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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
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`MYLAN PHARMACEUTICALS INC., CELLTRION, INC.,
`and APOTEX INC.,
`Petitioners,
`
`v.
`
`REGENERON PHARMACEUTICAL, INC.,
`Patent Owner
`
`——————————
`
`Inter Partes Review No. 2021-008811
`U.S. Patent No. 9,254,338 B2
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`
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`DECLARATION OF DIANA V. DO, M.D.
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`1 IPR2022-00258 and IPR2022-00298 have been joined with this proceeding.
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`Exhibit 2051
`Page 01 of 67
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`TABLE OF CONTENTS
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`Page
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`A.
`B.
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`A.
`B.
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`A.
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`B.
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`Claim 1 ................................................................................................ 11
`Claim 14 .............................................................................................. 12
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`“A Method for Treating an Angiogenic Eye Disorder in a Patient” ... 14
`“Tertiary Dose(s)” ............................................................................... 33
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`The United States Prescribing Information for Eylea Demonstrates
`Practice of the Challenged Claims ...................................................... 37
`Physicians’ Administration of Eylea to Patients Practices the
`Challenged Claims .............................................................................. 51
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`–i–
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`Exhibit 2051
`Page 02 of 67
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`I, Dr. Diana Do, declare:
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` INTRODUCTION
`1.
`I have been retained by counsel for Regeneron Pharmaceuticals, Inc.
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`(“Regeneron”) as a technical expert in connection with the above-captioned
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`proceeding. I have been asked to provide my opinions and views on the materials I
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`have reviewed in relation to the Petition for Inter Partes review (“IPR”) of U.S.
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`Patent No. 9,254,338 (the “’338 patent”) (Ex. 1001) and, in particular, how the
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`person of skill in the art as of the filing date of the ’338 patent would have understood
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`certain terms of the ’338 patent claims. I have also been asked to provide my
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`opinions and views about whether the dosage and administration criteria set forth in
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`the FDA label for Eylea practice one or more of the claims of the ’338 patent and
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`whether physicians in clinical practice treat patients with Eylea using the methods
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`recited in one or more claims of the ’338 patent. I have been further asked to respond
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`to the opinions and views of Petitioner’s declarant, Dr. Thomas A. Albini. I submit
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`this declaration in support of Regeneron’s Patent Owner Response (“POR”). I
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`reserve the right to provide further and additional opinions in the event that IPR is
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`instituted.
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`2.
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`I am being paid at an hourly rate for my work on this matter. I have no
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`personal or financial stake in the outcome of the present proceeding.
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`
`
`–1–
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`Exhibit 2051
`Page 03 of 67
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` QUALIFICATIONS AND EXPERIENCE
`3.
`I am a Professor of Ophthalmology and the Vice Chair for Clinical
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`
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`Affairs at the Byers Eye Institute at Stanford University School of Medicine and
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`have been since 2017. I also serve as a Physician Improvement Leader at Byers Eye
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`Institute, a position I have held since 2018. I have an active clinical and surgical
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`practice and I work as a clinical investigator to study novel treatments for retinal
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`diseases. In addition, I teach students, residents, and retina fellows at Stanford and
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`am a member of the Stanford Ophthalmology Education Committee.
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`4.
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`I graduated from the University of California Berkeley (summa cum
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`laude) with a B.A. degree in Molecular and Cellular Biology in 1995 and earned my
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`M.D. (Alpha Omega Alpha) from the University of California San Francisco School
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`of Medicine in 1999. Following medical school, I completed an internship in internal
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`medicine at Massachusetts General Hospital at Harvard Medical School. From
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`2000-2003, I completed my residency in Ophthalmology at the Wilmer Eye Institute
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`at Johns Hopkins University School of Medicine, and then remained at the Wilmer
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`Eye Institute for a Retina Fellowship in surgical and medical retina from 2003-2005.
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`5.
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`From 2005 through 2010, I served as Assistant Professor of
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`Ophthalmology and Assistant Head of the Retina Fellowship Training Program at
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`the Wilmer Eye Institute. In 2011, I was promoted to Associate Professor and Head
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`of the Retina Fellowship Training Program, positions I held through 2013.
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`
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`–2–
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`Exhibit 2051
`Page 04 of 67
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`In 2013, I joined the faculty at the Truhlsen Eye Institute at the
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`6.
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`University of Nebraska College of Medicine, where I became a full Professor of
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`Ophthalmology in 2015. At the Truhlsen Eye Institute, I was Head of the Retina
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`Fellowship Training Program and Program Director for the Ophthalmology
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`Residency. In my leadership roles at the Truhlsen Eye Institute, I also served as Vice
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`Chair of Education. I was recruited by Stanford University’s Ophthalmology
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`Department (the Byers Eye Institute) at Stanford in the beginning of 2017.
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`7.
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`As a physician-scientist, I am an international leader in the treatment of
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`diabetic retinopathy and wet AMD (“wAMD”). My research has led to more than
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`140 peer-reviewed publications. My research interest focuses on evaluating the
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`efficacy and safety of novel pharmacologic therapies for diabetic macular edema,
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`diabetic retinopathy, wAMD, retinal vein occlusion, and ocular inflammation. I have
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`led national and global clinical trials investigating intravitreal VEGF inhibitors
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`(aflibercept and ranibizumab) for diabetic eye disease and wet AMD. Our research
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`developed a greater understanding of how intraocular inhibition of VEGF reduces
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`vascular permeability and angiogenesis in diabetic eye disease, thereby reducing
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`diabetic macular edema and improving visual acuity. Before the onset of
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`pharmacologic therapies, thermal laser photocoagulation was the only treatment
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`option for diabetic macular edema and laser was not effective in improving vision.
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`Our research led to new treatment paradigms and better vision outcomes for patients
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`
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`–3–
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`Exhibit 2051
`Page 05 of 67
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`with diabetic macular edema, diabetic retinopathy, and wAMD. The results from the
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`collaborative research that I led has revolutionized how ophthalmologists
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`throughout the world think about and treat patients with VEGF-mediated retinal
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`diseases.
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`8.
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`Since 2009, I have been the lead investigator and a Steering Committee
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`member for the evaluation of aflibercept, a fusion protein that inhibits VEGF, in
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`diabetic macular edema. I initiated the first-in-human clinical trial of aflibercept. In
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`addition, I also was the principal investigator for the Phase II and III clinical trials
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`of aflibercept for diabetic macular edema to further evaluate efficacy, dosing
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`regimens, and safety. My leadership in these global clinical trials, which enrolled
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`over 1,000 subjects, contributed to FDA approval of aflibercept for diabetic macular
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`edema. Aflibercept has also been approved by FDA for other angiogenic ocular
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`diseases such as wAMD, central retinal vein occlusion, branch retinal vein
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`occlusion, and diabetic retinopathy.
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`9. My research efforts have also led to a greater understanding of the role
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`of ranibizumab, an intravitreal VEGF antibody fragment biologic, in diabetic
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`macular edema. I was a lead investigator in the Ranibizumab for Edema of the
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`Macula in Diabetes (READ) Study Group and was the lead author on multiple
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`manuscripts evaluating the efficacy and safety of ranibizumab. The collaborative
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`studies that I led contributed to understanding dosing regimens for intravitreal
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`–4–
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`Exhibit 2051
`Page 06 of 67
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`VEGF inhibitors, and led to the design of pivotal clinical trials involving
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`ranibizumab for diabetic macular edema. Ranibizumab was the first FDA approved
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`intravitreal VEGF inhibitor for diabetic macular edema, and helped to transform the
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`management of diabetic retinopathy. I continue to lead clinical trials investigating
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`new treatments for retinal diseases.
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`10. As a result of my research, I am recognized as an international thought
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`leader on the subject of the retina and am regularly invited to lecture and teach at
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`international and national meetings
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`including the American Academy of
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`Ophthalmology Retina Sub-Specialty Meeting, American Society of Retina
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`Specialists, Asian Pacific Vitreo-Retinal Society Meeting, Canadian Ophthalmology
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`Society Meeting, and congresses throughout Europe. I have organized and
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`participated as a faculty member in national continuing medical education courses
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`to teach my retina colleagues how to manage and treat diabetic macular edema, wet
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`AMD, retinal vein occlusion, diabetic retinopathy, and other retinal disorders.
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`Furthermore, I have held leadership positions at the American Society of Retina
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`Specialists (Communications Committee Member to curate and develop online
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`educational material), Women in Retina (Board Member and Secretary), Maryland
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`Eye Society (President).
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`11.
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`I am a practicing ophthalmologist with over 15 years of clinical and
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`surgical practice in retina. I am a leader in the management of diabetic retinopathy,
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`
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`–5–
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`Exhibit 2051
`Page 07 of 67
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`the leading cause of blindness in working age adults, and wAMD, the leading cause
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`of vision loss in elderly individuals in developed countries. I have a high-volume
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`clinical and surgical practice and spend approximately 1.5 days per week in clinic at
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`the Byers Eye Institute and half-day per week at the Santa Clara Valley County
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`Medical Center seeing patients in my clinical practice. In addition, I operate
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`approximately one day per week at the Byers Eye Institute.
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`12. Given my extensive experience and research on diabetic retinopathy
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`and wAMD, I have become the expert retinal specialist and surgeon in our
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`department for evaluating these chronic eye diseases. Since joining Stanford’s
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`Ophthalmology Department, I have also become one of the highest volume retina
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`surgeons among our faculty. Because proliferative diabetic retinopathy can lead to
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`tractional retinal detachment and bleeding within the eye, I am referred complex
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`cases that often require clinic-based treatments (such as intravitreal injections of
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`medicines or pan retinal laser photocoagulation) or surgical management. Since I
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`have clinical and research expertise using intravitreal vascular endothelial growth
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`factor (VEGF) inhibitors in wAMD, ophthalmologists refer patients to me for
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`consultation or co-management, particularly of chronic cases that have not
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`responded to therapy. The majority of my patients are from the Bay Area or central
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`California, and approximately 10% travel from more than 5 hours away to seek my
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`expert opinion. I have been recognized as a “Top Doctor” in the Bay Area for the
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`–6–
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`Exhibit 2051
`Page 08 of 67
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`past three years.
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`13.
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`I understand that a copy of my curriculum vitae was previously
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`submitted as Ex. 2002. That copy is still current.
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` SUMMARY OF OPINIONS
`14. My opinions and views set forth in this declaration are based on my
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`education, training, research, and clinical experience in ophthalmology, specifically
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`in researching and treating retinal diseases, as well as the materials I reviewed in
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`preparing this declaration and the state of scientific knowledge in the art pertaining
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`to the subject matter of the ’338 patent at the time of its earliest priority application.
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`15.
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`In forming my opinions, I have reviewed the following materials: (a)
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`the Petition for Inter Partes Review of the ’338 patent, IPR2021-00881, including
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`all cited exhibits, (b) all priority applications leading to the issuance of the ’338
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`patent, (c) all other documents and references herein, and (d) Patent Owner’s
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`Response to which my declaration relates.
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`16.
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`It is my opinion, for at least the reasons set forth below, that the
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`“method for treating” preamble language of Claims 1 and 14 requires treatment of
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`an angiogenic eye disorder.
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`17.
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`It is also my opinion, for at least the reasons set forth below, that the
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`claimed “method for treating” must achieve a high level of efficacy, one that is
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`non-inferior to the existing standard of care at the time the ’338 patent was filed.
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`
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`–7–
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`Exhibit 2051
`Page 09 of 67
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`18. Further, it is my opinion, for the reasons set forth below, that “tertiary
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`dose(s)” means “dose(s), administered after the initial and secondary doses, that
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`maintain(s) the efficacy gain achieved after the initial and secondary doses.”
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`IX. LEGAL FRAMEWORK
`19. For purposes of this declaration, I have been informed by counsel for
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`Patent Owner about certain aspects of the law that are relevant to my analysis and
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`opinions.
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`20.
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`I have been informed that patent claim terms are construed from the
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`vantage point of a skilled artisan to which the invention relates at the time of the
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`invention (or as of the effective filing date of the patent application). The skilled
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`artisan, I understand, is presumed to be familiar with what was known in the art at
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`the time.
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`21.
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` I have been informed that to determine the level of skill of the skilled
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`artisan, courts may consider several factors including, but not limited to: (1) the
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`educational level of the inventor; (2) type of problems encountered in the art; (3)
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`prior art solutions to those problems; (4) rapidity with which innovations are made;
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`(5) sophistication of the technology; and (6) educational level of active workers in
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`the field. I have also been informed that the skilled artisan is someone who must be
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`concerned with the problems the patent seeks to address.
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`22.
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`I have been informed that claim terms should be considered in the
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`
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`–8–
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`Exhibit 2051
`Page 10 of 67
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`context of the entire patent claim where they appear, as well as in the context of the
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`other claims, the specification, and the prosecution history of the patent at issue
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`(collectively, “intrinsic evidence”), taken as a whole (as opposed to in isolation
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`and/or out of context).
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`23.
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`I have been informed that absent an explicit statement to the contrary
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`by the patent applicant, a patent claim term should have its ordinary and customary
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`meaning and not be limited to a specific example that may appear in the patent
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`specification as referring to a preferred embodiment.
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`24.
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`I have been informed that where a term has no ordinary and customary
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`meaning to those of ordinary skill in the prior art, one looks to the specification in
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`the patent.
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`25.
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`I have also been informed that it is only necessary to construe terms
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`that are in controversy, and only to the extent necessary to resolve the controversy.
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`26.
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`I have also been informed that a nexus between a claimed invention and
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`a commercially successful product or process can be shown to exist by
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`demonstrating that the commercially successful product or process embodies or
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`practices the claimed invention, here, the Challenged Claims.
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` THE PERSON OF ORDINARY SKILL IN THE ART
`27.
`I understand that Dr. Albini has offered a definition of a person of
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`ordinary skill in the art (who I also refer to as the “skilled artisan”):
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`–9–
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`Exhibit 2051
`Page 11 of 67
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`[A] person of ordinary skill in the art 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
`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.
`Ex. 10022, ¶ 28.
`28.
`In my view, the skilled artisan is an ophthalmologist with experience
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`in treating angiogenic eye disorders, including through the use of VEGF antagonists.
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`In the event that Mylan argues that the skilled artisan need not be a licensed
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`physician (ophthalmologist), whatever other qualification they must possess, I
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`disagree because only an ophthalmologist would have the firsthand experience of
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`diagnosing and treating angiogenic eye disorders to which the patent is plainly
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`directed.
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`29. My opinions set forth in this declaration remain the same under either
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`Patent Owner’s or Petitioner’s definition of the skilled artisan. Also, under either
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`definition, I would have been at least a skilled artisan when the ’338 patent was filed.
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`
`2 Expert Declaration of Dr. Thomas A. Albini.
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`
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`–10–
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`Exhibit 2051
`Page 12 of 67
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`30. Likewise, for the purpose of preparing this declaration, I have been
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`informed and understand that the earliest filing date of the ’338 patent is January 13,
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`2011, based on the filing of a Provisional Application on that date.
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` THE ’338 PATENT
`31.
`I understand that Petitioner has challenged claims 1, 3-11, 13-14, 16-24
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`and 26 of the ’338 Patent (the “Challenged Claims”).
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`A. Claim 1
`32. The ’338 Patent has two independent claims, claim 1 and 14.
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`33. Claim 1 recites:
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`A method for treating an angiogenic eye disorder in a
`patient,
`said method
`comprising
`sequentially
`administering to the patient a single initial dose of a VEGF
`antagonist, followed by one or more secondary doses of
`the VEGF antagonist, followed by one or more tertiary
`doses of the VEGF antagonist;
`wherein each secondary dose is administered 2 to 4 weeks
`after the immediately preceding dose; and
`wherein each tertiary dose is administered at least 8 weeks
`after the immediately preceding dose;
`wherein the VEGF antagonist is a VEGF receptor-based
`chimeric molecule comprising (1) a VEGFR1 component
`comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a
`VEGFR2 component comprising amino acids 130-231 of
`SEQ ID NO:2; and (3) a multimerization component
`comprising amino acids 232-457 of SEQ ID NO:2.
`Ex. 1001 at 23:1-18.
`34. The dosing regimen of Claim 1 is directed to the treatment of any type
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`
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`–11–
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`Exhibit 2051
`Page 13 of 67
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`of angiogenic eye disorder with a VEGF antagonist that has a particular amino acid
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`sequence.
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`35. The dosing regimen of Claim 1 requires treatment of an angiogenic eye
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`disorder by administration of an initial dose of the claimed VEGF antagonist
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`followed by one or more “secondary” doses administered two to four weeks after
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`the preceding dose, and then one or more “tertiary” doses that are administered at
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`least eight weeks following the preceding dose.
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`36. Challenged Claims 3-11 and 13 depend from Claim 1, and further limit
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`the timing between dosage administration, the specific angiogenic eye disorder,
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`administration route, and dosage amount.
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`B. Claim 14
`37. Claim 14 recites:
`
`A method for treating an angiogenic eye disorder in a
`patient,
`said method
`comprising
`sequentially
`administering to the patient a single initial dose of a VEGF
`antagonist, followed by one or more secondary doses of
`the VEGF antagonist, followed by one or more tertiary
`doses of the VEGF antagonist;
`wherein each secondary dose is administered 2 to 4 weeks
`after the immediately preceding dose; and
`wherein each tertiary dose is administered at least 8 weeks
`after the immediately preceding dose;
`wherein the VEGF antagonist is a VEGF receptor-based
`chimeric molecule comprising VEGFR1R2-FcΔC1(a)
`encoded by the nucleic acid sequence of SEQ ID NO:1.
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`
`
`–12–
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`Exhibit 2051
`Page 14 of 67
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`Ex. 1001 at 24:3-15.
`38. The dosing regimen of Claim 14 is directed to the treatment of any type
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`of angiogenic eye disorder with a particular VEGF antagonist that is encoded by the
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`recited nucleic acid sequence.
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`39. Like Claim 1, the dosing regimen of Claim 14 requires treatment of an
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`angiogenic eye disorder by administration of an initial dose of the claimed VEGF
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`antagonist followed by one or more “secondary” doses administered two to four
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`weeks after the preceding dose, and then one or more “tertiary” doses that are
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`administered at least eight weeks following the preceding dose.
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`40. Thus, Claim 14 differs from Claim 1 only with respect to the last
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`“wherein clause” specifying the nucleic acid sequence of SEQ ID NO:1. I
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`understand that SEQ ID NO:2 is the corresponding amino acid sequence of the
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`nucleic acid sequence SEQ ID NO:1.
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`41. Challenged Claims 16-24 and 26 depend from Claim 14, and further
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`limit the timing between dose administration, the specific angiogenic eye disorder,
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`administration route, and dose amount.
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` CLAIM CONSTRUCTION
`42.
`I have been asked to consider the meaning of “[a] method for treating
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`an angiogenic eye disorder in a patient” and “tertiary dose(s)” from the perspective
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`of a skilled artisan as of January 13, 2011, and respond to Dr. Albini’s opinions
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`
`
`–13–
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`Exhibit 2051
`Page 15 of 67
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`
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`regarding the meaning of these terms.
`
`A.
`“A Method for Treating an Angiogenic Eye Disorder in a Patient”
`43. The preamble of Claims 1 and 14 recites “[a] method for treating an
`
`angiogenic eye disorder in a patient.” Ex. 1001 at 23:2-3, 24:3-4.
`
`1.
`Limiting preamble
`44. Dr. Albini states that the preamble language “method for treating”
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`simply means “administering a therapeutic agent to a patient.” Ex. 1002 (Albini
`
`Declaration), ¶ 43. This, however, ignores the remaining language in the preamble
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`which specifies what is being treated: “an angiogenic eye disorder in a patient.” No
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`ordinarily skilled artisan would think that this language encompasses administering
`
`the specified treatment to a person suffering, for example, solely from arthritis. Nor
`
`would the ordinarily skilled artisan think that the administration of an infinitesimal
`
`amount of the specified compound is encompassed by the claim. Neither would
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`constitute a “method for treating an angiogenic eye disorder in a patient.” Instead, a
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`skilled artisan would understand the language “[a] method for treating an angiogenic
`
`eye disorder in a patient” in the context of the ’338 patent to require actually treating
`
`a patient’s angiogenic eye condition.
`
`45.
`
`It is my understanding that in its Institution Decision, the Board
`
`preliminarily construed the preamble “[a] method for treating an angiogenic eye
`
`disorder in a patient” to be a limitation of the claim. Paper 21 at 18. That is, the
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`
`
`–14–
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`Exhibit 2051
`Page 16 of 67
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`Board found that the preamble requires an intent to treat a patient with an angiogenic
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`eye disorder. I agree with this determination.
`
`2.
`Treatment requires efficacy
`It is also my understanding that the Board preliminarily determined that
`
`46.
`
`the preamble does not “requir[e] any ‘specific degree of efficacy.’” Paper 21 at 20.
`
`For the reasons below, I disagree with this determination. It is my opinion that the
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`claims of the recited “method for treating” require not only an intent to treat, but also
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`that the treatment be effective. If administration of the drug is not effective, it would
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`not be a treatment. Furthermore, it would not be ethical for a clinician at the time of
`
`filing to administer a drug according to an ineffective dosing regimen because there
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`were effective treatments available that had already established a relatively high
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`standard of care.
`
`47. The ’338 Patent explains that the invention is a new method of
`
`treatment which is effective, and not inferior to, the existing standard of care,
`
`because it “allow[s] for less frequent dosing while maintaining a high level of
`
`efficacy.” Ex. 1001 at 1:57-58; see also id. at 2:3-10 (“The present inventors have
`
`surprisingly discovered that beneficial therapeutic effects can be achieved…)
`
`(emphasis added).
`
`48. The ’338 patent states, “[t]he amount of VEGF antagonist administered
`
`in each dose is, in most cases, a therapeutically effective amount.” Ex. 1001 at
`
`
`
`–15–
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`Exhibit 2051
`Page 17 of 67
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`
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`6:48-50. The ’338 Patent’s specification defines “therapeutically effective amount”
`
`as “a dose of VEGF antagonist that results in a detectable improvement in or more
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`symptoms or indicia of an angiogenic eye disorder, or a dose of VEGF antagonist
`
`that inhibits, prevents, lessens or delays the progression of an angiogenic eye
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`disorder.” Id. at 6:50-55.
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`49.
`
`I understand that the Patent Trial and Appeal Board (“PTAB”)
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`concluded that the “claims do not require the recited method steps to provide an
`
`effective treatment” because the patent states: “‘[t]he amount of VEGF antagonist
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`administered to the patient in each dose is, in most cases, a therapeutically effective
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`amount.’ Ex. 1001 at 6:48-50 (emphasis added).” Paper 21 at 20.
`
`50.
`
`I do not agree with this interpretation of the specification or the Board’s
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`conclusion. A skilled artisan would not read this passage in the context of the overall
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`disclosure or what was known at the time about standard of care treatments as
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`describing as part of the patentee’s invention, methods of treatment that did not in
`
`fact treat anyone because they were not effective. Instead, the passages quoted by
`
`the PTAB from column 6 merely observe that an amount which is therapeutically
`
`effective is effective “in most cases” even if some patients do not respond. That is
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`consistent with the data reported in the specification that show that while around
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`96% of the treated subjects achieved the “primary endpoint (prevention of moderate
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`
`
`–16–
`
`Exhibit 2051
`Page 18 of 67
`
`
`
`
`
`or severe vision loss as defined above),” the remaining ~ 4% did not achieve this
`
`endpoint. Ex. 1001 at 12:66-13:23.
`
`51. The skilled artisan would not understand the passages in column 6 to
`
`redefine the invention to include methods that are not therapeutically effective. Such
`
`methods would not be considered “treatment” as that term is understood by the
`
`skilled artisan. The ’338 patent’s specification elsewhere makes clear, repeatedly,
`
`that the “present invention” relates to “therapeutic treatment.” See Ex. 1001 at
`
`Abstract (“The methods of the present invention are useful for the treatment of
`
`angiogenic eye disorders…”); 1:17-20 (“The present invention relates to the field
`
`of therapeutic treatments…”); 2:3-10 (“The present inventors have surprisingly
`
`discovered that beneficial therapeutic effects can be achieved in patients suffering
`
`from angiogenic eye disorders by administering a VEGF antagonist to a patient at a
`
`frequency of once every 8 or more weeks, especially when such doses are preceded
`
`by about three doses administered to the patient at a frequency of about 2 to 4
`
`weeks.”); 7:19-24 (“Generally, the methods of the present invention demonstrate
`
`efficacy within 104 weeks of the initiation of the treatment regimen (with the initial
`
`dose administered at ‘week 0’), e.g., by the end of week 16, by the end of week 24,
`
`by the end of week 32, by the end of week 40, by the end of week 48, by the end of
`
`week 56, etc.”).
`
`
`
`–17–
`
`Exhibit 2051
`Page 19 of 67
`
`
`
`
`
`52. Furthermore, the ’338 patent specification also describes administration
`
`in some cases of non-therapeutically effective amounts—not as methods of
`
`treatment—but as a means to test the safety of a method in a Phase I clinical trial. In
`
`this trial, some doses were as low as 0.05 mg, which is 10-fold lower than the lowest
`
`dose in the Phase III clinical trial designed to test efficacy. Ex. 1001 at 7:60-67, 13:5-
`
`23. A skilled artisan would understand the need for including testing of non-
`
`therapeutic doses in a safety trial and would not view that as a “method for treating”
`
`as required by the claims.
`
`53.
`
`It is therefore my opinion that the recited “method for treatment” not
`
`only requires an intent to treat, but must actually treat.
`
`3.
`
`A treatment’s efficacy must be non-inferior to the existing
`standard of care
`54. The standard of care for treating wet AMD and many other angiogenic
`
`eye disorders improved drastically in the years leading up to the ’338 patent filing
`
`date, driven in large part by the testing and approval of Lucentis® (ranibizumab).
`
`55. Wet AMD is an angiogenic eye disorder characterized by abnormal
`
`growth of new blood vessels in the macula, the central portion of the retina
`
`responsible for high-resolution vision. Ex. 20253 at 2. Historically, wAMD was a
`
`
`3 A Phase 3 Safety and Efficacy Study of Fovista® (E10030) Intravitreous
`Administration
`in Combination With Lucentis® Compared
`to Lucentis®
`Monotherapy,
`ClinicalTrials.gov
`(August
`2,
`2021),
`–18–
`
`
`
`Exhibit 2051
`Page 20 of 67
`
`
`
`
`
`devastating diagnosis that frequently led to irreversible vision loss. Early treatments
`
`with laser and photodynamic therapy would often, at best, slow inevitable vision
`
`loss. At worst, these treatments could cause further vision damage through retinal
`
`scarring. Wet AMD was the first angiogenic eye disorder where anti-VEGF agents
`
`were widely tested as a potential therapy.
`
`56. 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®).
`
`57. Macugen® was the first anti-VEGF agent approved for treatment of
`
`neovascular (wet) age-related macular degeneration. Ex. 21174. Macugen was
`
`approved in 2004 based on two pivotal Phase 3 studies and its label instructs that it
`
`should be administered once every six weeks by intravitreous injection.” Ex. 20385
`
`at 7. The primary efficacy endpoint for Macugen trials was the proportion of patients
`
`losing less than 15 letters of visual acuity as measured by ETDRS. Id. at 3-4. “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
`
`
`https://clinicaltrials.gov/ct2/show/NCT01940900?term=fovista&phase=2&draw=2
`&rank=2.
`
` 4
`
` Macugen Approval Letter (December 17, 2004).
`5 Macugen label submitted with NDA 21-756.
`
`
`
`–19–
`
`Exhibit 2051
`Page 21 of 67
`
`
`
`
`
`group was slower than the rate in the patients who received sham treatment.” Id. at
`
`4 (emphasis added).
`
`58.
`
`It was Phase III clinical testing of Genentech’s drug, ranibizumab
`
`(Lucentis®), a VEGF antibody fragment, that established for the retinal community
`
`the potential effectiveness of anti-VEGF therapy.
`
`59.
`
`In 2003, Genentech began two large-scale, Phase III studies to test
`
`in patients with wAMD—MARINA and
`
`injections
`monthly ranibizumab
`ANCHOR. Ex. 21186; Ex. 21197.
`a. MARINA
`60. 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 who were randomly assigned to receive 24 monthly intravitreal
`
`injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. Ex. 2119
`
`(Rosenfeld) at 1419. The primary endpoint of the study was the proportion of
`
`patients losing fewer than 15 letters from baseline visual acuity at 12 months. Id.
`
`61. The one-year results of MARINA were presented in July of 2005 and
`
`showed that nearly ninety-five percent of patients treated with ranibizumab satisfied
`
`
`6 Brown DM, et al., Ranibizumab versus verteporfin for neovascular age-related
`macular degeneration, N Engl J Med. 2006;355(14):1432-44.
`7 Rosenfeld PJ, Brown DM, et al., Ranibizumab for neovascular age-related
`macular degeneration, N Engl J Med. 2006;355(14):1419-31.
`
`
`
`–20–
`
`Exhibit 2051
`Page 22 of 67
`
`
`
`
`
`the primary endpoint. Ex. 21208 at 4. The two-year results of the MARINA trial were
`
`then published in October of 2006 and showed that the mean improvement in vision
`
`demonstrated in the first 12 months of the study were sustained through the second
`
`years of study. Ex. 2119 (Rosenfeld) at 1419. The mean increases in visual acuity
`
`far exceeded the primary endpoint, resulting in gains of +6.5 letters in the 0.3 mg
`
`group and +7.2 letters in the 0.5 mg groups (compared with a decrease of -10.3
`
`letters in the sham group). Id.
`
`62. The unmasking of the one-year results of the MARINA study prompted
`
`a protocol amendment in the second year that allowed subjects still in the sham arm
`
`to be offered ranibizumab injections. Monthly ranibizumab injections were
`
`determined by this point to be a critical tool to not only arrest vision los
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