ( 1 ) : 202-208 .
`Korobelnik , “ Intravitreal Aflibercept for Diabetic Macular Edema . "
`Ophthalmology , 121 ( 11 ) : 2247-54 ( Nov. 2014 ) .
`Kuo , “ Comparative evaluation of the antitumor activity of antiangiogenic
`proteins delivered by gene transfer ” PNAS 98 ( 8 ) : 4605-4610 ( Apr.
`10 , 2001 ) .
`Krzystolik et al . ,
`“ Prevention of Experimental Choroidal
`NEovascularization With Intravitreal Anti - Vascular Endothelial Growth
`Factor Antibody Fragment ” Arch Ophthamol . , 120 : 338-346 ( Mar.
`2002 ) .
`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 ) .
`Lucentis Label Title , 7 pages , Jun . 30 , 2010 [ Cited in Third Party
`Observations filed in parent application U.S. Appl . No. 16 / 055,847 ] .
`Major et al . , “ DA VINCI : DME and VEGF Trap - Eye : Investigation
`of Clinical Impact : Phase 2 Study in Patients with Diabetic Macular
`Edema ( DME ) " ARVO Annual Meeting Abstract ( Apr. 2010 ) .
`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 ) .
`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 ) .
`Mitchell , Edith P. “ Targeted Therapy for Metastatic Colorectal
`Cancer : Role of Aflibercept ” Clinical Colorectal Cancer ( 2013 )
`12 ( 2 ) : 73-85 .
`N / A “ Materials from Jun . 2011 FDA Committee Mtg ” ( Jun . 17 ,
`2011 ) .
`N / A “ Materials from Dec. 2011 FDA Committee Mtg ” ( Dec .
`1 ,
`2011 ) .
`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 ) .
`Nguyen et al . , “ Randomized , Double - masked , Active - controlled
`Phase 3 Trial of the Efficacy and Safety of Intravitreal VEGF
`Trap - Eye in Wet AMD : One - year Results of the VIEW 1 Study ”
`ARVO Annual Meeting Abstract ( 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 ) .
`Nguyen et al . , “ Results of a Phase I , Dose - Escalation , Safety ,
`Tolerability , and Bioactivity Study of Intravitreous VEGF Trap in
`Patients with Neovascular Age - Related Macular Degeneration ”
`ARVO Annual Meeting Abstract ( May 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 , 2003 ) .
`Noguera - Troise et al . , “ Blockade of D114 inhibits tumour growth by
`promoting non - productive angiogenesis ” Nature ( Dec. 2006 ) 444 : 1032
`1037 .
`Ohr , “ Aflibercept in wet age - related macular degeneration : a per
`spective review ” Ther . Adv . Chronic Dis . , 3 ( 4 ) : 153-161 ( 2012 ) .
`Olivera et al . , “ VEGF Trap R1R2 suppresses experimental corneal
`angiogenesis ” European Journal of Ophthalmology , 20 ( 1 ) : 48-54
`( Jan. 1 , 2010 ) .
`
`Celltrion Exhibit 1001
`Page 4
`
`

`

`US 11,253,572 B2
`Page 5
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`Pai et al . , " Current concepts in intravitreal drug therapy for diabetic
`retinopathy ” Saudi Journal of Ophthalmology 24 ( 4 ) : 143-149 ( Jun .
`30 , 2010 ) .
`Papadppoulos , “ Binding and neutralization of vascular endothelial
`growth factor ( VEGF ) and related ligands by VEGF Trap , ranibizumab
`and bevacizumab ” Angiogenesis , 15 : 171-185 ( 2012 ) .
`Regeneron SEC Form 10 - K ( Feb. 27 , 2008 ) .
`Regeneron SEC Form 10 - K ( Feb. 26 , 2009 ) .
`Regeneron SEC Form 10 - K ( Feb. 17 , 2011 ) .
`Regeneron SEC Form 10 - Q ( May 8 , 2006 ) .
`Regeneron SEC Form 10 - Q ( Aug. 8 , 2006 ) .
`Regeneron SEC Form 10 - Q ( Nov. 6 , 2006 ) .
`Regeneron SEC Form 10 - Q ( May 4 , 2007 ) .
`Regeneron SEC Form 10 - Q ( Aug. 3 , 2007 ) .
`Regeneron SEC Form 10 - Q ( Apr. 30 , 2009 ) .
`Regeneron SEC Form 10 - Q ( Nov. 3 , 2009 ) .
`Regeneron SEC Form 10 - Q ( Apr. 29 , 2010 ) .
`Regeneron SEC Form 10 - Q ( Jul . 28 , 2010 ) .
`Regeneron SEC Form 10 - Q ( Oct. 28 , 2010 ) .
`Regeneron SEC Form 10 - Q ( May 3 , 2011 ) .
`Regeneron SEC Form 10 - Q ( Jul . 28 , 2011 ) .
`Regeneron SEC Form 10 - Q ( Oct. 27 , 2011 ) .
`Regeneron SEC Form 8 - K Exhibit :
`“ Press Release of Regeneron
`Pharmaceuticals , Inc. dated May 1 , 2006 ” ( May 2 , 2006 ) .
`Regeneron SEC Form 8 - K Exhibit :
`“ Press Release of Regeneron
`Pharmaceuticals , Inc. dated May 3 , 2006 ” ( May 5 , 2006 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Slides presented at the Com
`pany's 2006 Annual Meeting of Shareholders held on Jun . 9 , 2006 ”
`( Jun . 9 , 2006 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Press Release dated May 2 ,
`2007 ” ( May 3 , 2007 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Overheads for presentation at
`Regeneron's Annual Meeting of Shareholders to be held on Jun . 8 ,
`2007 ” ( Jun . 8 , 2007 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Press Release dated Oct. 1 ,
`2007 " ( Oct. 1 , 2007 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Press Release dated Nov. 6 ,
`2007 ” ( Nov. 6 , 2007 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Press Release dated May 1 ,
`2008 ” ( May 2 , 2008 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Press Release dated Nov. 4 ,
`2008 ” ( Nov. 4 , 2008 ) .
`Regeneron SEC Form 8 - K Exhibit : “ 99 ( a ) Slides that Regeneron
`Pharmaceuticals , Inc. intends to use in conjunction with meetings
`with investors at the J.P. Morgan 27th Annual Healthcare Confer
`ence in San Francisco on Jan. 12-15 , 2009. ” ( Jan. 9 , 2009 ) .
`Regeneron SEC Form 8 - K Exhibit :
`“ Press Release dated Apr. 30 ,
`2009 ” ( May 1 , 2009 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Press Release dated Nov. 3 ,
`2009. ” ( Nov. 4 , 2009 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Press Release Reporting Posi
`tive 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 ) dated Dec. 20 , 2010. " ( Dec. 20 , 2010 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Press Release dated Feb. 17 ,
`2011 ” ( Feb. 18 , 2011 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Press Release Reporting Posi
`tive Results for VEGF Trap - Eye in Second Phase 3 Study in Central
`Retinal Vein Occlusion , dated Apr. 27 , 2011 ” ( Apr. 27 , 2011 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Press Release dated May 3 ,
`2011. " ( May 3 , 2011 ) .
`Regeneron SEC Form 8 - K Exhibit :
`“ Press Release , dated Jun . 17 ,
`2011 , Announcing that EYLEATM ( aflibercept ophthalmic solution )
`Received Unanimous Recommendation for Approval for Treatment
`of Wet AMD from FDA Advisory Committee . ” ( Jun . 21 , 2011 ) .
`Regeneron SEC Form 8 - K Exhibit : “ Presentation entitled VEGF
`Trap - Eye in CRVO : 1 - year Results of the Phase 3 COPERNICUS
`Study ” ( Aug. 22 , 2011 ) .
`
`2
`
`Regeneron SEC Form 8 - K Exhibit : “ Press Release Announcing
`FDA Approval of EYLEATM ( aflibercept ) Injection for the Treat
`ment of Wet Age - Related Macular Degeneration , dated Nov. 18 ,
`2011 ” ( Nov. 21 , 2011 ) .
`Regeneron Press Release “ Positive Interim Phase 2 Data Reported
`For VEGF Trap - Eye In Age - Related Macular Degeneration ” ( Mar.
`27 , 2007 ) .
`Regeneron Press Release “ VEGF