UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`SAMSUNG BIOEPIS CO., LTD.
`Petitioner,
`v.
`REGENERON PHARMACEUTICALS, INC.
`Patent Owner.
`
`Patent No. 11,253,572
`
`_______________
`Inter Partes Review No. IPR2023-00884
`____________________________________________________________
`
`DECLARATION OF DAVID M. BROWN, M.D.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2066 Page 1
`
`
`_______________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`SAMSUNG BIOEPIS CO., LTD.
`Petitioner,
`v.
`REGENERON PHARMACEUTICALS, INC.
`Patent Owner.
`
`Patent No. 11,253,572
`
`_______________
`Inter Partes Review No. IPR2023-00884
`____________________________________________________________
`
`DECLARATION OF DAVID M. BROWN, M.D.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2066 Page 1
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`IPR2023-00884
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`Table of Contents
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`
`
`Page
`
`INTRODUCTION ............................................................................................................. 2
`I.
`QUALIFICATIONS .......................................................................................................... 3
`II.
`III. MATERIALS CONSIDERED .......................................................................................... 6
`IV.
`THE ANCHOR, MARINA, AND PIER TRIALS ............................................................ 6
`A.
`ANCHOR and MARINA: Trials establishing effectiveness of monthly
`ranibizumab............................................................................................................ 6
`PIER and other trials testing less frequent ranibizumab ...................................... 10
`B.
`THE DA VINCI TRIAL AND 2010 ARVO ABSTRACT ............................................. 17
`A.
`My and other clinical investigators’ roles in the DA VINCI trial ....................... 17
`B.
`My and Dr. James Major’s roles on the 2010 ARVO Abstract ........................... 19
`
`
`V.
`
`
`
`1
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`I, David M. Brown, M.D., declare as follows:
`
`I.
`
`INTRODUCTION
`
`
`
`1.
`
`I have been retained by counsel for Patent Owner, Regeneron
`
`Pharmaceuticals, Inc., as a technical expert in connection with the Inter Partes
`
`Review proceeding identified above. I submit this declaration in support of
`
`Regeneron’s Response in this proceeding.
`
`2.
`
`I understand that Petitioner Samsung Bioepis Co., Ltd. challenges a
`
`number of claims of United States Patent No. 11,253,572 (“the ’572 Patent”) in this
`
`proceeding.
`
`3.
`
`I understand that Petitioner has asserted Shams (Ex.1017), a Genentech
`
`patent application filed in 2004, as one of its prior art references. The Shams
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`reference focuses on the protocol for Genentech’s PIER trial. I was a principal
`
`investigator on PIER, and so I have been asked to opine on aspects of PIER that
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`could color a POSA’s understanding of the Shams reference.
`
`4.
`
`I understand that Petitioner has asserted the 2010 ARVO Abstract
`
`(Ex.1010) reporting certain top-line results of the DA VINCI trial. I was a clinical
`
`investigator on the DA VINCI trial, so I have been asked to explain my and the other
`
`clinical investigators’ role on the DA VINCI trial. I am also listed with Dr. James
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`Major as one of the authors on the 2010 ARVO Abstract, so I have been asked to
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`explain my and Dr. Major’s roles in preparing the abstract.
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`5.
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`I have personal knowledge of Exhibits 2022–2023 and 2077–2080 cited
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`in this declaration, which are true and correct copies of documents I received, sent,
`
`or reviewed.
`
`6.
`
`I am being paid my usual hourly rate for my work on this matter. I have
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`no personal or financial stake or interest in the outcome of the present proceeding.
`
`II. QUALIFICATIONS
`
`7.
`
`I am the Director of the Greater Houston Retina Research Center, where
`
`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.
`
`8.
`
`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 to 1990. From 1990 to 1995, I completed ophthalmology and retina training at
`
`the University of Iowa, where I was a Thomas Heed Fellow and a Hermann Knapp
`
`Fellow, and was awarded the Ron Michels Fellowship award presented to the top
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`retinal surgery fellow in the United States in 1994.
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`9.
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`I have served on the Board of Directors of the American Society of
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`Retina Specialists since 2014; the Macula Society Credentials Committee since
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`2013; and the Retina Society Finance Committee since 2018. I have served in
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`numerous additional leadership roles in professional organizations and societies in
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`the retina and ophthalmology field over the past three decades. I have also been a
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`peer reviewer for the journals in these fields, including Ophthalmology, Retina, and
`
`the New England Journal of Medicine.
`
`10.
`
`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 to 2024 and “Texas Super Docs” from 2009 to 2024. 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).
`
`11. My research and clinical trial experience has led to my recognition as
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`an international thought leader on treatments and current standards of care for
`
`age-related macular degeneration, retinal vein occlusion, and diabetic retinopathy. I
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`have written and published over 400 national meeting presentations, abstracts, and
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`scientific papers, including many of the primary papers establishing the safety and
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`efficacy of use of anti-vascular endothelial growth factor (anti-VEGF) agents for
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`
`
`angiogenic eye disorders, including wet age-related macular degeneration (wAMD),
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`diabetic macular edema (DME), and diabetic retinopathy (DR).
`
`12.
`
`I have served as an investigator on Phase III clinical trials of anti-VEGF
`
`agents ranibizumab (Genentech’s Lucentis) and aflibercept (Regeneron’s Eylea) in
`
`wAMD, DME, and DR. For example, I was an investigator on:
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Genentech’s ANCHOR and MARINA trials, phase III trials of
`
`ranibizumab patients with AMD;
`
`Genentech’s PIER trial, a phase IIIb trial of ranibizumab in
`
`patients with AMD;
`
`Genentech’s RISE and RIDE trials, phase III trials of
`
`ranibizumab in patients with DME;
`
`Regeneron’s VIEW1 trial, a phase III trial of aflibercept in
`
`patients with AMD; and
`
`Regeneron’s PANORAMA trial, a phase III trial of aflibercept
`
`in patients with DR without center involved DME.
`
`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.2081.
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`III. MATERIALS CONSIDERED
`
`
`
`13.
`
`In preparing this declaration, I have reviewed, among other things, the
`
`following materials:
`
`•
`
`•
`
`•
`
`•
`
`The Petition for Inter Partes Review of the ’572 Patent, Paper 2
`
`(“Petition”);
`
`The Declaration of Dr. Edward Chaum (Ex.1002) (“Chaum
`
`Declaration”);
`
`The Board’s Decision Granting Institution of Inter Partes
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`Review, Paper 13; and
`
`All exhibits cited in this declaration.
`
`IV. THE ANCHOR, MARINA, AND PIER TRIALS
`
`14.
`
`I understand that the parties dispute the priority date of claim 25 of
`
`the ’572 Patent. I have been asked by counsel to assume that the priority date for this
`
`claim is January 13, 2011, and to discuss the art as it was understood before that
`
`date. My opinions would not change if the priority date were instead July 12, 2013.
`
`A. ANCHOR and MARINA: Trials establishing effectiveness of
`
`monthly ranibizumab
`
`15.
`
`In 2003, Genentech began two large-scale, randomized Phase III
`
`clinical trials to test monthly ranibizumab injections in subjects with wAMD—
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`MARINA and ANCHOR. I served as a principal investigator for both studies.
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`
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`Ex.20821 (ANCHOR); Ex.20832 (MARINA).
`
`16.
`
`MARINA ran from March 2003 to December 2005. 716 subjects
`
`with wAMD, with either minimally classic or occult choroidal neovascularization
`
`(CNV), were randomly assigned to receive 24 monthly intravitreal injections of
`
`Lucentis (either 0.3 mg or 0.5 mg) or sham injections. Ex.2083 (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.
`
`17.
`
`The one-year results of MARINA, presented in July 2005, showed
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`that nearly 95% of subjects treated with Lucentis® maintained or improved vision
`
`at 12 months. Ex.2084 at 4. The two-year results, published in October 2006, showed
`
`that the mean improvements in vision demonstrated in the first 12 months of the
`
`study were sustained through the second year of study. Ex.2083 (MARINA) at 11.
`
`Mean increases in visual acuity were +6.5 letters in the 0.3 mg group and +7.2 letters
`
`
`
` 1
`
` David M. Brown et al., Ranibizumab Versus Verteporfin for Neovascular
`Age-Related Macular Degeneration, 355 N. ENG. J. MED. 1432 (2006).
`2 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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`in the 0.5 mg groups, compared with a decrease of -10.5 letters in the sham-injection
`
`
`
`group. Ex.20843 (Dec. 30, 2005, Genentech Press Release) at 4.
`
`18.
`
`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, two 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. 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.
`
`19.
`
`The MARINA results were supplemented by the outcomes from the
`
`ANCHOR trial. ANCHOR ran from May 2003 to September 2006 and enrolled
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`423 subjects with predominantly classic choroidal neovascularization in wAMD.
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`Ex.2082 (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
`
`
`
` 3
`
` 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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`primary endpoint of the study was also the proportion of patients losing fewer than
`
`
`
`15 letters from baseline visual acuity at 12 months. Id.
`
`20.
`
`One-year results of the ANCHOR trial, presented in November of
`
`2005, showed that 94–96% of those treated with 0.5 mg of Lucentis maintained or
`
`improved vision compared
`
`to approximately 64% of
`
`those
`
`treated with
`
`photodynamic therapy (PDT) alone. Ex.2084 (Dec. 30, 2005, Genentech Press
`
`Release) at 2–3. The two-year results, published in January 2009 showed 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. Ex.10494 at 1.
`
`21.
`
`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.1049 (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
`
`
`
` 4
`
` 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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`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.
`
`B.
`
`22.
`
`PIER and other trials testing less frequent ranibizumab
`
`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. Each of these prior
`
`art studies with Lucentis demonstrated inferior results to the fixed monthly dosing
`
`regimen of ANCHOR and MARINA.
`
`23.
`
`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.1021 at 2, 4.5 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, the PIER Study revealed that fixed quarterly intravitreal injections of
`
`
`
` 5
`
` Carl D. Regillo, David M. Brown et al., Randomized, Double-Masked,
`Sham-Controlled Trial of Ranibizumab for Neovascular Age-Related Macular
`Degeneration: PIER Study Year 1, 145 AM. J. OPHTHALMOLOGY 239 (2008).
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`ranibizumab over an extended treatment period was not an effective method of
`
`
`
`treatment.
`
`24.
`
`From the results of the MARINA and ANCHOR trials and my
`
`experience administering monthly ranibizumab as part of those trials, I knew that
`
`monthly ranibizumab could improve AMD relatively quickly, with a majority of the
`
`visual gain achieved within the first three months. After this initial improvement, I
`
`and other PIER investigators did not expect symptoms to recur quickly, and so we
`
`thought that a longer dosing interval could work to prevent AMD symptoms from
`
`recurring. I thought it would be feasible to find a longer dosing interval that would
`
`maintain at least some of the initial vision gains, and I thought the PIER dosing
`
`schedule was likely to work for this purpose.
`
`25.
`
`As one of the lead clinical investigators on the PIER trial, I received
`
`the first read-out of the one-year data from the study from Genentech in early 2006
`
`and was the first to present on this data at the Retinal Physician Symposium held in
`
`the Bahamas from May 31 to June 3, 2006. The data was highly disappointing to say
`
`the least. While patients saw an initial gain in visual acuity during the three-monthly
`
`loading doses, these gains were entirely lost once quarterly dosing began. Ex.1021
`
`(PIER 2008) at 7 (“On average, there was 4.5-letter decline in VA between month
`
`three and month 12 for both ranibizumab dose groups.”). By month 12, the 0.3 mg
`
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`study arm saw a -1.6 letter difference from baseline visual acuity, and the 0.5 mg
`
`
`
`study arm saw a -0.2 letter difference from baseline. Id. at 5 fig.1.
`
`26.
`
`Optical coherence tomography (OCT) assessed anatomic outcomes
`
`in the Year One data also confirmed ranibizumab’s failure to maintain efficacy over
`
`the quarterly dosing period. The maximal decrease in foveal center point thickness
`
`was seen at months two and three for both ranibizumab groups. Ex.1021 (PIER
`
`2008) at 7. During assessments made at months five and eight, the foveal center
`
`point thickness was on average greater than at months two and three, and was also
`
`greater than at month 12, which had followed a ranibizumab dose at month 11. Id.
`
`This suggested that, on average, ranibizumab’s therapeutic effectiveness in a patient
`
`would wane between injections, pointing to recurrent neovascular activity and
`
`associated exudation occurring between injections. Ex.20856 at 4.
`
`27.
`
`Over the course of the PIER study, the study sponsor (Genentech)
`
`implemented two key protocol amendments. First, the protocol was amended on
`
`February 27, 2006, to provide sham injection patients the opportunity to cross over
`
`to receive 0.5 mg ranibizumab quarterly after completing the month-12 visit (i.e.,
`
`
`
` 6
`
` Jonathan P. Levine et al., Macular Hemorrhage in Neovascular Age-Related
`Macular Degeneration After Stabilization with Antiangiogenic Therapy, 29 RETINA
`1074 (2009).
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`the assessment time point for the primary analysis). Ex.20517 at 2. As explained
`
`
`
`above, the 12-month data from MARINA and ANCHOR had established to the
`
`retinal community that it would be in the best interest of subjects in the sham cohorts
`
`to be treated with ranibizumab, rather than be put further at risk for severe,
`
`irreversible vision loss under an observation-only or PDT scheme.
`
`28.
`
`The second protocol amendment was the direct result of the review
`
`of the 12-month PIER data and the disappointing lack of efficacy of subjects in the
`
`treatment arms. On August 21, 2006, the study was amended to provide all patients
`
`remaining in the study the opportunity to roll over to receive 0.5 mg ranibizumab
`
`monthly for the remainder of the study. Ex.2051 (Abraham 2010) at 2. The second
`
`year of the PIER study was functionally designed to be confirmatory of fixed
`
`quarterly dosing’s efficacy and, given the disappointing lack of efficacy observed in
`
`the PIER quarterly treatment regimen, the study sponsor initiated a rollover at this
`
`point to mitigate against future visual acuity losses, which would be expected on
`
`continued quarterly dosing.
`
`29.
`
`The year-two results from PIER confirmed the disappointing lack
`
`of efficacy of the dosing regimen. The 0.3 mg ranibizumab group saw a mean loss
`
`
`
` 7
`
` Prema Abraham et al., Randomized, Double-Masked, Sham-Controlled Trial of
`Ranibizumab for Neovascular Age-Related Macular Degeneration: PIER Study
`Year 2, 150 AM. J. OPHTHALMOLOGY 315 (2010).
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`of -2.2 letters as compared to baseline, and the 0.5 mg ranibizumab arm saw a mean
`
`
`
`loss of -2.3 letters as compared to baseline. Ex.2051 (Abraham 2010) at 5 tbl.3. This
`
`stood in stark contrast to MARINA and ANCHOR. Id. at 8 (“In those studies,
`
`patients who received monthly injections of ranibizumab experienced a gain of 5 to
`
`11 letters from baseline at month 24 compared to a loss of approximately 2 letters
`
`with the PIER dosing regimen.”). After approval of Lucentis, and certainly by 2011,
`
`the goal of any treatment regimen for age-related macular degeneration was to
`
`improve vision, maintain those gains, and prevent blindness.
`
`30.
`
`Post-hoc analyses of the study data from MARINA, ANCHOR, and
`
`PIER also demonstrated that while patients on monthly ranibizumab were
`
`significantly less likely to develop macular hemorrhages as compared to sham
`
`control, patients in the treatment arm of PIER saw no benefit in the incidence of
`
`macular hemorrhage as compared to sham control and, indeed, incidence rates were
`
`numerically higher. Ex.20868 at 3, 7.
`
`31.
`
`Importantly, macular hemorrhages are a hallmark of active wAMD
`
`and are considered to be a definitive sign of disease progression. “[W]hen occupying
`
`larger areas or located in the subfoveal region, they are usually associated with a
`
`
`
` 8
`
` Irene Barbazetto et al., Dosing Regimen and the Frequency of Macular
`Hemorrhages in Neovascular Age-Related Macular Degeneration Treated with
`Ranibizumab, 30 RETINA 1376 (2010).
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`poor visual prognosis in a majority of cases.” Ex.2086 (Barbazetto 2010) at 1. It was
`
`
`
`a serious concern, therefore, that quarterly dosing did not decrease the incidence of
`
`macular hemorrhage as compared to sham and it was recognized that “switching
`
`from monthly to quarterly injection intervals may not have the same beneficial effect
`
`and could put the patient at an increased risk for vision-threatening complications.”
`
`Id. at 9.
`
`32.
`
`As a result, my conclusion from the PIER Study results was that
`
`“we cannot just mandatorily treat on a quarterly basis and maintain the visual gains
`
`seen with the first three monthly injections.” Ex.20879 at 1, 2 (“You can’t just do
`
`mandatory quarterly injections.”). My expressed concerns with fixed quarterly
`
`injections were shared across the retina community at the time. E.g., Ex.2085
`
`(Levine 2009) at 4–5 (“A recent analysis of the ANCHOR, MARINA, and PIER
`
`data demonstrated that monthly intravitreal ranibizumab dosing significantly
`
`reduced the frequency of macular hemorrhages compared with the sham controls or
`
`photodynamic therapy-treated patients regardless of lesion type. The effect was lost
`
`when patients were switched from monthly to quarterly dosing in the PIER study.
`
`
`
` 9
`
` Daniele Cruz, PIER Data Suggest a Need for Tailored Injection Schedule, OCULAR
`SURGERY NEWS (Sept. 1, 2006),
`https://www.healio.com/news/ophthalmology/20120331/pier-data-suggest-a-need-
`for-tailored-injection-schedule.
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`Reducing the frequency of injections should, therefore, be done with caution.”)
`
`
`
`(emphasis added).
`
`33.
`
`At the outset of the PIER trial, I had no reason to think visual acuity
`
`outcomes in the quarterly dosing arm would fall so far short of the outcomes in the
`
`monthly dosing arm. The results of the PIER trial showed it was more challenging
`
`than I had thought it would be to find a fixed extended dosing regimen that could
`
`still effectively treat AMD and other angiogenic eye disorders. Others shared this
`
`view. Based on the PIER data, Genentech “recommend[ed] that patients receive
`
`either monthly injections of ranibizumab, or have their retreatment schedules
`
`determined through individualized testing.” Ex.205010 at 2.
`
`34.
`
`These concerns were also reflected in the FDA’s labeling when
`
`Lucentis was approved for wAMD treatment in June 2006, as PIER’s year-one
`
`results were included in the FDA’s review. Ex.208811 (Genentech June 30, 2006,
`
`press release) at 2. The label explains: “Although less effective, treatment may be
`
`reduced to one injection every three months after the first four injections if monthly
`
`injections are not feasible. Compared to continued monthly dosing, dosing every
`
`
`
`
`10 Retinal Physician Symposium Covers Broad Range of Topics, RETINAL PHYSICIAN
`(Sept.
`1,
`2006),
`https://www.retinalphysician.com/issues/2006/september-
`2006/retinal-physician-symposium-covers-broad-range-of.
`11 Press Release, Genentech, FDA Approves Lucentis for the Treatment of Wet
`Age-Related Macular Degeneration (June 30, 2006).
`16
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2066 Page 17
`
`
`
`IPR2023-00884
`
`3 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit,
`
`
`
`on average, over the following 9 months. Patients should be evaluated regularly.”
`
`Ex.208912 at 2.
`
`V. THE DA VINCI TRIAL AND 2010 ARVO ABSTRACT
`
`35.
`
`The DA VINCI trial was a phase II trial of VEGF Trap-Eye in
`
`subjects with DME. Ex.2014, 2. Patients were enrolled between December 2008 and
`
`June 2009. Id. The primary endpoint was change in Best-Corrected Visual Acuity at
`
`24 weeks. Id. Although Regeneron and Bayer collaborated on the development of
`
`VEGF Trap-Eye, Regeneron was the primary sponsor of the DA VINCI trial and
`
`interfaced with the clinical investigators on its execution. See Ex.1031, 8; Ex.2016,
`
`7.
`
`A. My and other clinical investigators’ roles in the DA VINCI trial
`
`36.
`
`I was a clinical investigator on the DA VINCI trial. My role, like
`
`that of the other DA VINCI clinical investigators, was to execute the clinical trial
`
`protocol at my clinical trial site. Specifically, the other clinical investigators and I
`
`were responsible for recruiting subjects, obtaining their informed consent,
`
`administering the study drug and laser treatment to those subjects in accordance with
`
`the clinical trial protocol, reporting adverse events, and documenting the information
`
`
`
`
`12 CDER Approved Labeling for BLA Application 125156 (Lucentis®) (2006).
`17
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2066 Page 18
`
`
`
`IPR2023-00884
`
`required by the clinical trial protocol. We also received monitors who visited to site
`
`
`
`to ensure adherence to the protocol and collect our data to report back to Regeneron.
`
`Some of these tasks were performed by the clinical investigators, and others were
`
`performed by staff under our supervision. DA VINCI was a double-masked trial, so
`
`each site had both masked and unmasked clinical investigators. Unmasked
`
`investigators administered the study drug and laser treatment, whereas masked
`
`investigators assessed adverse events and efficacy.
`
`37.
`
`I did not play a role in developing the DA VINCI clinical trial
`
`protocol. Neither I nor, to my knowledge, the other clinical investigators chose to
`
`test VEGF Trap-Eye in DME, chose the dosing regimen for the VEGF Trap-Eye
`
`arms, or chose the visual acuity endpoints. My understanding was that Regeneron,
`
`as the study sponsor, had the idea to include these features before communicating
`
`them to the clinical investigators, and Regeneron made the final decision to proceed
`
`with this clinical trial with these features. This was consistent with the usual role of
`
`study sponsors in industry-sponsored trials.
`
`38.
`
`Other clinical investigators and I authored publications describing
`
`the results of the DA VINCI trial. E.g., Ex.2014, 1. The usual practice in the field,
`
`which was followed for DA VINCI, was to include some of a trial’s clinical
`
`investigators as authors on publications of the results. For example, clinical
`
`investigators who played the largest roles in executing the clinical trial protocol and
`18
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2066 Page 19
`
`
`
`IPR2023-00884
`
`preparing the article for publication were typically named as authors. The fact that a
`
`
`
`clinical investigator is listed as an author on these publications does not imply that
`
`they chose the disease, dosing regimen, or endpoints of the trial.
`
`B. My and Dr. James Major’s roles on the 2010 ARVO Abstract
`Following the last 24-week study visit, Regeneron reported the
`39.
`
`top-line results in a press release on February 18, 2010. Ex.2020.
`
`40.
`
`Around the same time, Regeneron sought to have the 24-week
`
`results presented at the 2010 Association for Research in Vision and Ophthalmology
`
`(ARVO) Annual Meeting in Fort Lauderdale, Florida, scheduled for May 2-6, 2010.
`
`It was the usual practice of Regeneron and other pharmaceutical companies to
`
`choose one of the clinical investigators to present clinical trial results.
`
`41.
`
`By the time the 24-week DA VINCI results became available, the
`
`deadline to submit abstracts for the 2010 ARVO Annual Meeting had passed.
`
`However, ARVO made an exception for “late breaking” abstracts reporting research
`
`and data not available by the first deadline.
`
`42.
`
`On February 25, 2010, Regeneron contacted me about submitting
`
`the 24-week DA VINCI results to ARVO. Ex.2077, 2. I received an email from
`
`Dr. Alyson Berliner, a Regeneron employee who was involved in the execution of
`
`the DA VINCI trial. Id. She asked if I would be willing to submit the 24-week DA
`
`VINCI results to ARVO as a late-breaking abstract. Id. I agreed, and on February 26,
`19
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2066 Page 20
`
`
`
`IPR2023-00884
`
`Dr. Berliner sent me a draft abstract to review. Ex.2077, 1. She re-attached this draft
`
`
`
`to a follow-up email on March 1, 2010. Exhibit 2077 is a true and correct copy of
`
`Dr. Berliner’s email sent to me on March 1, 2010, and Exhibit 2022 is a true and
`
`correct copy of the draft abstract attached to Dr. Berliner’s email.
`
`43.
`
`The draft abstract that Dr. Berliner provided me stated that that DA
`
`VINCI was a trial assessing VEGF Trap-Eye in patients with DME, described the
`
`VEGF Trap-Eye dosing regimens tested, and stated the top-line visual acuity results
`
`at 24 weeks. It was typical industry practice for the study sponsor to provide a full
`
`draft abstract with this information, as Dr. Berliner did, rather than ask a clinical
`
`investigator to prepare the first draft. And consistent with industry practice, when
`
`the abstract was submitted, I only had access to the top-line results provided in the
`
`draft abstract and Regeneron’s public press release, Ex.2020. I did not have access
`
`to the full results used to calculate the averages reported in the abstract.
`
`44.
`
`I did not make any material changes to these portions of the
`
`abstract. Dr. Berliner and I exchanged revisions of the abstract on March 2 and
`
`March 3. Exhibits 2023 and 2078 are true and correct copies of emails exchanged
`
`between Dr. Berliner and myself regarding these revisions, and Exhibit 2079 is a
`
`true and correct copy of the revised draft abstract that I sent to Dr. Berliner on
`
`March 2. Exhibit 2080 is a true and correct copy of the attachment to my March 3
`
`email to Dr. Berliner, Exhibit 2023, and it is a copy of the version of the abstract I
`20
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2066 Page 21
`
`
`
`IPR2023-00884
`
`submitted to ARVO on that date. Through these revisions, the language quoted in
`
`
`
`the table below stayed the same, which can be seen by comparing Exhibit 2022 with
`
`Exhibit 1010:
`
`Feb. 26 Draft Abstract (Ex.2022)
`DA VINCI: DME And VEGF
`Trap-Eye: INvestigation of Clinical
`Impact: Phase 2 study in patients
`with Diabetic Macular Edema (DME)
`…
`DA VINCI is … designed to assess
`safety and efficacy of 4 dose/dose
`intervals of VEGF Trap-Eye (VTE) …:
`0.5mg q4wks, 2mg q4wks, 2mg q8wks,
`2mg prn ….
`...
`At 6 months, the mean change in BCVA
`for each VTE group ranged from +8.5 to
`+11.4 letters …, and no significant
`difference was noted among the VTE
`arms.
`
`2010 ARVO Abstract (Ex.1010)
`DA VINCI: DME And VEGF
`Trap-Eye: INvestigation of Clinical
`Impact: Phase 2 study in patients
`with Diabetic Macular Edema (DME)
`…
`DA VINCI is … designed to assess
`safety and efficacy of 4 dose/dose
`intervals of
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