`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC., CELLTRION, INC.,
`and APOTEX INC.,
`Petitioners
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.
`Patent Owner
`
`____________
`
`Case IPR2021-008801
`Patent 9,669,069 B2
`
`***
`
`Case IPR2021-00881
`Patent 9,254,338 B2
`____________
`
`
`
`
`EXPERT DECLARATION OF DAVID M. BROWN, M.D.
`
`
`
`
`
`
`
`
`
`
`
`1 IPR2022-00257, IPR2022-00258, IPR2022-00298, and IPR2022-00301 have been
`joined with this proceeding.
`
`Exhibit 2050
`Page 01 of 92
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`

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`
`
`TABLE OF CONTENTS
`
`Page No.
`
`Contents
`Introduction ...................................................................................................... 1
`I.
`Qualifications and Experience ......................................................................... 2
`II.
`Summary of Opinions ...................................................................................... 4
`III.
`IV. The Person of Ordinary Skill in the Art .......................................................... 5
`V.
`Legal Standards ............................................................................................... 6
`A.
`Burden of Proof ..................................................................................... 6
`B.
`Obviousness ........................................................................................... 6
`C.
`Anticipation ........................................................................................... 8
`VI. The State Of The Art ....................................................................................... 8
`A.
`The Prior Art Treatment of Angiogenic Eye Disorders with Anti-
`VEGF Therapies .................................................................................... 8
`The Need for an Extended Dosing Regimen ....................................... 17
`B.
`Extended Dosing Failures in the Prior Art .......................................... 18
`C.
`VII. Clinical Testing And Approval Of Eylea® ................................................... 32
`A.
`CLEAR-IT 2 ........................................................................................ 34
`B.
`VIEW 1 and VIEW 2 .......................................................................... 35
`C.
`Approval of Eylea® ............................................................................ 43
`VIII. The ’338 Patent .............................................................................................. 44
`A.
`The Claimed Invention ........................................................................ 44
`B.
`Claim Construction ............................................................................. 46
`1.
`“A method for treating an angiogenic eye disorder in a
`patient” ...................................................................................... 46
`“tertiary dose” ........................................................................... 47
`
`2.
`
`
`
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`2.
`
`3.
`
`4.
`
`IX. The ’069 Patent .............................................................................................. 47
`X.
`’338 Patent, Ground 6: The Challanged claims are not Obvious
`Based on Dixon .............................................................................................. 49
`A.
`The POSA Would Not Have Had a Reasonable Expectation of
`Success That the Claimed Q8 Dosing Regimen Would Be
`Effective Until After Regeneron’s VIEW Trials. ............................... 49
`1.
`Failures to Achieve an Extended Dosing Regimen in the Art
`Would Have Led the POSA to Be Skeptical About the
`Disclosed Q8 Dosing Regimen. ................................................ 50
`The Fact That Regeneron Initiated Phase 3 Testing Would
`Not Have Provided the POSA with a Reasonable
`Expectation of Success. ............................................................ 51
`The Results of CLEAR-IT 2 Would Not Have Provided the
`POSA With a Reasonable Expectation of Success. .................. 55
`Dixon Cautioned That the Most Effective Dosing Regimen
`Was Not Established. ................................................................ 61
`’069 Patent, Ground 4: The Challenged Claims Are not anticipated
`or obvious Based on VIEW 1/VIEW 2 as Disclosed In Dixon. .................... 62
`A.
`The VIEW 8-Week Dosing Regimen is Fixed, Not As-Needed /
`Pro Re Nata (PRN).............................................................................. 62
`The POSA Would Not Have Been Motivated to Replace VIEW’s
`8-Week Fixed Dosing Regimen with PRN Dosing. ........................... 62
`’069 Patent, Ground 5: The Challenged Claims Are not obvious
`Based on HEIER-2009 In View Of Mitchell Or Dixon. ............................... 67
`XIII. Objective Indicia Of Non-Obviousness ......................................................... 74
`A.
`Long-Felt Need for an Extended Dosing Regimen ............................. 74
`B.
`Satisfaction of a Long-Felt Need ........................................................ 77
`C.
`Failure of Others to Achieve an Extended Dosing Regimen .............. 79
`1.
`Lucentis (ranibizumab) ............................................................. 79
`2. Macugen .................................................................................... 81
`3.
`Conbercept ................................................................................ 83
`
`XI.
`
`B.
`
`XII.
`
`
`
`
`–ii–
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`D. Unexpected Benefits ........................................................................... 84
`E.
`Industry Praise and Recognition ......................................................... 86
`
`
`
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`
`I, Dr. David Brown, declare as follows:
`
`I.
`
`INTRODUCTION
`I have been retained by counsel for Regeneron Pharmaceuticals, Inc.
`1.
`
`(“Regeneron”) as a technical expert in connection with the above-captioned
`
`proceeding. I have been asked to provide my opinions and views on the materials I
`
`have reviewed in relation to the Petition for Inter Partes review of U.S. Patent No.
`
`9,254,338 (“the’338 Patent”) (Ex. 1001)2 and the Petition for Inter Partes review of
`
`U.S. Patent No. 9,669,069 (“the ’069 Patent”) (Ex. 1019). In particular, I have been
`
`asked to comment on the state of the art as of the earliest filing date (“priority date”)
`
`of the ’338 and ’069 Patents and to respond to the opinion and views of Petitioner’s
`
`declarant, Thomas A. Albini, M.D. I submit this declaration in support of
`
`Regeneron’s Patent Owner Responses (“PORs”).
`
`2.
`
`I am being paid at my usual and customary rate for my work on this
`
`matter. I have no personal or financial stake in, or affiliation with, the petitioner,
`
`real-parties-in-interest, or the patent owner. My compensation is not dependent
`
`upon the outcome of, or my testimony in, the present proceeding.
`
`
`2 Unless otherwise noted, all citations to exhibits refer to exhibits filed in
`IPR2021-00881, and all pin cites refer to the stamped exhibit page.
`
`
`
`
`–1–
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`II. QUALIFICATIONS AND EXPERIENCE
`I am the Director of the Greater Houston Retina Research Center, where
`3.
`
`I have been a Physician Partner and Researcher since 1995. I also have a series of
`
`academic appointments: Clinical Professor of Ophthalmology, Cullen Eye Institute
`
`at Baylor College of Medicine; Vice-Chair of Ophthalmology for Research and
`
`Associate Clinical Professor of Ophthalmology at the Methodist Hospital, Weill
`
`Cornell College of Medicine in Houston, Texas; and the NASA Research and
`
`Clinical Advisory Panel—Space Associated Neuro-Ophthalmic Syndrome at NASA
`
`Johnson Space Center in Houston, Texas.
`
`4.
`
`I graduated from Baylor College of Medicine with highest honors in
`
`1988. I completed a medical/surgical internship at Baylor College of Medicine from
`
`1989-1990. From 1990-1995, I completed ophthalmology and retina training at the
`
`University of Iowa where I was a Thomas Heed Fellow, a Hermann Knapp Fellow,
`
`and was awarded the Ron Michels Fellowship award presented to the top retinal
`
`surgery fellow in the United States in 1994.
`
`5.
`
`I have served on the Board of Directors of the American Society of
`
`Retina Specialists since 2014; the Macula Society Credentials Committee since 2013;
`
`and the Retina Society Finance Committee since 2018. I have served in numerous
`
`additional leadership roles in professional organizations and societies in the retina
`
`and ophthalmology field over the past three decades. I have also been a peer
`
`
`
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`reviewer for the journals in these fields, including OPHTHALMOLOGY, RETINA,
`
`and the New England Journal of Medicine,
`
`6.
`
`I maintain an active medical and surgical practice focused on treatment
`
`of retinal diseases and have continuously been elected as one of the “Best Doctors
`
`in America” from 2007-2021 and “Texas Super Docs” from 2009-2021. I am also
`
`an elected member of the Macula Society, the Retina Society, and the Club Jules
`
`Gonin. My honors include the American Academy of Ophthalmology Honor Award
`
`(2000), the American Society of Retina Specialists Honor Award (2008), the ASRS
`
`Senior Honor Award (2010), the AAO Senior Honor Award (2014), and Retina Hall
`
`of Fame inaugural inductee (2017).
`
`7. My research and clinical trial experience has led to my recognition as
`
`an international thought leader on treatments and current standards of care for age
`
`related macular degeneration, retinal vein occlusion, and diabetic retinopathy. I have
`
`written and published over 400 national meeting presentations, abstracts, and
`
`scientific papers including many of the primary papers establishing the safety and
`
`efficacy of use of anti-vascular endothelial growth factor (“anti-VEGF”) agents for
`
`wet age-related macular degeneration (“wAMD”), retinal vein occlusion, and
`
`diabetic retinopathy.
`
`8.
`
`I have served as a key investigator on the seminal Phase III clinical
`
`trials establishing the efficacy of anti-VEGF agents ranibizumab (Genentech’s
`
`
`
`
`–3–
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`Lucentis) and aflibercept (Regeneron’s Eylea) in wAMD, diabetic macular edema
`
`and diabetic retinopathy, and retinal vein occlusions. For example, I was a lead
`
`investigator on Genentech’s Anti-VEGF Antibody for
`
`the Treatment of
`
`Predominantly Classic Choroidal Neovascularization in Age-related Macular
`
`Degeneration (ANCHOR) Study, the Minimally Classic/Occult Trial of the Anti-
`
`VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA)
`
`Study, and Regeneron’s VEGF Trap-Eye: Investigation of Efficacy and Safety in
`
`Wet AMD (VIEW1) Study. My research efforts have contributed to a
`
`transformation in the nature of treatments and outcomes for angiogenic eye disorders.
`
`A current copy of my curriculum vitae is filed herewith as Ex. 2083.
`
`III. SUMMARY OF OPINIONS
`9. My opinions and views set forth in this declaration are based on my
`
`education, training, research, and clinical experience in ophthalmology, specifically
`
`in researching and treating retinal diseases, as well as the materials I reviewed in
`
`preparing this declaration and the state of scientific knowledge in the art pertaining
`
`to the subject matter of the ’338 patent at the time of its earliest priority application.
`
`10.
`
`In forming my opinions, I have reviewed the following materials: (a)
`
`the Petition for Inter Partes Review of U.S. Patent No. 9,254,338 B2, IPR2021-
`
`00881, including all cited exhibits; (b) the Petition for Inter Partes review of U.S.
`
`Patent No. 9,669,069 B2, IPR2021-00880, including all cited exhibits; (c) all other
`
`
`
`
`–4–
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`documents and references herein; and (d) the Patent Owner’s Response to which my
`
`declaration relates.
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART
`I am informed that the person of ordinary skill in the art is a hypothetical
`11.
`
`person who is presumed to have access to, and be aware of, all of the relevant prior
`
`art at the time of the invention. At times I will refer to such person as the “POSA.”
`
`12.
`
`In forming my opinions, I have been asked to consider the level of
`
`ordinary skill in the art as it relates to the earliest effective filing date of the ’338
`
`Patent and ’069 Patents. I understand that the application that led to the ’338 Patent
`
`was filed on July 12, 2013. I understand that the application that led to the ’069
`
`Patent was filed on December 17, 2015. I further understand that both applications
`
`claim priority to provisional applications filed on January 13, 2011, January 21,
`
`2011, and November 21, 2011. I have been informed and understand that the earliest
`
`filing date of the ‘338 Patent and the ’069 Patent is January 13, 2011.
`
`13.
`
`I understand that Petitioner contends that a person of ordinary skill in
`
`the art of the ’338 and ’069 Patents would have:
`
`(1) knowledge regarding the diagnosis and treatment of
`angiogenic eye disorders, including the administration of
`therapies to treat said disorders; and (2) the ability to
`understand results and findings presented or published by
`others in the field, including the publications discussed
`herein. Typically, such a person would have an advanced
`degree, such as an M.D. or Ph.D. (or equivalent, or less
`education but considerable professional experience in the
`
`
`
`
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`medical, biotechnological, or pharmaceutical field), with
`practical academic or medical experience
`in:
`(i)
`developing treatments for angiogenic eye disorders, such
`as AMD, including through the use of VEGF antagonists,
`or (ii) treating of same, including through the use of VEGF
`antagonists.
`
`14.
`
`I understand that Patent Owner contends that the skilled artisan is an
`
`ophthalmologist with experience in treating angiogenic eye disorders, including
`
`through the use of VEGF antagonists.
`
`15. My opinions set forth in this declaration remain the same under either
`
`Petitioner’s or Patent Owner’s definition.
`
`V. LEGAL STANDARDS
`I am not an expert in the law. The legal standards I have applied were
`16.
`
`explained to me by counsel for Patent Owner.
`
`A. Burden of Proof
`I have been informed that each claim of an issued patent is presumed to
`17.
`
`be valid. To overcome that presumption of validity, the party challenging the claim’s
`
`validity must establish unpatentability by a preponderance of the evidence.
`
`B. Obviousness
`I have been informed that a patent challenger may contend that a patent
`18.
`
`claim is invalid by arguing that it would have been obvious to a person of ordinary
`
`skill in the art at the time of the claimed invention.
`
`
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`19.
`
`I have been informed that a patent claim is obvious in view of the prior
`
`art if the differences between the patented claims and the prior art are such that, at
`
`the time of the invention, the subject matter as a whole would have been obvious to
`
`a POSA.
`
`20.
`
`I have been informed that the factors to be considered in analyzing
`
`whether a claim was obvious are (i) the scope and content of the prior art; (ii) the
`
`differences between the prior art and the claims; (iii) the level of ordinary skill in the
`
`art; and (iv) any asserted objective indicia of non-obviousness.
`
`21.
`
`I have been further informed that objective indica of non-obviousness
`
`are considered when assessing whether an invention would have been obvious at the
`
`time of the invention, as a check against “hindsight bias”—the inclination after a
`
`problem has been solved to see the solution as obvious or predictable when it was
`
`not.
`
`22.
`
`I have been informed that objective indicia of non-obviousness may
`
`include satisfying a long-standing problem or long-felt need, failure of other,
`
`unexpected benefits or results, industry skepticism, and praise for the invention.
`
`23.
`
`I have been informed that the objective indicia of non-obviousness
`
`should have a “nexus” to the claimed invention, that is, a link to the claimed
`
`invention. I am informed that such a “nexus” may exist when the objective indicia
`
`
`
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`are tied to a product that embodies the claimed invention or a product whose use
`
`embodies the claimed invention.
`
`C. Anticipation
`I have been informed that for a patent to be valid, the invention claimed
`24.
`
`must be novel (i.e., new). A claimed invention that is not novel is said to be
`
`“anticipated.”
`
`25.
`
` I have also been informed that for a claim to be anticipated, every
`
`limitation of the claimed invention must be found in a single prior art reference,
`
`either expressly or inherently. I understand that the words of a prior art reference do
`
`not have to be in the same words as the claim but that all limitations must be present.
`
`VI. THE STATE OF THE ART
`A. The Prior Art Treatment of Angiogenic Eye Disorders with Anti-
`VEGF Therapies
`26. Angiogenic eye disorders, characterized by pathologic growth of
`
`abnormal blood vessels and vascular leakage from damaged blood vessels in the
`
`retina, present significant risks to patients’ vision absent treatment. Angiogenic eye
`
`disorders, or neovascular eye diseases,
`
`include conditions such as
`
`iris
`
`neovascularization, retinal vein occlusion, diabetic retinopathy, diabetic macular
`
`edema, neovascular glaucoma, wAMD, and retinopathy of prematurity. Ex. 2084 at
`
`
`
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`5.3 A shared feature of angiogenic eye disorders is the presence of elevated ocular
`
`levels of VEGF, a molecule that plays a critical role in the pathology of angiogenesis
`
`and vascular permeability.
`
`27. By 2005, it was recognized by the POSA that treating patients with
`
`certain anti-VEGF agents, which reduce ocular VEGF levels, could reduce the
`
`incidence of pathologic angiogenesis and vascular permeability, and prevent loss of
`
`vision and even, in many cases, improve vision. Before the use of anti-VEGF agents,
`
`treatments for angiogenic eye disorders included methods such as laser ablation and
`
`photodynamic therapy (“PDT”). These treatments generally did not improve vision
`
`in a clinically significant manner and often carried risks of further vision loss through,
`
`for example, irreversible scarring of the retina and choroid at the site targeted by the
`
`treatment.
`
`28. Of the angiogenic eye disorders, wAMD had a particularly poor
`
`prognosis, as vision loss in these patients could be sudden, severe, and irreversible.
`
`Laser and PDT treatments generally could only slow eventual vision loss or mitigate
`
`the extent of the area of central total vision loss. Unlike certain other angiogenic eye
`
`disorders such as diabetic macular edema and retinal vein occlusion, wAMD is less
`
`
`3 Anthony P. Adamis, Ocular Angiogenesis: Vascular Endothelial Growth Factor
`and Other Factors, in Retinal Pharmacotherapy 23 (Quan Dong Nguyen et al. eds.,
`2010).
`
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`forgiving if patients wait too long to receive initial treatment or are not treated at
`
`sufficiently regular intervals. With wAMD, irreversible vision loss stems from a
`
`combination of retinal pigment epithelium (“RPE”) rips, subretinal hemorrhages,
`
`and atrophy of the photoreceptors overlying the RPE, as well as fibrosis secondary
`
`to long-standing retinal and subretinal edema.
`
`29. Early investigation of anti-VEGF agents to treat wAMD included the
`
`use of pegaptanib (Macugen®) and investigation of the use of off-label injections of
`
`Genentech’s VEGF antibody drug bevacizumab (Avastin®).
`
`30. Macugen® was the first anti-VEGF agent approved for treatment of
`
`angiogenic eye disorders, specifically wAMD. Ex. 2117.4 Macugen was approved
`
`in 2004 for administration once every six weeks based on two pivotal Phase 3 studies.
`
`Ex. 2038 at 3-5, 7.5 The primary efficacy endpoint for Macugen trials was the
`
`proportion of patients losing less than 15 letters of visual acuity. Id. at 4 (“On
`
`average, Macugen 0.3 mg treated patients and sham treated patients continued to
`
`experience vision loss. However, the rate of vision decline in the Macugen treated
`
`group was slower than the rate in the patients who received sham treatment.”
`
`(emphasis added)).
`
`
`4 Letter from Jonca C. Bull, Dir., Office of Drug Evaluation V, CDER, to Loni
`da Silva, Vice President, Glob. Regulatory Affairs, Eyetech Pharms., Inc. (Dec. 17,
`2004).
`5 Macugen Label (2004).
`
`
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`31. The major clinical experimentation that established for the retinal
`
`community the efficacy of anti-VEGF therapy, however, came with Genentech’s
`
`drug, ranibizumab (Lucentis®), a VEGF antibody fragment designed to be injected
`
`intravitreally into the patient’s eye at regular intervals.
`
`32.
`
`In 2003, before the approval of Macugen, Genentech began two large-
`
`scale, randomized Phase III clinical trials to test monthly ranibizumab injections in
`
`subjects with wAMD—MARINA and ANCHOR. I served as a principal
`
`investigator for both of these studies and was the first author on the NEJM primary
`
`manuscript for ANCHOR, Ex. 2118, 6 and second author on the NEJM primary
`
`manuscript for MARINA, Ex. 2119.7
`
`33. The MARINA trial ran from March of 2003 to December 2005 and
`
`enrolled 716 subjects with wAMD, with either minimally classic or occult choroidal
`
`neovascularization (“CNV”), were randomly assigned to received 24 monthly
`
`intravitreal injections of Lucentis (either 0.3 mg or 0.5 mg) or sham injections. Ex.
`
`2119 (MARINA) at 2-3. The primary endpoint of the study was the proportion of
`
`subjects losing fewer than 15 letters from baseline visual acuity at 12 months. Id. at
`
`2.
`
`
`6 David M. Brown et al., Ranibizumab Versus Verteporfin for Neovascular Age-
`Related Macular Degeneration, 355 N. Eng. J. Med. 1432 (2006).
`7 Philip J. Rosenfeld, David M. Brown et al., Ranibizumab for Neovascular Age-
`Related Macular Degeneration, 355 N. Eng. J. Med. 1419 (2006).
`
`
`
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`34. One-year results of the MARINA trial were presented by Genentech in
`
`July of 2005. Ex. 2120 at 4.8 The results showed that nearly ninety-five percent of
`
`subjects treated with Lucentis® maintained or improved vision at 12 months. Id.
`
`The two-year results of the MARINA trial were then published in the New England
`
`Journal of Medicine on October 5, 2006. Ex. 2119 (MARINA). The mean
`
`improvements in vision demonstrated in the first 12 months of the study were
`
`sustained through the second years of study. Id. at 11. Mean increases in visual
`
`acuity were +6.5 letters in the 0.3 mg group and +7.2 letters in the 0.5 mg groups,
`
`compared with a decrease of -10.5 letters in the sham-injection group. Ex. 2120
`
`(Dec. 30, 2005, Genentech Press Release) at 4. Impressively, visual acuity improved
`
`by 15 or more letters in 24.8% of the 0.3 mg group and 33.8% of the 0.5 mg group.
`
`Id.
`
`35. The unmasking of the one-year results of the MARINA study prompted
`
`discussion with the data and safety monitoring committee, and it was determined in
`
`October 2005, 2 months before the end of the patient’s final study visit at 24 months,
`
`that all subjects still in the sham arm could be offered ranibizumab injections.
`
`
`8 Press Release, Genentech, Inc. Submits Biologics License Application for FDA
`Review of Lucentis(TM) In Wet Age-Related Macular Degeneration (Dec. 30, 2005),
`https://www.biospace.com/article/releases/genentech-inc-submits-biologics-
`license-application-for-fda-review-of-lucentis-tm-in-wet-age-related-macular-
`degeneration-/.
`
`
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`Monthly ranibizumab injections were determined by this point to be a critical tool
`
`to not only arrest vision loss in wAMD patients, but to offer hope for sustained
`
`improvements in visual acuity.
`
`36. The MARINA results were supplemented by the outcomes from the
`
`ANCHOR trial. The ANCHOR trial ran from May of 2003 to September of 2006
`
`and enrolled 423 subjects with predominantly classic choroidal neovascularization
`
`in wAMD. Ex. 2118 (ANCHOR) at 1. Study subjects were randomized to receive
`
`monthly intravitreal Lucentis (0.3 mg or 0.5 mg) plus sham photodynamic
`
`verteporfin therapy or monthly sham injections plus active verteporfin therapy. Id.
`
`As in MARINA, the primary endpoint of the study was also the proportion of
`
`patients losing fewer than 15 letters from baseline visual acuity at 12 months. Id.
`
`37. One-year results of the ANCHOR trial were presented by Genentech in
`
`November of 2005. Ex. 2120 (Dec. 30, 2005, Genentech Press Release) at 2-3.
`
`Preliminary one-year data showed that approximately 94 percent of subjects treated
`
`with 0.3 mg of Lucentis and 96 percent of those treated with 0.5 mg of Lucentis
`
`maintained or improved vision compared to approximately 64 percent of those
`
`treated with PDT alone. Id. The one-year results were published in the New England
`
`Journal of Medicine on October 5, 2006, a paper on which I served as the first author.
`
`Ex. 2118 (ANCHOR). The two-year results of ANCHOR were then published in
`
`
`
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`January 2009 in Ophthalmology. Ex. 2085.9 In the ANCHOR study, visual acuity
`
`improved from baseline, on average, by +8.1 to +10.7 letters, versus a mean decline
`
`of -9.8 letters in the verteporfin photodynamic group. Id. at 1. Impressively, visual
`
`acuity improved by 15 or more letters in 35.7% of the 0.3-mg group and 40.3% of
`
`the 0.5-mg group at Month 12. Id. at 4.
`
`38. ANCHOR, while confirming the effectiveness of a monthly intravitreal
`
`ranibizumab treatment regimen, also represented a “major breakthrough in the
`
`treatment of predominantly classic CNV secondary to AMD” by showing this
`
`treatment was “superior to verteporfin PDT” treatment. Ex. 2085 (ANCHOR 2009)
`
`at 7. “The VA benefit from ranibizumab was both rapid and sustained: The
`
`superiority of ranibizumab to PDT was evident by 1 month after starting treatment,
`
`increased to a plateau by the end of the first year, and then persisted through month
`
`24.” Id. Like the MARINA study, the positive results demonstrated in the
`
`ranibizumab treatment arms resulted in a protocol amendment that allowed subjects
`
`in the PDT-alone arm of the study to cross over to ranibizumab injections during the
`
`latter part of the study. Id. at 4.
`
`
`9 David M. Brown et al., Ranibizumab Versus Verteporfin Photodymanic Therapy
`for Neovascular Age-Related Macular Degeneration: Two-Year Results of the
`ANCHOR Study, 116 Ophthalmology 57 (2009).
`
`
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`39. To put this in perspective if a patient were to come to me with 20/80
`
`vision, which was the average vision at study initiation of subjects in Regeneron’s
`
`VIEW 1 trial, Ex. 1018, tbl.1,10 they would no longer be able to have a driver’s
`
`license in any state in the United States. If I could treat that patient’s underlying
`
`angiogenic eye disorder and the patient were to gain between 8-10 letters from anti-
`
`VEGF therapy, that would translate into vision better than 20/63, putting that patient
`
`well within the guidelines for a daytime driver’s license. Thus, a gain of letters can
`
`translate into a meaningful real-world difference for patients. Once a therapy was
`
`available that could deliver visual acuity gains, physicians and their patients were no
`
`longer content to simply slow disease progression.
`
`40. Based on this data from MARINA and ANCHOR, Lucentis received
`
`FDA approval for the treatment of wAMD in June 2006. Ex. 2121 at 2.11 By this
`
`point in time, it was well established in the retinal community that standard of care
`
`had moved beyond observation and monitoring or destructive therapies (MPS
`
`photocoagulation-style laser or PDT with verteporfin) for wAMD to frequent
`
`intravitreal injections of ranibizumab (or off-label Avastin), which demonstrated the
`
`ability to improve vision , and maintain those gains over the course of treatment.
`
`
`10 Jeffrey S. Heier, David M. Brown et al., Intravitreal Aflibercept (VEGF Trap-Eye)
`in Wet Age-Related Macular Degeneration, 119 Ophthalmology 2537 (2012).
`11 Press Release, Genentech, FDA Approves Lucentis for the Treatment of Wet Age-
`Related Macular Degeneration (June 30, 2006).
`
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`41. After Lucentis approval, the POSA would not have viewed “loss of less
`
`than 15 letters on ETDRS best corrected visual acuity” as an effective treatment for
`
`an angiogenic eye disorder.
`
`42.
`
`Indeed, Macugen use, which was approved based on a primary endpoint
`
`of “loss of less than 15 letters on ETDRS best corrected visual acuity,” all but
`
`disappeared once Lucentis was approved. Ex. 2038 (Macugen 2004 label) at 3-4.
`
`Even though Macugen was indicated for injection every 6 weeks, as compared to
`
`Lucentis’ recommended dosing regimen of once every 4 weeks, retina doctors
`
`promptly stopped using Macugen in favor of Lucentis or off-label Avastin. Simply
`
`put, Lucentis moved the goal post and visual acuity gains became the new standard-
`
`of-care in treating wAMD. The slow decline of vision loss was no longer viewed as
`
`effective treatment of angiogenic eye disorders once there was an approved therapy
`
`that could significantly improve vision in the average patient even if this meant that
`
`patients needed more frequent visits and injections.
`
`43.
`
`In fact, clinical trials conducted after Lucentis’ approval typically
`
`measured efficacy in terms of visual acuity gains, not losses, for example:
`
`• RISE/RIDE (Genentech, Inc.): percentage of patients who
`gained ≥ 15 letters in BCVA at month 24 (Exs. 2122 and 2123);
`
`• BRAVO/CRUISE (Genentech, Inc.): mean change from
`baseline in BCVA score at 6 months (Exs. 2124 and 2125); and
`
`
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`• COPERNICUS/GALILEO (Bayer/Regeneron): percentage of
`participants who gained at least 15 letters in BCVA as measured
`by ETDRS Letter Score at week 24 (Exs. 2126 and 2127).
`Indeed, Regeneron’s clinical trials of VEGF Trap-Eye (that were not
`
`44.
`
`designed as non-inferiority trials), used mean change in visual acuity from baseline
`
`(Phase II DME Study, Example 5) and proportion of patients who gained ≥ 15 letters
`
`in BCVA at month 24 (Phase III Study in CRVO, Example 6) as primary endpoint
`
`measures of efficacy. See Ex. 1001 (’338 Patent) at 13:50-14:26, 14:35-15:8.
`
`The Need for an Extended Dosing Regimen
`B.
`45. While MARINA and ANCHOR changed the treatment paradigm for
`
`wAMD, a persistent goal of the retinal community was to find a treatment regimen
`
`that required less than monthly visits to an ophthalmologist. Intravitreal injections,
`
`while generally safe, present the risk of rare but serious adverse events such as
`
`endophthalmitis, severe intraocular inflammation, and retinal detachment. Further,
`
`monthly visits for injections are costly and burdensome to patients, their caregivers,
`
`and physician practices. Even simple monthly monitoring, while reducing risk from
`
`IVT injections themselves, is burdensome, as patients with wAMD are typically
`
`elderly and in-person visits present a challenge for the patient and their caretakers.
`
`See Ex. 1018 (Heier 2012) at 9 (“Because of the large treatment burden, extensive
`
`efforts have been devoted toward developing an optimized treatment paradigm that
`
`avoids the need for monthly injections or monitoring visits.”).
`
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`C. Extended Dosing Failures in the Prior Art
`46. Dr. Albini notes that after ANCHOR and MARINA, Genentech also
`
`conducted a number of studies with Lucentis in an effort to explore less frequent
`
`dosing, including SUSTAIN, EXCITE, PrONTO, SAILOR, and PIER. Ex. 1002
`
`(Albini Decl.) at ¶ 60, citing Ex. 1030 (Mitchell) at 6-7. Yet, each of these prior art
`
`studies with Lucentis demonstrated inferior results to the fixed monthly dosing
`
`regimen of ANCHOR and MARINA.
`
`47.
`
`In 2004, Genentech initiated the PIER Study, which ran from August
`
`2004 to March 2007, and was designed to compare three monthly loading doses
`
`followed by fixed quarterly dosing of 0.3 mg and 0.5 mg Lucentis against sham
`
`control over 24 months in 184 patients. Ex. 2086 at 2, 4.12 I participated as a clinical
`
`investigator, was part of the PIER Study Group, and was also involved in the
`
`presentation and publication of the Year One data from PIER. As explained below,
`