UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`SAMSUNG BIOEPIS CO. LTD,
`Petitioner
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`
`____________
`
`Case IPR2023-00884
`Patent No. 11,253,572
`
`____________
`
`EXPERT DECLARATION OF RICHARD MANNING. PH.D.
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`CONFIDENTIAL MATERIAL - SUBJECT TO PROTECTIVE ORDER
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`CONFIDENTIAL MATERIAL – SUBJECT TO PROTECTIVE ORDER
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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2067 Page 1
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`Table of Contents
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`1.
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`Introduction ............................................................................................. 1
`1.1. Qualifications .................................................................................... 1
`1.2. Scope of work ................................................................................... 3
`1.3. Framework for commercial success ................................................. 4
`2. U.S. Patent No. 11,253,572 ..................................................................... 7
`3. Commercial Success ............................................................................. 10
`3.1. U.S. Eylea sales .............................................................................. 11
`3.2. Eylea’s share of anti-VEGF sales ................................................... 11
`3.2.1. Data sources ........................................................................... 12
`3.2.2. Eylea’s historic sales share as an indicator of commercial
`success .................................................................................... 12
`3.2.3. Eylea’s sales growth trends as an indicator of commercial
`success .................................................................................... 17
`3.2.4. Eylea status as physicians’ most used treatment .................... 21
`4. Dosing Regimen is An Important Driver of Demand for Eylea ........... 23
`4.1. Eylea’s patented dosing regimen addressed an unmet need for
`longer dosing intervals ................................................................... 24
`4.2. Eylea’s patented dosing regimen, including the 8-week fixed
`dosing interval in the maintenance phase, is a key
`differentiating factor ....................................................................... 27
`4.3. The most common dosing interval for Eylea is approximately
`eight weeks ..................................................................................... 29
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`Expert Declaration of Richard Manning, Ph.D.
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`Table of Attachments
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`Expert Materials
`Section A
`Attachment A-1 Curriculum Vitae of Richard Manning, Ph.D
`Attachment A-2 Expert Testimony of Richard Manning, Ph.D
`
`FDA Labels
`Section B
`Attachment B-1 Dosing Directions on FDA Labels
`
`Sales Share Summaries
`Section C
`Attachment C-1 Sales Share Summary - All Indications
`Attachment C-2 Sales Share Summary - DME
`Attachment C-3 Sales Share Summary - DR without DME
`Attachment C-4 Sales Share Summary - Wet AMD
`Attachment C-5 Sales Share Summary - RVO
`Attachment C-6 Eylea's Sales Share Across Different Data Sources - All
`Indications
`Attachment C-7 Eylea's Sales Share Across Different Data Sources - DME
`Attachment C-8 Eylea's Sales Share Across Different Data Sources - DR
`without DME
`Attachment C-9 Eylea's Sales Share Across Different Data Sources - Wet
`AMD
`Attachment C-10 Eylea's Sales Share Across Different Data Sources - RVO
`Attachment C-11 Percentage Point Change in Total Sales Share Since Eylea
`Launch – ATU Data
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`Expert Declaration of Richard Manning, Ph.D.
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`Attachment C-12 Percentage Point Change in Total Sales Share Since Eylea
`Launch – Medicare Part B Data
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`P&L and ASP Analyses
`Section D
`Attachment D-1 Eylea Profit and Loss Data (Actuals, 2011–2021)
`Attachment D-2 Eylea Volume and Revenue Performance (2011–2021)
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`Other Analyses
`Section E
`Attachment E-1 Most Prescribed Treatment Options (2012–2020)
`Attachment E-2 Volume of Medicare Patients by Brand – Medicare Part B
`Attachment E-3 Summary of Most Common Dosing Intervals for DME
`According to ATU Surveys
`Attachment E-4 Summary of Most Common Dosing Intervals for Wet AMD
`According to ATU Surveys
`Attachment E-5 Medicare Part B Patients Treated, By Year and Treatment
`(2012 – 2021)
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`Data
`Section X
`Attachment X-1 Vestrum Sales Share Data by Indication
`Attachment X-2 ATU Sales Share Data by Indication
`Attachment X-3 Medicare Part B Sales Shares Data (2012–2021)
`Attachment X-4 HCPCS Code to Brand Name Mapping
`Attachment X-5 Summary of ATU Survey Reports: Dosing Frequencies by
`Indication and Treatment
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`Section Y
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`STATA Log Files
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`Expert Declaration of Richard Manning, Ph.D.
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`Attachment Y-1 Log File for Importing 2021 CMS Medicare Part B Data
`Attachment Y-2 Log File for Appending Data into Final Complete Dataset
`Attachment Y-3 Log File for Attachment X-3
`Attachment Y-4 Log File for Attachment E-1
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`Expert Declaration of Richard Manning, Ph.D.
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`I, Richard Manning, Ph.D., do hereby declare:
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`1. Introduction
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`1.1. Qualifications
`
`(1)
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`I am a Managing Director at Intensity, a Secretariat Company. I provide economics
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`and data-driven insights to help clients address complex questions. Among other
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`things, I have experience conducting economic analyses in matters involving breach
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`of contract, fraud, pricing, economic valuation, intellectual property, antitrust, patent
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`infringement, business strategy, and public policy.
`
`(2)
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`I earned my B.A. in Economics from Brigham Young University. I received my
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`Ph.D. in Economics from the University of Chicago. After obtaining my Ph.D., I
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`was an economics professor at Brigham Young University and a visiting professor
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`in the Graduate School of Business at the University of Chicago. As an academic,
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`my teaching and research focused on price theory, the economic analysis of law,
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`industrial organization, and the economics of government regulation.
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`(3) My career includes 14 years as an executive at multinational pharmaceutical
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`companies. I was Senior Director at Pfizer Inc and Executive Director at Merck &
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`Co., Inc. I led economic analysis and strategy development to shape practices related
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`to emerging business concerns. Examples of my work include:
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` Leading and undertaking economic analysis and strategy relative to
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`challenges affecting pricing, reimbursement, and intellectual property
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`protection in global markets.
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` Collaborating with outside academic economists to analyze critical issues
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`including healthcare benefit design, healthcare system reform proposals,
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`marketing and advertising, intellectual property protection, FDA regulatory
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`reform, including biosimilars approval processes and safety, and new product
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`R&D.
`
`(4)
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`Previously, I was Director of Advisory Strategy at PricewaterhouseCoopers where
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`my responsibilities included working on strategic partnerships, merger and
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`acquisitions activity, economic valuation of early-stage companies, and other
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`economic analyses for biopharmaceutical, medical device, financial, and healthcare
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`clients.
`
`(5)
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`Prior to joining Intensity, I was a Partner at Bates White, an economics consulting
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`firm offering analysis and expert testimony services to law firms, Fortune 500
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`companies, and government agencies.
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`(6) My areas of expertise include:
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` Economic Valuation and Damages
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` Breach of Contract, Fraud, and other Commercial Litigation
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` Intellectual Property
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` Securities Litigation
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` Tax, Antitrust and Competition
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` Public Policy
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`(7)
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`I have provided expert testimony in the U.S. District Court, the Delaware Court of
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`Chancery, the U.S. Bankruptcy Court for the District of Delaware, the U.S. Patent
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`and Trademark Office Patent Trials and Appeals Board, and the International
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`Chamber of Commerce; served as consulting expert; and prepared reports on various
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`matters in the biopharmaceutical and healthcare industries. A comprehensive list of
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`my qualifications can be found in my CV. See Attachment A-1. My testimony
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`experience over the past four years can be found in Attachment A-2.
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`1.2.
`
`Scope of work
`
`(8)
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`Intensity has been retained by Morrison & Foerster LLP on behalf of Regeneron
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`Pharmaceuticals, Inc. (Regeneron). Intensity is being compensated at my standard
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`hourly rate of $1,150 for my work in this matter. Intensity is being compensated for
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`time spent by others on my team at rates lower than my hourly rate. Neither
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`Intensity’s nor my compensation depends upon the substance of my testimony or the
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`outcome of this matter.
`
`(9)
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`I was asked to evaluate and, if called upon, to testify concerning commercial success
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`as an objective indicator of non-obviousness in Inter Partes review No. IPR2023-
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`00884 regarding U.S. Patent No. 11,253,572 (the ’572 Patent).
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`(10) In forming the opinions expressed in this declaration, I relied upon my education,
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`experience, and knowledge of the subjects discussed. Additionally, I relied on the
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`Declaration of Michael W. Stewart, M.D. (Ex. 2065). I held a conversation with Dr.
`
`Stewart. I also have considered documents and other materials, which are cited
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`herein.
`
`1.3.
`
`Framework for commercial success
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`(11) I understand that evidence of commercial success is one of the objective indicators
`
`that a patent owner may rely upon to support an argument of non-obviousness of a
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`claimed invention.1 I understand that the Federal Circuit has stated that
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`“[c]ommercial success is relevant because the law presumes an idea would
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`successfully have been brought to market sooner, in response to market forces, had
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`the idea been obvious to persons skilled in the art.”2 I understand that, for
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`commercial success to constitute evidence of non-obviousness of a patent, there
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`must be a nexus between the claimed technology and evidence of commercial
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`
`
` 1
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` Demaco Corp. v. F. Von-Langsdorff Licensing Ltd., 851 F.2d 1387, 1391–92
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`(Fed. Cir. 1988).
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`2 Merck & Co., Inc. v. Teva Pharm. USA, Inc., 395 F.3d 1364, 1376 (Fed. Cir.
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`2005).
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`success. Moreover, the evidence must demonstrate that the commercial success is
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`due at least in part to the claimed features of the invention and not entirely to factors
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`unrelated to the claimed invention.3 Additionally, I understand that the commercial
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`success must not relate exclusively to a feature that was known in the prior art.4 I
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`further understand that Federal Circuit case law holds that “if the commercial
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`success is due to an unclaimed feature of the device, the commercial success is
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`irrelevant.”5
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`(12) It is my understanding that the courts commonly accept indicators including
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`significant sales levels, significant sales growth, substitution towards the novel
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`product or method and away from alternative products or methods, persistent price
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`
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` 3
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` United States Patent and Trademark Office, Manual of Patent Examining
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`Procedure, Ninth Edition, Revision: 2/2023, 716.03 I., at 700–257; and
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`716.03(b) at 700–278 and 700–259.
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`
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`Demaco Corp. v. F. Von-Langsdorff Licensing Ltd., 851 F.2d 1387, 1391–92
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`(Fed. Cir. 1988).
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`4
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`Yita LLC v. MacNeil IP LLC, 69 F.4th 1356, 1364–65 (Fed. Cir. 2023).
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`5 Ormco Corporation, et al. v. Align Technology, Inc., 463 F.3d 1299, 1312 (Fed.
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`Cir. 2006).
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`premiums, or the absence of substantial discounting, and other economic indicators
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`as evidence of commercial success of a novel product.6 In the context of
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`pharmaceutical products (and by extension biologic products), sales can be
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`measured in terms of revenues, prescriptions, or daily doses, and sales growth can
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`be measured in terms of sales or share of sales within a product category.7
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`
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`Ex.2155 (Guha, Rahul, Jian Li, and Andrea L. Scott (2009), “The Economics
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`of Commercial Success in Pharmaceutical Patent Litigation,” Landslide 1(5)).
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`
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` 6
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`7
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`Ex.2155 (Guha, Rahul, Jian Li, and Andrea L. Scott (2009), “The Economics
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`of Commercial Success in Pharmaceutical Patent Litigation,” Landslide 1(5)).
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`2.
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`U.S. Patent No. 11,253,572
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`(13) The application for the ’572 Patent, entitled Use of a VEGF Antagonist to Treat
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`Angiogenic Eye Disorders, was filed on June 21, 2021 and issued as the ’572 Patent
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`on February 22, 2022.8 The abstract of the ’572 Patent reads as follows:
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`The present invention provides methods for treating angiogenic eye
`disorders by sequentially administering multiple doses of a VEGF
`antagonist to a patient. The methods of the present invention include
`the administration of multiple doses of a VEGF antagonist to a patient
`at a frequency of once every 8 or more weeks. The methods of the
`present invention are useful for the treatment of angiogenic eye
`disorders such as age related macular degeneration, diabetic
`retinopathy, diabetic macular edema, central retinal vein occlusion,
`branch retinal vein occlusion, and corneal neovascularization.9
`
`
`
`Ex. 1001 (Use of a VEGF Antagonist to Treat Angiogenic Eye Disorders, U.S.
`
`Patent No. 11,253,572 (filed 6/21/2021, issued 2/22/2022)).
`
`
`
` 8
`
`
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`According to the patent, the earliest provisional application, No. 61/432,245,
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`was filed on January 13, 2011.
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`9
`
`Ex. 1001 (Use of a VEGF Antagonist to Treat Angiogenic Eye Disorders, U.S.
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`Patent No. 11,253,572 (filed 6/21/2021, issued 2/22/2022)).
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`(14) I understand claims 1–30 of the ’572 Patent are under review in this proceeding.10
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`Generally, I understand that the ’572 Patent describes the use of a VEGF antagonist
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`to treat angiogenic eye disorders, including diabetic macular edema (“DME”) and
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`wet age-related macular degeneration (“wet AMD”) according to the methods of
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`treatment recited in the claims, which include multiple treatment phases, the last of
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`which includes treatments administered in intervals of approximately every 8
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`weeks.11
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`(15) The most recent FDA approved label for Eylea recommends three to five monthly
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`injections in the affected eye, depending on the indication, followed by a fixed
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`dosing interval. See Attachment B-1. For example, wet AMD has three initial
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`monthly injections followed by an 8-week fixed dosing interval, DME has five initial
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`monthly injections followed by an 8-week fixed dosing interval, and DR has five
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`initial monthly injections followed by an 8-week fixed dosing interval. See
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`Attachment B-1. I will refer to these initial monthly doses (i.e., the single initial dose
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`and the one or more secondary doses administered 4 weeks after the preceding dose)
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`
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`10 Decision Granting Institution of Inter Partes Review: Paper 13, 11/17/2023, at
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`2, 78.
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`11 Ex. 2065 (Declaration of Michael W. Stewart, M.D., 2/21/2024, at § VII).
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`as the “loading doses” or loading period, and tertiary doses as the “fixed dosing
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`interval” phase.
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`3.
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`Commercial Success
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`(16) In 2011, the FDA approved Regeneron’s EYLEA (aflibercept) injection.12 EYLEA
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`is a prescription medicine approved for the treatment of patients with a variety of
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`angiogenic eye diseases and is the subject of this proceeding.13 Eylea has achieved
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`commercial success as a treatment for angiogenic eye disorders, including wet
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`AMD, DME, diabetic retinopathy (“DR”) without DME, and macular edema
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`following retinal vein occlusion (“RVO”). This commercial success is demonstrated
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`by the large number of patients who have benefitted from Eylea since its launch, as
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`shown from Eylea’s sales since launch and by its performance relative to other
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`available treatments. These sales have a nexus to the method of treatment covered
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`by the claims of the ’572 Patent, including the 8-week fixed dosing interval. Eylea’s
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`historical commercial performance is discussed below.
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`12 Ex.
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`
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`2061
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`(Regeneron
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`Website,
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`History,
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`https://www.regeneron.com/about/history (accessed 1/15/2024)).
`
`
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`Ex.
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`1059
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`(Eylea
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`Label,
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`11/2011,
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`at
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`1,
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`available
`
`at:
`
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf).
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`13 Ex. 2233 (Regeneron, Form 10-K, 2020, at 3).
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`3.1. U.S. Eylea sales
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`(17) Eylea’s U.S. net sales grew
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`
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` Eylea’s successful growth of
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`net and gross sales has been driven by its increasing use by physicians.
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`3.2. Eylea’s share of anti-VEGF sales
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`
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`(18) In addition to sales since launch, a product’s performance relative to other available
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`products provides evidence of commercial performance that may demonstrate
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`commercial success for purposes of U.S. patent law, providing context necessary for
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`evaluating whether a patented product was commercially successful. Moreover, if a
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`patented product captures sales previously made by other products, the patented
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`product demonstrates that it offers, at least for some consumers, a value proposition
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`superior to that offered by the previously available products. Given a nexus to the
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`patented features, these captured sales demonstrate demand for the patented features
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`and show that the patented feature directly contributed to the commercial success of
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`the product.
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`3.2.1. Data sources
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`(19) For analysis of relative sales performance among potential treatments for the
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`relevant angiogenic eye disorders, I rely on three data sources: Medicare Part B
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`physician treatment data provided by the Centers for Medicare & Medicaid Services
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`(CMS), Vestrum data (which I understand are used by Regeneron in the course of
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`business), and Regeneron’s Awareness, Trial, and Usage (ATU) surveys (which I
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`also understand are used by Regeneron in the course of business). I consider all three
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`data sources as each has its respective merits. However, all of the data sources show
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`strong sales growth and overall sales share for Eylea since launch.
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`3.2.2. Eylea’s historic sales share as an indicator of commercial success
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`(20) Eylea was approved for sale in the United States by the FDA on November 18, 2011
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`for the treatment of wet AMD.14 According to ATU data, by the first quarter of 2012
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`it had achieved an
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`14 Ex. 2152
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`(Drugs.com Website, Eylea FDA Approval History,
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`https://www.drugs.com/history/eylea.html (accessed 1/16/2024)).
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`Ex. 1059 (Eylea Label, 11/2011, at 1, available at:
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`https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf).
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`(22) Eylea was approved to treat DME in July 2014.18 As shown in Chart 2, for DME,
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`Eylea achieved a sales share of
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` in 2014. By the end of 2021, Eylea’s sales
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`share in the DME indication was
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`16
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`17 For DR without DME,
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`18 Ex. 2160 (Regeneron Press Release, “Eylea (Aflibercept) Injection Receives
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`FDA Approval for the Treatment of Diabetic Macular Edema (DME),”
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`7/29/2014,
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`https://investor.regeneron.com/news-releases/news-release-
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`details/eylear-aflibercept-injection-receives-fda-approval-treatment).
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`(23) Measures of sales share for patients with DR without DME vary more greatly across
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`data sources than measures for other indications.
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` As shown in Chart 3, Eylea’s sales share for DR
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`without DME patients has grown since it was first tracked.
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`19 Attachment C-7.
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`(24) As shown in Chart 4, for wet AMD,
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`20 Attachment C-8.
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`Expert Declaration of Richard Manning, Ph.D.
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`Page 16
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`(25) Similar patterns can be seen for RVO. See Attachments C-5 and C-10.
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`3.2.3. Eylea’s sales growth trends as an indicator of commercial success
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`(26) Eylea’s increased utilization has come both from contributing to overall growth in
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`the use of anti-VEGF treatments as well as by switching patients to Eylea from two
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`available and established anti-VEGF treatments, Avastin and Lucentis, which had
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`been in wide use for several years before Eylea’s introduction. Chart 5 below
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`21 Attachment C-9.
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`Expert Declaration of Richard Manning, Ph.D.
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`Page 17
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`provides a summary of the number of unique Medicare patients treated with Eylea,
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`Lucentis, and Avastin each year from 2012 to 2021.
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`(27) As seen in Chart 5, the number of Medicare patients for which Eylea was used
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`increased annually,
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`22 Attachment E-5.
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`Page 18
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` Additionally, from 2019 to
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`2020 the number of total treated patients in the anti-VEGF category
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` Similarly, from 2020 to 2021, the number of total treated patients
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`in the anti-VEGF category
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`(28) Eylea’s commercial success is further supported by the fact that Eylea is the
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`dominant option for second-line therapy. According to the National Cancer Institute,
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`second-line therapy is a “[t]reatment that is given when initial treatment (first-line
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`therapy) doesn’t work, or stops working.24
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`23 Moreover, even in years during which all three anti-VEGF treatments were
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`used on more patients, had Eylea not been available it is likely that Avastin and
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`Lucentis would have been used for at least some of the patients who historically
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`were treated with Eylea. Even in such years, some portion of Eylea sales would
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`represent sales that were in some sense taken from Avastin or Lucentis.
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`24 Ex. 2159 (NCI, Second-Line Therapy,
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`https://www.cancer.gov/publications/dictionaries/cancer-terms/def/second-
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`line-therapy (accessed 1/16/2024)).
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`Dosing Regimen is An Important Driver of Demand for Eylea
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`4.
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`(31) The eye diseases treated by Eylea and the other products discussed here impose a
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`very large cost on patients. Loss of vision is one of the most serious health insults
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`an individual can experience, imposing substantial physical, social, and economic
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`burdens on individuals.30 Adults with vision impairment often have lower rates of
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`workforce participation and higher rates of depression and anxiety.31 In older adults,
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`30 Ex. 2150 (Centers for Disease Control and Prevention, “Vision Loss:
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`A
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`Public
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`Health
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`Problem,”
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`12/19/2022,
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`https://www.cdc.gov/visionhealth/basic_information/vision_loss.htm).
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`(“People with vision loss are more likely to report depression, diabetes, hearing
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`impairment, stroke, falls, cognitive decline, and premature death. Decreased
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`ability to see often leads to the inability to drive, read, keep accounts, and travel
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`in unfamiliar places, thus substantially compromising quality of life. The cost
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`of vision loss, including direct costs and lost productivity, is estimated to
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`exceed $35 billion[.]”)
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`31 Ex. 2239 (World Health Organization, “Blindness and Vision Impairment Fact
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`Sheet,”
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`8/10/2023,
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`https://www.who.int/news-room/fact-
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`sheets/detail/blindness-and-visual-impairment.)
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`vision impairment can “contribute to social isolation, difficulty walking, [and] a
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`higher risk of falls and fractures[.]”32 Hence, a treatment that meaningfully
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`diminishes the likelihood of vision loss or that extends the time until vision
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`deteriorates is something on which most patients, and, in turn, their treating
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`physicians, would place a very high value.33
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`4.1. Eylea’s patented dosing regimen addressed an unmet need for longer
`dosing intervals
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`(32) Frequent dosing, and the risk of significant harm to vision if doses are missed,
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`represents a significant treatment burden for patients with the relevant angiogenic
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`eye disorders. Physicians identified the need to alleviate this treatment burden as an
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`unmet need in treating these disorders prior to the launch of Eylea.
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`32 Ex. 2239 (World Health Organization, “Blindness and Vision Impairment Fact
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`Sheet,”
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`8/10/2023,
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`https://www.who.int/news-room/fact-
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`sheets/detail/blindness-and-visual-impairment.)
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`33
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`I have not seen evidence demonstrating that other factors, such as marketing or
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`rebates, were the driving force behind Eylea’s commercial success. I reserve
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`the right to amend or supplement my opinions to address any contrary showing
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`if attempted by Petitioner.
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` The ongoing
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`need for increased dosing intervals means that the patented dosing regimen,
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`including the 8-week fixed dosing interval in the maintenance phase, would be a
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`relevant consideration for physicians and patients selecting treatment options.
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`(33) Dr. Stewart, Regeneron’s technical expert, identifies various aspects of the treatment
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`burden associated with more frequent visits, including travel and time burden for
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`both the patient and assisting caregiver; risks associated with frequent injections,
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`such as infections that can lead to blindness; and financial costs.36 Dr. Stewart
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`explains that because of these downsides, the retinal community was in search of a
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`34 Ex. 2147 (American Society of Retina Specialists, “2009 Preferences and
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`Trends Membership Survey,” c. 2009, at slide 92).
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`35 Ex. 2147 (American Society of Retina Specialists, “2009 Preferences and
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`Trends Membership Survey,” c. 2009, at slide 92).
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`36 Ex. 2065 (Declaration of Michael W. Stewart, M.D., 2/21/2024, at § XII).
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`treatment regimen that “reduced the frequency of injections required to effectively
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`treat patients[,]” which Eylea made possible.37
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`(34) Dr. Stewart further explained that there is a consensus among treating physicians
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`that:
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` Less frequent dosing was a preferred option due to the nature of intravitreal
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`injections.38
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` Intravitreal injections can cause “significant pain and discomfort.” Every
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`intravitreal injection carries a risk of infection, and those infections can lead
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`to blindness. Fewer injections would reduce these negative outcomes.39
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` The “cost and inconvenience of monthly visits and injections can be a major
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`drawback for patients, many of whom are elderly[,]” who cannot drive due to
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`their deteriorating vision. These drawbacks and risks were a recognized
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`concern in the mid- and late-2000’s.40
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`37 Ex. 2065 (Declaration of Michael W. Stewart, M.D., 2/21/2024, at § XII).
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`38 Ex. 2065 (Declaration of Michael W. Stewart, M.D., 2/21/2024, at § XII).
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`39 Ex. 2065 (Declaration of Michael W. Stewart, M.D., 2/21/2024, at § XII).
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`40 Ex. 2065 (Declaration of Michael W. Stewart, M.D., 2/21/2024, at § XII).
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`4.2. Eylea’s patented dosing regimen, including the 8-week fixed dosing
`interval in the maintenance phase, is a key differentiating factor
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`(35) As compared to other anti-VEGF treatments available for the relevant diseases,
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`Eylea’s patented dosing regimen, including the 8-week fixed dosing interval in the
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`maintenance phase, is a key differentiating factor. I understand that when seeking
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`i