UNITED STATES PATENT AND TRADEMARK OFFICE
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`———————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`———————————
`
`REGENERON PHARMACEUTICALS, INC.
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`Petitioner,
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`
`Patent Owners.
`
`
`———————————
`
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`Patent Number: 9,220,631
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`
`———————————
`
`DECLARATION OF DR. SZILÁRD KISS
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`
`
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`
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`Regeneron Exhibit 1031.001
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`
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`———————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`———————————
`
`REGENERON PHARMACEUTICALS, INC.
`
`Petitioner,
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`
`Patent Owners.
`
`
`———————————
`
`
`Patent Number: 9,220,631
`
`
`———————————
`
`DECLARATION OF DR. SZILÁRD KISS
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`
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`Regeneron Exhibit 1031.001
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`TABLE OF CONTENTS
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`Page
`I.
`Introduction ...................................................................................................... 1
`II. Qualifications and Compensation .................................................................... 1
`III. Relevant Legal Standards ................................................................................ 5
`A.
`Claim Construction ............................................................................... 5
`B.
`Invalidity ............................................................................................... 5
`IV. Person of Ordinary Skill in the Art .................................................................. 8
`V.
`Relevant Technical Background .................................................................... 10
`VI. Obviousness of Claim 24 ............................................................................... 15
`VII. Obviousness of Claim 25 ............................................................................... 18
`VIII. Obviousness of Claim 26 ............................................................................... 19
`IX. Declaration ..................................................................................................... 22
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`
`
`
`
`i
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`Regeneron Exhibit 1031.002
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`I.
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`Introduction
`1.
`I have been retained by Petitioner Regeneron Pharmaceuticals, Inc.
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`(“Petitioner” or “Regeneron”), as an independent expert witness in the above-
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`captioned inter partes review (“IPR”), in which Regeneron has requested that the
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`U.S. Patent and Trademark Office cancel as unpatentable all claims of U.S. Patent
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`No. 9,220,631 (“the ’631 patent”). This declaration sets forth my analyses and
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`opinions based on my knowledge, experience, and the materials I have considered.
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`2.
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`I provide this declaration to explain that certain ophthalmology-related
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`subject matter disclosed and claimed in the ’631 patent was well-known prior to
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`2012, and also to specifically opine on the obviousness of claims 24-26.
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`3.
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`For purposes of this declaration, I have assumed that claim 1 of the ’631
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`patent has separately been shown to be obvious based on the prior art and the
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`Declaration of Horst Koller (Ex. 1003).
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`II. Qualifications and Compensation
`4.
`I received my B.A. in Biology from Columbia College in 1997 and my
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`M.D. from Columbia University in 2002. Following graduation from medical
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`school, I was an intern in the Department of Internal Medicine at St. Luke’s
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`Roosevelt Hospital, Columbia University College of Physicians & Surgeons, from
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`2002 to 2003. I then became a Resident in the Ophthalmology Department of the
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`
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`1
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`Regeneron Exhibit 1031.003
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`
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`Massachusetts Eye and Ear Infirmary of Harvard Medical School from 2003 to 2006.
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`I was certified by the American Board of Ophthalmology in 2007.
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`5.
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`Following my Residency, I was appointed as a Fellow of the Vitreo-
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`Retinal Service in the Ophthalmology Department of the Massachusetts Eye & Ear
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`Infirmary at Harvard Medical School in 2006, and promoted to Chief Fellow in
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`2007. I am the current Associate Attending at New York Presbyterian Hospital/Weill
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`Cornell Medical Center and the Associate Attending Surgeon at Memorial Sloan
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`Kettering. I am the chief of the retina service at Weill Cornell.
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`6.
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`In addition to my clinical duties, in 2008, I became an Assistant
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`Professor of Ophthalmology at Weill Cornell Medical College, and I was promoted
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`to Associate Professor in 2013. I was subsequently promoted to my current position,
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`the Bob and Dolores Hope Robert M. Ellsworth MD Distinguished Associate
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`Professor in Ophthalmology. In addition to my position in Ophthalmology, in 2019,
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`I was promoted to Associate Dean, Clinical Compliance at Weill Cornell Medical
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`College and, in August 2020, I was named Vice Chair of Compliance and Vice Chair
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`of Research at Weill Cornell Medical College. I am also the chair of the general
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`faculty counsel.
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`7. My clinical duties involve outpatient evaluation and management for
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`complex vitreoretinal pathologies such as age-related macular degeneration, diabetic
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`retinopathy, retinal vascular disorders, inherited retinal degenerations, infectious and
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`
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`2
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`Regeneron Exhibit 1031.004
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`non-infectious uveitis, and inherited and acquired maculopathies. I also perform
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`intraocular surgery on patients with vitreoretinal pathologies.
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`8.
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`In addition to my work experience, I have many years of experience
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`participating in professional organizations relating to ophthalmology. Specifically, I
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`am a member of the Retina Society, the Macula Society, Club Jules Gonin, the
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`American Academy of Ophthalmology, the Association for Research in Vision and
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`Ophthalmology, the American Society of Retina Specialists, the Pan-American
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`Association of Ophthalmology, and a number of other professional societies and
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`organizations. I have also participated as a principal investigator in over three-dozen
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`prospective clinical trials and laboratory investigations.
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`9.
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`In addition to the above, I have given over 200 invited lectureships
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`worldwide at industry meetings and medical conferences relating to ocular diseases,
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`including wet macular degeneration. These include, for example, a presentation
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`regarding anti-VEGF agents in wet age-related macular degeneration, sustained
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`delivery systems, keratoprosthesis, retinal vein occlusion, uveitis, macular edema
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`secondary to diabetic retinopathy, retinal vein occlusion, and diseases of the
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`vitreomacular interface. I have authored or co-authored nearly 300 peer-reviewed
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`publications, I am on the editorial board of several journals, and I am an ad hoc
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`reviewer for other journals and grants. My research has a focus in four main areas:
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`
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`3
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`Regeneron Exhibit 1031.005
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`
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`ocular gene and cellular
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`therapy, novel
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`therapeutic
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`targets
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`for ocular
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`neovascularization, complex vitreoretinal surgical techniques, and retinal imaging.
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`10.
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`I have also received numerous academic and scientific awards,
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`including the Honor and Senior Honor Awards from the American Society of Retina
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`Specialists and the Honor Award from the American Academy of Ophthalmology. I
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`was among a select group of retina specialists world-wide to be elected by my peers
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`as a Charter Member of the Retina Hall of Fame, and I have also been named to
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`several regional, national and international Top Doctors lists, including The
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`Ophthalmologist Power List Top 40 Under 40 Ophthalmologist Worldwide, Castle
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`Connolly’s Top Doctors, and New York Super Doctors. A copy of my current
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`curriculum vitae is attached as Ex. 1032.
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`11. Through my professional experience, I have gained extensive expertise
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`in a wide variety of complex vitreoretinal pathologies. I have experience with
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`treatment of all of the following conditions by using intravitreal administration of
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`VEGF antagonists: choroidal neovascularisation, wet age-related macular
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`degeneration, macular edema secondary to retinal vein occlusion (RVO) including
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`both branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation
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`secondary to pathologic myopia (PM), diabetic macular edema (DME), diabetic
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`retinopathy, and proliferative retinopathy.
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`4
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`Regeneron Exhibit 1031.006
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`12.
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`I am being compensated at my standard rate of $850/hour. My
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`compensation is in no way contingent upon my opinions or the outcome of the
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`proceeding. I may testify on any or all of the opinions expressed in this declaration.
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`III. Relevant Legal Standards
`13.
`I am not an attorney, and therefore my understanding of patent law and
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`the legal standards set forth in this report is based on explanations provided to me
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`by counsel.
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`A. Claim Construction
`14.
`It is my understanding that the numbered paragraphs at the end of the
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`disclosure of a U.S. Patent are the patent “claims” that define the metes and bounds
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`of the alleged invention. I understand that the claims of the ’631 patent are what is
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`being challenged in the present IPR proceeding.
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`15.
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`I have been informed that, in this proceeding, the Board must determine
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`the scope of the claims by giving the claims their ordinary and customary meaning
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`in light of the specification, as the claims would be interpreted by one of ordinary
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`skill in the art.
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`B.
`16.
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`Invalidity
`I understand that Regeneron bears the burden of proving that the
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`challenged claims of the ’631 patent are invalid, and must prove this by a
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`preponderance of the evidence, which means that invalidity must be shown to be
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`more likely than not.
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`5
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`Regeneron Exhibit 1031.007
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`17.
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`I have been asked to consider the question of whether certain claims of
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`the ’631 patent would have been obvious. I understand that this analysis must be
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`conducted from the perspective of the person of ordinary skill in the art, and whether
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`the skilled artisan would consider any differences between the prior art and what is
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`claimed to have been obvious. To make this assessment, I have been informed that
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`the concept of patent obviousness involves four factual inquiries: (1) the scope and
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`content of the prior art; (2) the differences between the claimed invention and the
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`prior art; (3) the level of ordinary skill in the art; and (4) secondary considerations
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`of non-obviousness. I have been instructed that one must not engage in hindsight.
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`Rather, the better approach is to consider what the person of ordinary skill in the art
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`would have reason to pursue further, and steps that were routinely done, such as in
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`response to known problems, steps, or obstacles.
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`18.
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`It is my understanding that some teaching, suggestion, or motivation in
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`the prior art that would have led one of ordinary skill to modify the prior art reference
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`or to combine prior art reference teachings to arrive at the claimed invention may
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`support the obviousness of an invention. Other rationales that may support the
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`obviousness of the invention include a simple substitution of one known element for
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`another to obtain predictable results, and applying a known technique to a known
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`device ready for improvement to yield predictable results.
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`6
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`Regeneron Exhibit 1031.008
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`19.
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`It is my understanding that the motivation to combine prior art
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`references may be implicit and may be found in the knowledge of one of ordinary
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`skill in the art, or in the nature of the problem to be solved. Specifically, it is my
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`understanding that an implicit motivation to combine exists not only when a
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`suggestion may be gleaned from the prior art as a whole, but when the
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`“improvement” is technology-independent and the combination of references results
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`in a product or process that is more desirable, for example, because it is stronger,
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`cheaper, cleaner, faster, lighter, smaller, more durable or more efficient. It is my
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`further understanding that the motivation to combine references may be found in the
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`nature of the problem to be solved where prior art references are directed to precisely
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`the same problem.
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`20.
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`I also understand that prior art may be relied on for its express
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`disclosure and teachings. I also understand that the prior art may be relied upon for
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`a teaching of features that are necessarily present in the prior art reference even if
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`that specific feature is not expressly or explicitly disclosed.
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`21.
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`I understand that before reaching any final conclusion on obviousness,
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`the obviousness analysis requires consideration of objective indicia of non-
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`obviousness, if any such indicia are offered. These must be considered to ensure that,
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`for example, there were not some unanticipated problems, obstacles or hurdles that
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`may seem easy to overcome in hindsight, but which were not readily overcome prior
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`7
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`Regeneron Exhibit 1031.009
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`to the relevant invention date of the patents/claims at issue here. I understand that
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`these objective indicia are also known as “secondary considerations of non-
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`obviousness,” and may include long-felt but unmet need, unexpected results,
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`commercial success, and industry praise, among others. I understand that for
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`secondary considerations such as, for example, commercial success, evidence is only
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`relevant if there is a nexus between the unique characteristics of the claimed
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`invention and the secondary consideration it is alleged to support. I also understand
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`it is the Patentee who has the burden of proving that a nexus exists, and I understand
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`that secondary considerations will not overcome a strong showing of obviousness.1
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`IV. Person of Ordinary Skill in the Art
`22.
`I have been asked to review the ’631 patent from the perspective of a
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`person of ordinary skill in the art (“POSITA”). I understand that the ’631 patent
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`claims an earliest priority date of July 3, 2012.2 Therefore, I have considered the
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`state of the art as of July 3, 2012 and before that date, and the level of knowledge
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`that a POSITA would have possessed at that time. Unless I state otherwise,
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`1 I understand that the declaration of Mr. Koller explains that there are no secondary
`considerations that would support a finding that the claims of the ’631 patent are not
`obvious. I reserve the right to address any evidence of alleged secondary
`considerations that is put forth by Patent Owner in this proceeding, including any
`evidence specific to claims 24-26
`2 I have been informed that the date of “July 30, 2012” for EP 12174860 listed on
`the face of the ’631 patent is a typographical error and should be July 3, 2012.
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`8
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`Regeneron Exhibit 1031.010
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`whenever I refer to any principle or technical subject matter as having been known
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`or understood, this is meant to denote the knowledge and understanding of a
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`POSITA at or prior to July 3, 2012.3
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`23.
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`I have reviewed and adopted the definition of POSITA as of July 2012
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`set forth in the Koller Decl (Ex. 1003). Specific to claims 24-26, I agree that a
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`POSITA with respect to these claims would be an ophthalmologist with some
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`experience administering VEGF-antagonist drugs to patients via the intravitreal
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`route, because claims 24-26 relate to methods of treating a patient suffering from
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`eye disease by administering an ophthalmic solution using a pre-filled syringe. See
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`Ex. 1015.036 (“Since an excellent knowledge of the anatomy and function of the
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`eye is required, only an ophthalmologist should attempt these procedures.”). My use
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`of the term “ophthalmologist” in this declaration will be in reference to the
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`aforementioned POSITA ophthalmologist, unless specified otherwise. I note that by
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`2012, administering drugs by intravitreal injection was standard practice for
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`ophthalmologists, even before VEGF-antagonists were regularly administered. One
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`example is Trivaris®, which I discuss further below.
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`3 I understand that the ’631 patent may not be entitled to the July 3, 2012 priority
`date, and that the next earliest priority date claimed by the patent would be October
`23, 2012. For purposes of my opinions, there is no appreciable difference in the
`state of the art between July 3 and October 23, 2012, because the subject matter I
`describe herein as it relates to the ’631 patent was well-known and conventional well
`before July 3, 2012.
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`9
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`Regeneron Exhibit 1031.011
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`V. Relevant Technical Background
`24.
`“VEGF” is short for “vascular endothelial growth factor,” which is a
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`protein within the human body. It was well-known prior to 2012 that the
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`overexpression of VEGF contributes to diseases, including cancer and vascular
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`diseases of the eye, and therefore that compounds that inhibit the expression of
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`VEGF are useful in the treatment of such diseases. Diseases that were known to be
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`related to the expression or over-expression of VEGF, and therefore treatable by
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`administration of VEGF-antagonist drug
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`formulations,
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`include choroidal
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`neovascularisation, wet age-related macular degeneration (wet AMD), macular
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`edema secondary to retinal vein occlusion (RVO) including both branch RVO
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`(bRVO) and central RVO (cRVO), choroidal neovascularisation secondary to
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`pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and
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`proliferative retinopathy. See, e.g., Ex. 1054.002-.003; Ex. 1055.018, .029.
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`25. Several VEGF-antagonists were known and commercially available
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`prior to 2012 that an ophthalmologist would have known were approved to be used
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`for the treatment of some or all of the eye diseases mentioned above. These include
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`ranibizumab (Lucentis®), aflibercept (Eylea®), and pegaptanib (Macugen).4 See
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`Ex. 1027, Ex. 1040, Ex. 1009. All three of these VEGF-antagonist drug
`
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`4 Lucentis® and Eylea® are now the preferred treatments and Macugen is no longer
`widely used.
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`
`
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`10
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`Regeneron Exhibit 1031.012
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`
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`formulations are intended for administration via the intravitreal route. As used
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`herein, “intravitreal” administration refers to “injection directly into the vitreous
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`cavity of the eye.” Ex. 1015.035. An intravitreal injection is a type of “intraocular
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`injection”—a more general term for injection into the eye. Id.
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`26. Because of the delicate structures in the eye, an ophthalmologist would
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`have been well aware that “[e]xtreme care and precise technique are required to
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`minimize or prevent damage to the eye, especially to the corneal endothelium.” Ex.
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`1015.036. It was known that numerous medical complications could occur from
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`incorrect intravitreal administration, such as retinal detachment and ocular
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`hemorrhage, including massive subretinal hemorrhage, and infection is always a
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`threat, which can lead to further complications. As such, intravitreal injections are
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`typically administered only by ophthalmologists. Id.
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`27.
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`It was also known that only small volumes of around 0.1 mL
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`(sometimes 0.15 mL) or typically even less than that should be injected
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`intravitreally, unless fluid from the vitreous humour is first removed from the eye of
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`the patient via paracentesis. Id.; see Ex. 1059.004. This prevents elevation of ocular
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`pressure. Ex. 1059.004. The Macugen label, for example, states that the deliverable
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`volume is 90 µL, or 0.090 mL. Ex. 1009.009. Because VEGF-antagonist
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`formulations are administered by injection into the eye, they are typically dispensed
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`either in vials to be used with empty disposable syringes (see Ex. 1040.014), or in a
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`
`
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`11
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`Regeneron Exhibit 1031.013
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`
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`pre-filled syringe (see Ex. 1009.001). Because of the low injection volume needed
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`for intravitreal administration, pre-filled syringes for injection of such small doses
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`are likewise small. For example, the original 2004 prescribing information for
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`Macugen specified that the supplied syringe was a “1 mL glass syringe.” Ex.
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`1062.009; see also Ex. 1063.016 (describing Macugen clinical trial intravitreal
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`injection performed with pegaptanib packaged in a “single-use, USP type 1
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`graduated glass 1 mL syringe”). International Patent Application Publication No.
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`WO 2007/149334 also discloses a VEGF-antagonist in a 1 mL pre-filled glass
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`syringe. Ex. 1021 at [0059], [0061].
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`28. Ophthalmologists were well aware of pre-filled syringes that had been
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`FDA approved and commercially available for intravitreal administration prior to
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`2012. One example is Allergan’s Trivaris®, which was available as a pre-filled
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`syringe containing a corticosteroid for intravitreal administration to treat
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`sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory
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`conditions unresponsive to topical corticosteroids. See Ex. 1056.003-.005.
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`Similarly, Macugen (pegaptanib sodium injection), was a well-known VEGF-
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`antagonist formulation indicated for the treatment of neovascular (wet) age-related
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`macular degeneration (AMD) and available in a pre-filled syringe. See Ex. 1009.001.
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`29. Macugen has been sold as a pre-filled syringe since it was approved
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`in 2004. See 2004 Macugen Label at 1 (Ex. 1062.001). The 2008 Macugen Label
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`12
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`Regeneron Exhibit 1031.014
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`
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`(revised as of August 2008) (Ex. 1009) provides the prescribing information for
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`Macugen as presented on the drugs.com website as of March 7, 2011. I was aware
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`of the drugs.com website at that time, and I used the drugs.com website in my
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`professional capacity to find prescribing information and data about drugs.
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`Physicians in general knew that drugs.com was a source for drug prescribing
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`information as of 2011, and physicians could and did access drug prescribing
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`information on drugs.com, as I did. Likewise, a person interested in the art in 2011,
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`would have accessed drugs.com and been able to use its searching and indexing
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`capabilities to find prescribing information for specific drugs.
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`30.
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`I first became aware of Macugen in 2002 or 2003 when it was under
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`investigation in clinical trials. I was aware that Macugen was administered by
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`intravitreal injection, and was supplied in a pre-filled syringe. I personally
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`administered Macugen during the time period of 2006-2008 in the United States. I
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`have reviewed the 2004 Macugen Label (Ex. 1062) and the 2008 Macugen Label
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`(Ex. 1009)5 from the drugs.com website, and recognize the contents of those labels
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`based on my past experience administering Macugen.
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`5 I have also reviewed Ex. 1081, which is an actual copy of the Macugen label
`(revised as of 08/2008). The contents of the Macugen Label in Ex. 1081 match the
`contents of the Macugen label available on the drugs.com website as of March 7,
`2011 (Ex. 1009).
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`13
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`Regeneron Exhibit 1031.015
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`31. Ophthalmologists were well aware in 2012 and before, that thin needle
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`sizes and short needle lengths are preferred for intravitreal administration. A 30-
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`gauge needle size was preferred by surgeons performing intravitreal injections,
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`although 27-gauge needles were also used as of 2012. See Ex. 1058.002. Thin needle
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`sizes are desirable in order to reduce patient discomfort that may be caused by
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`thicker needles, as well as to reduce the risk of retinal detachment and
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`endophthalmitis. See Ex. 1059.004. Shorter needle lengths are preferred because of
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`the limited depth of injection into the eye, as illustrated in Nema. See Ex. 1015.036;
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`see also, Ex. 1059.003 (recommending an injection depth of 5 to 7 mm, which is
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`about half of the 0.5 inch needle (12.7 mm)). The 2008 Macugen Label states that
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`the pre-filled syringe was supplied with a 30-gauge needle, described as a “30 G x
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`0.5” inch needle. See 2008 Macugen Label at 9 (Ex. 1009.009). Thus, it was
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`generally known that syringes for intravitreal administration had a 27-gauge needle
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`or higher (such as 30 gauge), and generally had a 0.5 inch length. See, e.g., Trivaris®
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`Label at 4 (Ex. 1056.004); 2008 Macugen Label at 9 (Ex. 1009.009); Lucentis®
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`Label at 2 (Ex. 1027.002).
`
`32. The ’631 patent describes priming as “allow[ing] the physician to align
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`a pre-determined part of the stopper (such as the tip of the front surface or one of the
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`circumferential ribs, discussed later) or plunger with the mark, thus expelling excess
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`ophthalmic solution and any air bubbles from the syringe. The priming process
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`14
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`Regeneron Exhibit 1031.016
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`
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`ensures that an exact, pre-determined dosage is administered to the patient.” Ex.
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`1001 at 2:26-32. It is known that prior to administering a drug using a pre-filled
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`syringe or any syringe for that matter, ophthalmologists routinely perform the step
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`of aligning the syringe stopper with a mark provided on the syringe to expel excess
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`solution and ensure accurate dosing. 2008 Macugen Label at 2, 7 (Ex. 1009.001-
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`.002, .007) (describing the priming step in which the physician depresses the plunger
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`“to eliminate all the bubbles and to expel the excess drug so that the top edge of the
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`3rd rib on the plunger stopper aligns with the pre-printed black dosing line” of the
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`pre-filled syringe); Trivaris® Label at 4 (Ex. 1056.004) (“Prepare the proper volume
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`of TRIVARIS™ to be injected by advancing the plunger to the single line marked
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`on the pre-filled glass syringe shaft.”). Having dosing marks on a syringe was and is
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`a common feature of pre-filled syringes that is not unique to any specific drug.
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`Accordingly, “priming” has been a known and routine step in the intravitreal drug
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`administration process since well before 2012.
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`VI. Obviousness of Claim 24
`33.
`I understand that claim 24 depends from claim 1 and therefore
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`incorporates all of the features of claim 1. Claim 24 is reproduced below:
`
` 24. A method of treating a patient suffering from of [sic]- an ocular
`disease selected from choroidal neovascularisation, wet age-related
`macular degeneration, macular edema secondary to retinal vein
`occlusion (RVO) including both branch RVO (bRVO) and central RVO
`
`
`
`
`15
`
`Regeneron Exhibit 1031.017
`
`
`
`
`
`
`
`
`
`(cRVO), choroidal neovascularisation secondary to pathologic myopia
`(PM), diabetic macular edema (DME), diabetic retinopathy, and
`proliferative retinopathy, comprising the step of administering an
`ophthalmic solution to the patient using a pre-filled syringe according
`to claim 1.
`
`34. The ’631 patent contains no disclosure showing that any of these
`
`diseases could have been treated by any substance or method described in the ’631
`
`patent. Nevertheless, ophthalmologists were well aware that the listed diseases were
`
`caused by or related to abnormal VEGF expression and therefore could be treated
`
`by a VEGF-antagonist. See generally, Ex. 1054; Ex. 1055.
`
`35. For example, ophthalmologists prior to 2012 knew that ranibizumab
`
`(Lucentis®) was FDA approved in 2006 for the treatment of wet age-related macular
`
`degeneration, and for macular edema secondary to retinal vein occlusion (RVO). Ex.
`
`1027.001, .006. Macugen® (pegaptanib sodium injection) was FDA approved in a
`
`pre-filled syringe in 2004 for the treatment of wet age-related macular degeneration.
`
`Ex. 1009.005, .011. Eylea® (aflibercept) was FDA approved in 2011 for the
`
`treatment of wet age-related macular degeneration. Ex. 1040.001. A POSITA would
`
`further have known that Lucentis®, Macugen, and Eylea® are all VEGF-antagonist
`
`solutions.6
`
`
`6 Eylea is a non-antibody VEGF-antagonist and Lucentis® is an anti-VEGF antibody
`fragment, which is characterized in the ’631 patent as an antibody VEGF-antagonist.
`
`
`
`
`16
`
`Regeneron Exhibit 1031.018
`
`
`
`
`
`
`
`36.
`
`It is my understanding that the Sigg (Ex. 1007) and Lam (Ex. 1029)
`
`references disclose a sterilized, pre-filled syringe including Lucentis®. Ex. 1007 at
`
`9:11-14; 20:17-21; Ex. 1029 at 13:14-15. Ophthalmologists understood that the very
`
`purpose of a pre-filled syringe including Lucentis® is to treat a patient suffering from
`
`ocular diseases listed in claim 24. Indeed, the Lucentis® label (June 2010 revision)
`
`specifically states that Lucentis® is indicated for the treatment of patients with
`
`Neovascular (wet) Age-Related Macular Degeneration (AMD) and Macular Edema
`
`Following Retinal Vein Occlusion (RVO). Ex. 1027.001.
`
`37.
`
`I have been informed that Regeneron’s expert Horst Koller has opined
`
`that claim 1 of the ’631 patent would have been obvious in view of Sigg or Lam and
`
`Boulange. Assuming, as I have for purposes of this declaration, that the pre-filled
`
`syringe of claim 1 is obvious, then the step of using an ophthalmic solution in a pre-
`
`filled syringe to treat the recited list of diseases would also have been obvious and
`
`well within the ordinary skill and routine practice of an ophthalmologist. The
`
`“ophthalmic solution” is merely the VEGF-antagonist solution (i.e., drug
`
`formulation) recited in claim 1, and administering such an ophthalmic solution to a
`
`patient to treat the recited list of diseases was a routine and expected step for an
`
`ophthalmologist. As explained above, for example, Macugen had been used to treat
`
`
`Ex. 1001 at 6:33-36 (“Two antibody VEGF antagonists have been approved for
`human use, namely ranibizumab (Lucentis®) and bevacizumab (Avastin®).”).
`
`
`
`
`17
`
`Regeneron Exhibit 1031.019
`
`
`
`
`
`
`
`wet age-related macular degeneration since 2004, while Lucentis® (as disclosed in
`
`Sigg and Lam) had been approved to treat wet AMD as of 2006. As such, assuming
`
`that claim 1 is obvious in view of the prior art, it is my opinion that claim 24 is also
`
`obvious.
`
`VII. Obviousness of Claim 25
`38.
`I understand that claim 25 depends from and incorporates all of the
`
`features of claims 1 and 24. Claim 24 is obvious as discussed in Section VI above.
`
`Claim 25 recites the method of claim 24 and adds the additional routine and well-
`
`known step of “priming” the pre-filled syringe. This is and was a common step
`
`performed by an ophthalmologist prior to administration to expel excess solution
`
`and ensure accurate dosing.
`
`39. For example, the 2008 Macugen Label describes and illustrates the
`
`priming step in which the physician depresses the plunger “to eliminate all the
`
`bubbles and to expel the excess drug so that the top edge of the 3rd rib on the plunger
`
`stopper aligns with the pre-printed black dosing line” of the pre-filled syringe. Ex.
`
`1009.007.
`
`
`
`
`18
`
`Regeneron Exhibit 1031.020
`
`
`
`
`
`
`
`2008 Macugen Label (Ex. 1009.001)
`
`
`
`As explained in ¶ 32 above, it would have been readily understood that the “black
`
`dosing line” described in the 2008 Macugen Label is a “priming mark” as recited
`
`in claim 25. Moreover, the step of priming a pre-filled syringe before administration
`
`was completely routine and conventional prior to 2012, and was not specific to any
`
`drug or syringe but rather a typical step that would have been performed to ensure
`
`accurate dosing of the drug. See, e.g., Trivaris® Label at 4 (Ex. 1056.004) (“Prepare
`
`the proper volume of TRIVARIS™ to be injected by advancing the plunger to the
`
`single line marked on the pre-filled glass syringe shaft.”). Thus, assuming that claim
`
`1 is obvious, it is my opinion that claim 25 is also obvious.
`
`VIII. Obviousness of Claim 26
`40.
`I understand that claim 26 depends from and incorporates all of the
`
`features of claims 1 and 24. Claim 24 is obvious as discussed in Section VII above.
`
`Claim 26 recites the method of claim 24 and adds the additional limitation that “the
`
`
`
`
`19
`
`Regeneron Exhibit 1031.021
`
`
`
`
`
`
`
`VEGF antagonist administered is a non-antibody VEGF antagonist and wherein the
`
`patient has previously received treatment with an antibody VEGF antagonist.”
`
`41. Dixon, published in 2009, reviewed the then-current literature for
`
`VEGF-Trap-Eye, an earlier name for aflibercept (Eylea®). Dixon discloses that “[i]f
`
`effective at 8 week intervals, [aflibercept] offers the opportunity to significantly
`
`reduce treatment burden on patients and physicians, and would probably find wide
`
`acceptance.” Ex. 1030.008. Dixon supports this statement with results from studies
`
`indicating that aflibercept had an advantage over ranibizumab or bevacizumab, thus
`
`motivating one of ordinary skill in the art to switch from an antibody VEGF-
`
`antagonist (ranibizumab or bevacizumab) to non-antibody VEGF-antagonist
`
`(aflibercept). Id. Notably “[i]n contrast to current anti-VEGF antibodies, which are
`
`rapidly cleared, [aflibercept] is relatively inert, and is degraded more slowly” (Ex.
`
`1030.008), thus making it a desirable option for clinicians to switch to. Before
`
`aflibercept was approved, “[b]y far the most commonly used anti-VEGF drugs
`
`currently in use for neovascular AMD are ranibizumab and bevacizumab,”
`
`(Lucentis® and Avastin®7) which are both antibody VEGF-antagonists. Ex.
`
`1030.005. Aflibercept was approved
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