UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC, INNOPHARMA
`INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS INC. and MYLAN INC.
`Petitioners
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`v.
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`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INCORPORATED, and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner
`
`
`Case IPR2015-00903
`Patent 8,129,431
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`DECLARATION OF WILLIAM B. TRATTLER, M.D.
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`SENJU EXHIBIT 2116
`INNOPHARMA v SENJU
`IPR2015-00903
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`PAGE 1 OF 20
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`I, William B. Trattler, M.D., under penalty of perjury, declare as follows:
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`I.
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`INTRODUCTION
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`1.
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`I have been retained by Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
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`on behalf of Patent Owner Senju Pharmaceutical, Co., Ltd. (“Senju”), Bausch + Lomb
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`Incorporated and Bausch + Lomb Pharma Holdings Corp. in connection with two inter partes
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`review (“IPR”) proceedings (IPR2015-00902 and IPR2015-00903) before the United States
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`Patent and Trademark Office Patent Trial and Appeal Board as a medical expert in the field of
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`ophthalmology, including cataract, corneal and refractive surgery.
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`A.
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`2.
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`Qualifications
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`I am an ophthalmologist specializing in refractive, corneal and cataract eye
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`surgery at the Center for Excellence in Eye Care in Miami, FL, where I have practiced since July
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`1997. I perform a wide variety of cataract and refractive surgeries, including photorefractive
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`keratectomy (“PRK”), all laser LASIK, and no-injection sutureless cataract surgery as well as
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`laser cataract surgery. In connection with these surgeries, I administer various medications,
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`including Prolensa® (bromfenac ophthalmic solution 0.07%), to patients to treat post-operative
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`inflammation and pain.
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`3.
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`I received my Bachelor of Arts degree in biology from Dartmouth College in
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`1988 and my M.D. degree, with research distinction, from the University of Miami School of
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`Medicine in 1992. I completed an internal medicine internship at Mount Sinai Medical Center in
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`June 1993, an ophthalmology residency at the University of Pennsylvania Scheie Eye Institute in
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`July 1996, and a cornea and external disease fellowship from the University of Texas-
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`Southwestern Medical Center in 1997. I received board certification in ophthalmology in
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`October 1998, and in January 2009 I was recertified through 2018.
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`4.
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`While practicing at the Center for Excellence in Eye Care, I also served on the
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`surgical staff of the V.A. Hospital in Miami from July 1997 through July 2001, supervising
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`University of Miami ophthalmology residents in surgery and in the clinic. I additionally assisted
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`at the Bascom Palmer Eye Institute on a part-time basis from July 2002 through July 2006,
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`supervising residents in the eye emergency department and instructing residents in cataract and
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`corneal surgery. From 2002 to the present, I also have worked as a volunteer for the Good News
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`Care Center in Miami, which provides free medical services to uninsured low-income patients
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`regardless of race, occupation, national origin or immigrant status. In this role, I have provided
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`between 50 and 100 free examinations and 5 to 10 free surgeries to low-income patients each
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`year.
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`5.
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`I also have held two academic appointments during my career as an
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`ophthalmologist. From July 2000 through the present, I have been a Volunteer Assistant
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`Professor of Ophthalmology at the Bascom Palmer Eye Institute. From January 2012 through
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`the present, I have been a volunteer faculty member in the Department of Ophthalmology at the
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`Herbert Wertheim College of Medicine at Florida International University.
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`6.
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`I have received numerous awards and honors over the course of my professional
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`career, including an Achievement Award and Senior Achievement Award from the American
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`Academy of Ophthalmology,
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`the Curtis D. Benton, Jr., M.D. Outstanding Young
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`Ophthalmologist Leadership Award presented by the Florida Society of Ophthalmology, and the
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`Scheie Eye Institute Teaching Award on two separate occasions. I have been qualified and listed
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`as a Trusted LASIK Surgeon, a LASIK directory service that screens surgeons based on
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`experience, premier patient care and professional credentials. I also have been voted by readers
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`of the publication Cataract and Refractive Surgery Today as a top 50 opinion leader in the field
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`of cataract and refractive surgery. I have received a Patient Choice Award and, for the past
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`several years, have been elected to Best Doctors in America. I also have been selected by my
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`peers as a Florida Super Doctor for South Florida, a distinction bestowed upon the top 5% of
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`South Florida doctors, based on peer nominations as well as a panel review process and
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`independent research on candidates. A full list of awards and honors I have received can be
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`found in my curriculum vitae. (EX2051 at 1-2.)
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`7.
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`I have conducted research in the field of ophthalmology for over 30 years and
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`have been an investigator on nearly 70 clinical trials for ophthalmic products, a full list of which
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`can be found in my curriculum vitae. (EX2051 at 2-6.) I have conducted clinical trials for
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`bromfenac formulations, including clinical trials for Xibrom® and Bromday® that led to their
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`approval by the U.S. Food and Drug Administration (“FDA”).
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`8.
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`I have authored scores of publications in both peer-reviewed and non-peer
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`reviewed journals, and I have co-authored four textbooks and two chapters in textbooks. I also
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`have co-authored chapters in four different online textbooks. A full list of my publications can
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`be found in my curriculum vitae. (EX2051 at 6-8.)
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`9.
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`I regularly attend a variety of scientific meetings in the field of ophthalmology
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`and have given hundreds of presentations at these meetings. I also have served on a number of
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`scientific panels, as both a panelist and moderator. I have given numerous lectures to local
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`ophthalmology and medical groups. A full list of these activities can be found in my curriculum
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`vitae. (EX2051 at 8-11, 19-34.)
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`10.
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`I have served as a reviewer for the American Academy of Ophthalmology, and I
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`currently serve as a peer reviewer for five journals: Ophthalmology, Journal of Cataract and
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`Refractive Surgery, Cornea, American Journal of Ophthalmology, and Ophthalmic Research. I
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`also have served on the editorial boards for several publications, which are listed in my
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`curriculum vitae. (EX2051 at 34.)
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`11.
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`I have been a member of several professional associations for many years. I have
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`been a member of the American Academy of Ophthalmology since 1996 and have served in
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`various capacities, including on the Annual Meeting Program Committee for Refractive Surgery,
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`on the Ophthalmic Technology Assessment Committee Refractive Surgery Panel, and as
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`Chairperson of the Refractive Management/Intervention Panel. Since 1997 I have been a
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`member of the American Society of Cataract and Refractive Surgery, as well as the Miami
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`Ophthalmology Society, for which I served as Secretary in 2004, Treasurer in 2005 and President
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`in 2006. Since 2000 I have been a member of the Florida Society of Ophthalmology, and since
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`2007 I have been a member of The Cornea Society. I also have been a member of the
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`International Society of Refractive Surgery since 2007 and was appointed to the Executive Board
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`in 2011. I am a founding board member of the American-European Congress of Ophthalmic
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`Surgery and a founding member of CEDARS, which stands for Cornea, External Disease and
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`Refractive Surgeons. A full list of these activities can be found in my curriculum vitae.
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`(EX2051 at 34-35.)
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`12.
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`I have consulted for numerous pharmaceutical companies over the years. I also
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`have served as an expert witness in the field of ophthalmology, and my testimony has been
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`credited in court.
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`13.
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`On the basis of my education and experience, I believe I am qualified to express
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`the opinions provided below.
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`B. Materials Considered
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`14.
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`In forming my opinions, I had available the documents cited herein as well as the
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`publications listed on my curriculum vitae. (EX2051 at 6-8.) I have also reviewed Dr. Paul
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`Laskar’s declaration, including some of the references cited therein.
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`(EX1003.)
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`I have also
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`reviewed the declaration of Robert 0. Williams, IE1. O3X2082.) For reasons discussed below, I
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`disagree with Dr. Laskar’s conclusions that the claims of the patents at issue are invalid based on
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`obviousness.
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`C.
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`The Patents at Issue
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`15.
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`I understand that InnoPha1ma has challenged Senj11’s U.S. Patent Nos. 8,129,431
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`(“the ’43l patent”) and 8,669,290 (“the ’290 patent”).
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`I further understand that January 21,
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`2003, is the filing date of the applications to which the ’43l and ’290 patents claim priority.
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`16.
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`I also understand that Prolensa® (bromfenac ophthalmic solution 0.07%) is an
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`embodiment of the aqueous liquid preparations disclosed and claimed in the ’43l patent.
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`(EX2082 at 1|'1] 151-52.)
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`I lmderstand that the claimed aqueous liq11id preparations of the ’431
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`patent require at least bromfenac and tyloxapol.
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`(Id.) I further understand that certain claimed
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`preparations of the ’43l patent require 0.02 w/V % tyloxapol.
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`(Id.)
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` I understand that the inclusion of tyloxapol resulted in
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`unexpectedly superior stability of bromfenac fonnulations.
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`(EX2082 at
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`111] 163-73.) As
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`discussed further below,
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`the formulation of bromfenac with tyloxapol and tyloxapol’s
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`lulexpected stabilization effect
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`led to several beneficial
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`improvements manifested in the
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`commercial formulation of Prolensa®.
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`II.
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`STATEMENT OF OPINIONS EXPRESSED AND BASES AND REASONS
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`THEREFOR
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`A.
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`General Background of Cataract Surgery
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`17.
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`A cataract is a clouding of the patient’s natural lens in the eye that reduces quality
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`of vision and causes vis11al aberrations, including glare and blurring.
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`(EX2067 at 606.) If left
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`untreated, cataracts can grow larger and denser, and they can lead to severe loss of vision and
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`even blindness. (EX2052 at 447.) In fact, cataracts are one of the most common causes of
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`blindness worldwide. (Id.) Even where cataracts have not yet caused blindness, cataracts may
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`interfere with a patient’s daily activities including, for example, the ability to work, read, drive a
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`car, and engage in social and leisure activities. (EX2067 at 607.)
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`18.
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`A common cause of cataracts is age-related changes to the lens of the eye. (Id. at
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`606.) Other factors, however, such as diabetes, exposure to radiation and trauma to the eye can
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`also contribute to cataracts. (Id.) Once cataracts have progressed to a point where vision is
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`impaired, surgery is required to remove the lens and replace it with a new lens. (Id. at 606-607.)
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`19.
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`One of the first modern surgical techniques developed for cataract extraction was
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`intracapsular cataract extraction, or “ICCE.” (EX2069 at S5.) ICCE was first performed in the
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`1700s, and it required a large incision and removal of the entire lens capsule. (Id. at S7; EX2067
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`at 607.)
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`20.
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`Another major improvement to cataract surgery was extracapsular cataract
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`extraction, or “ECCE.” (EX2069 at S6.) ECCE allowed for removing the lens without removing
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`the lens capsule, but required a “ripe” lens, or a lens that had become so hardened with advanced
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`cataract that it would not break during removal. (Id. at S7.) Leaving the capsule intact prevents
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`material from falling into the vitreous cavity of the eye. (Id. at S11.)
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`21.
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`In 1967, Dr. Charles Kelman developed phacoemulsification surgery for cataract
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`extraction. (EX2069 at S11.) Phacoemulsification surgery uses ultrasonography to break the
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`lens into minute fragments that can be aspirated, allowing for a small incision. (Id.; EX2067 at
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`607.) A smaller incision heals more quickly and has a decreased risk of complications.
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`(EX2052 at 448; EX2067 at 607.) Phacoemulsification techniques have continued to progress,
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`and they remain the standard of care today. (EX2052 at 448; EX2067 at 607.)
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`22.
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`Although cataract surgery techniques have advanced considerably over the last
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`three centuries, incisions into the eye are still required. (EX2069 at S13; EX2067 at 607.) This
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`results in pain and inflammation in virtually all patients, thereby necessitating medicinal
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`treatment.
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`B.
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`23.
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`Other NSAID Therapies
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`Despite continuing improvement in cataract surgery techniques in the 20th
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`century, no topical non-steroidal anti-inflammatory drug (“NSAID”) was approved until the
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`1990s for treatment of pain and inflammation in patients after surgery. NSAIDs are a
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`structurally diverse group of compounds that treat inflammation by a different mechanism in the
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`cyclooxygenase (“COX”) enzyme pathway than steroidal compounds such as corticosteroids.
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`(EX2117 at 41.) Corticosteroids inhibit only COX-2 whereas NSAIDs inhibit both COX-1 and
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`COX-2. (Id.) Prostaglandin synthesis, which is the major inflammatory response following
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`surgical trauma, is mediated differently by corticosteroids and NSAIDs: corticosteroids act on
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`the enzyme phospholipase A2, whereas NSAIDs act on the enzymes cyclo-oxygenase and
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`lipoxygenase. (Id.) Moreover, based on their different mechanisms of action, NSAIDs and
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`corticosteroids have different side effect profiles. (Id. at 44.)
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`24.
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`NSAID eye drop technology for reduction in pain and inflammation following
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`cataract surgery was developed and approved in the 1990s, but as discussed below, these
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`therapies continued to have various drawbacks.
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`25.
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`The first NSAID eye drop approved commercially in the United States was
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`flurbiprofen sodium ophthalmic solution, marketed under the name Ocufen®. (EX2053 at 1-3).
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`The FDA approved Ocufen® in 1986, but only for the inhibition of intraoperative miosis.
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`(EX2054 at 1; EX2053 at 1.) Intraoperative miosis refers to the constriction of the eye pupil
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`during cataract surgery, and inhibition of this constriction phenomenon helps improve surgical
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`outcomes. Thus, Ocufen® was approved for use prior to surgery, but not for post-surgical use to
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`treat inflammation and pain. (EX2053 at 1, 3.) Adverse reactions to Ocufen® included transient
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`burning and stinging upon instillation and other symptoms of ocular irritation. (Id. at 3.)
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`26.
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`A few years later, in 1988, the NSAID suprofen, marketed under the name
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`Profenal®, was also approved for inhibition of intraoperative miosis, the same indication as
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`Ocufen®. (EX2055 at 1; EX2056 at 1.) Profenal® exhibited similar adverse ocular reactions as
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`Ocufen®, including burning and stinging. (EX2056 at 3.) Instances of discomfort, itching and
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`redness were also reported. (Id.) Other adverse reactions associated with Profenal ® include
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`allergy, iritis, pain, chemosis, photophobia, irritation and punctuate epithelia staining. (Id.)
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`27.
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`In 1991, the first NSAID eye drop approved for treatment of postoperative
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`inflammation in patients undergoing cataract surgery was diclofenac sodium, marketed as
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`Voltaren®. (EX2057 at 3-7; EX2044 at 1.) Voltaren® was approved for treatment of
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`postoperative inflammation in patients who have undergone cataract extraction and temporary
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`relief of pain and photophobia in patients undergoing corneal refractive surgery. (EX2057 at 4.)
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`For its postoperative inflammation indication, Voltaren® requires application 4 times daily
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`beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the post-
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`operative period. (Id. at 6.) Similar to Suprofen® and Profenal®, with Voltaren® transient
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`burning and stinging were reported in approximately 15% of patients across studies. (Id.)
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`28.
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`In 1992, a 0.5% solution of the NSAID ketorolac tromethamine, or Acular®, was
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`approved for treatment of postoperative inflammation in patients who have undergone cataract
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`extraction. (EX2059 at 1; EX2060 at 5.) Acular® was additionally approved for temporary relief
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`of ocular itching due to seasonal allergic conjunctivitis. (EX2060 at 5.) Like Voltaren ® and all
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`other commercially available ophthalmic NSAIDs to that date, adverse events reported included
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`transient stinging and burning on instillation. (Id. at 7-8.) Notably, for Acular®, these side
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`effects were reported by up to 40% of patients participating in clinical trials. (Id. at 7.) For
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`treatment of postoperative inflammation, Acular® requires application 4 times daily beginning 24
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`hours after surgery and continuing for 2 weeks of the post-operative period. (Id. at 8.)
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`29.
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`A preservative free version of Acular®, marketed under the name Acular® PF, was
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`approved in 1997. (EX2060 at 9-13; EX2061 at 1.) Acular® PF was sold in single use vials for
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`administration 4 times per day for 2 weeks following incisional refractive surgery. (EX2060 at
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`12.) Unlike Acular®, Acular® PF was not indicated for the treatment of postoperative
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`inflammation in patients who have undergone cataract extraction. (Id. at 10.) Rather, it was
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`approved for the reduction of ocular pain and photophobia following incisional refractive
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`surgery. (Id.) Even without inclusion of a preservative in the formulation, adverse events for
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`Acular® PF still included transient burning and stinging upon instillation in approximately 20%
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`of patients participating in clinical trials. (Id. at 12.)
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`30.
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`In 2000, Bronuck, a 0.1% bromfenac sodium NSAID ophthalmic formulation,
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`was first approved in Japan. (EX2111 at 2; EX2112 at 1.) I understand that because Bronuck
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`was only sold in Japan and not in the United States, sales of Bronuck are not “prior art” to the
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`’431 and ’290 patents.
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`31.
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`Bronuck was approved in Japan for the treatment of inflammatory ailments of the
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`external eye and anterior eye (blepharitis, conjunctivitis, scleritis (including episcleritis), and
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`postoperative inflammation). Bronuck exhibited various adverse events, including ocular pain,
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`stinging and burning sensation. (EX2111 at 2, column 2; EX2112 at 2, column 2.) These events
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`were reported in 0.1% to less than 5% of patents. (EX2111 at 2, column 2; EX2112 at 2, column
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`2.)
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`32.
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`In 2005, the FDA approved Xibrom®, a 0.09% bromfenac sodium NSAID
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`ophthalmic formulation. (EX2062 at 1.) As discussed above, I understand that January 21,
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`2003, is the filing date of the applications to which the ’431 and ’290 patents claim priority. I
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`thus understand that Xibrom® is not “prior art” to the ’431 and ’290 patents.
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`33.
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`Xibrom® was approved for the treatment of postoperative inflammation in patients
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`who have undergone cataract extraction. (EX2026 at 1.) Xibrom ® exhibited various adverse
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`events, including abnormal sensation in eye, conjunctival hyperemia, eye irritation (including
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`burning/stinging), eye pain, eye pruritus, eye redness, headache and iritis. (Id. at 3.) These
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`events were reported in 2-7% of patients. (Id.)
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`34.
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`In 2010, the FDA approved Bromday®, a 0.09% bromfenac sodium NSAID
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`ophthalmic formulation identical to Xibrom® except indicated for once daily usage instead of
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`twice daily usage. (EX2063 at 1; EX2027 at 4.) As discussed above, I understand that January
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`21, 2003, is the filing date of the applications to which the ’431 and ’290 patents claim priority.
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`I thus understand that Bromday® is not “prior art” to the ’431 and ’290 patents.
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`35.
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`Bromday® was approved for the treatment of postoperative inflammation and
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`reduction of ocular pain in patients who have undergone cataract extraction. (EX2027 at 4.)
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`Bromday® exhibited various adverse events, including abnormal sensation in eye, conjunctival
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`hyperemia, eye irritation (including burning/stinging), eye pain, eye pruritus, eye redness,
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`headache and iritis. (Id. at 6.) These events were reported in 2-7% of patients. (Id.)
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`36.
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`Unfortunately, each of Voltaren®, Acular®, Bronuck, Xibrom® and Bromday® are
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`limited by their side effects when treating postoperative inflammation in patients who have
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`undergone cataract extraction. (EX2057 at 6; EX2060 at 7-8; EX2111 at 2, column 2; EX2026 at
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`3; EX2027 at 6.) For example, each causes burning and stinging upon administration in a
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`significant proportion of patients. (EX2057 at 6; EX2060 at 7-8; EX2111 at 2, column 2;
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`EX2026 at 3; EX2027 at 6.) These complaints are typical of what I have observed from patients
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`whom I have treated in my practice. Burning and stinging are significant side effects because
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`they are painful and impact patient compliance, resulting in patients not using their medication.
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`(EX2119 at 928.) When patients avoid using available therapies and thus do not treat
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`inflammation after undergoing cataract surgery, they have a higher risk of developing cystoid
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`macular edema (“CME”), which is a serious post-operative complication, among other
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`complications. (EX2068 at 568; EX2113 at 966.) Not treating inflammation also leads to
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`greater post-surgical pain and dissatisfaction with the surgery.
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`C.
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`Development of Prolensa® as a Safe and Effective Treatment of Pain and
`Inflammation Following Cataract Surgery
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`37.
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`In light of the shortcomings, including burning and stinging, of available NSAID
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`eye drops for treating postoperative inflammation in patients who have undergone cataract
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`extraction, researchers continued to develop other formulations.
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`38.
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`In 2013, the FDA approved Prolensa®, 0.07% bromfenac sodium, for the
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`treatment of postoperative inflammation and reduction of ocular pain in patients who have
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`undergone cataract surgery. (EX2015 at 1; EX2013 at 4.) Reported adverse events included
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`anterior chamber inflammation, foreign body sensation, eye pain, photophobia and vision
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`blurred. (EX2013 at 6.) These reactions were reported in 3 to 8% of patients. (Id.)
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`39.
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`Notably, and unlike all other approved NSAID ophthalmic eye drops, Prolensa®
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`was not reported to cause burning and stinging upon administration. (Id.) This comports with
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`what I observe from patients whom I treat in my practice, who describe Prolensa® as very
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`comfortable to administer and well-tolerated. As discussed above, this is a major benefit of
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`Prolensa®, and it increases patient compliance, which in turn minimizes the potential for pain and
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`complications such as post-operative CME. (EX2068 at 568; EX2113 at 966; EX2119 at 928.)
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`40.
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`Dr. Laskar acknowledges that Prolensa®’s package insert does not identify
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`burning or stinging as an adverse event, but then states that the inclusion of eye pain as an
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`adverse event in the Prolensa® package insert connotes or is equivalent to burning and stinging.
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`(EX2114 at 38:14 - 39:3.) I disagree. Eye pain is a separate and distinct adverse event from
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`burning or stinging a patient may experience. For example, ocular pain is a separate adverse
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`event from burning and stinging associated with Bronuck. (EX2111 at 2, column 2; EX2112 at
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`2, column 2.) Similarly, eye pain is listed separately from burning and stinging in both the
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`Xibrom® and Bromday® package inserts. (EX2026 at 3; EX2027 at 6.) Thus, the inclusion of
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`eye pain as an adverse event in the Prolensa® package insert does not in any way indicate that it
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`connotes or is equivalent to burning and stinging.
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`41. Moreover, I understand that Prolensa® is formulated at a lower pH of 7.8, closer
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`to that of natural tears (pH 7.4), as compared to the higher pH of 8.3 at which Xibrom® and
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`Bromday® were formulated. (EX2082 at ¶ 178; EX2113 at 966; compare EX2013 at 7 with
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`EX2026 at 5 and EX2027 at 7.) Prolensa® also contains far less surfactant, 0.02 w/v% tyloxapol
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`compared to 0.15 w/v% polysorbate 80 in Xibrom® and Bromday®. (EX2082 at ¶ 178.) The
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`reduced pH and amount of surfactant in Prolensa® eliminated the burning and stinging sensation,
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`making it more comfortable and ensuring greater patient compliance. (EX2113 at 966; EX2119
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`at 928)
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`42.
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`Prolensa®’s lower pH also led to improved ocular penetration, even at a lower
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`concentration of bromfenac (0.07%) as compared to Xibrom® and Bromday® (0.09%). (EX2030
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`at 1722 (“Even at a lower concentration, the bromfenac 0.07%, pH 7.8 solution exhibited similar,
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`and in the case of scleral tissue, increased, penetration of ocular tissues studied, when compared
`
`with bromfenac 0.09%, pH 8.3 solution.”); EX2113 at 966; compare EX2013 at 7 with EX2026
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`at 3 and EX2027 at 7.) In addition, the lower concentration of bromfenac in Prolensa® places
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`less drug in contact with surgically compromised ocular tissue without a reduction in efficacy.
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`(EX2030 at 1718; compare EX2013 at 4 with EX2026 at 3 and EX2027 at 4.) These additional
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`benefits of Prolensa® are substantial for patients undergoing cataract surgery, and further make
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`Prolensa® my drug of choice in treating post-operative pain and inflammation in my patients.
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`43.
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`Furthermore, Prolensa® exhibits these significant patient benefits, including a
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`remarkably safe adverse event profile, despite containing the preservative benzalkonium chloride
`
`(“BAK”) in its formulation. (EX2013 at 7.) BAK has long been known to be toxic to the eye,
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`even at low concentrations, significantly lower than those used in Prolensa®. (EX2064 at 114
`
`(“[W]e observed a decrease in cell viability after a benzalkonium chloride treatment at a
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`concentration of 0.001% (p < 0.01).”); EX2081 at S228.) BAK rapidly impacts the ocular
`
`surface, with 0.007% BAK inducing the death of 50% of cultured epithelial cells in less than 2
`
`minutes. (EX2080 at 422.) In fact, in a recent patent infringement case involving the
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`ophthalmic drug Lumigan®, the Court of Appeals for the Federal Circuit noted that the patent
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`challenger’s expert summarized the prior art’s widespread concern over the toxicity of BAK by
`
`describing BAK as “a natural-born killer” that was “from Satan.” (EX2134 at 16.)
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`44. Moreover, in de-epithelialized corneas in vivo, which result as a consequence of
`
`ocular surgery, BAK was found to decrease ocular absorption of ketorolac. (EX2090 at 418.)
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`This finding led the author to urge that a preservative-free ketorolac formulation may be a better
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`postoperative ocular analgesic than the preserved ketorolac formulation. (Id.)
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`45.
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`Accordingly, as of 2003, researchers were actively researching formulations
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`avoiding BAK. (EX2089 and EX2091.) In September 2001, Noecker et al. published results
`
`comparing several preservatives, including stabilized oxychloro complex (“SOC,” also known as
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`Purite®) and BAK, recognized by Noecker as having significant cytotoxic effects in animals and
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`humans. (EX2089 at Abstract.) Noecker indicated a better approach to using toxic
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`preservatives, such as BAK, was to use more tolerated preservatives and specifically described
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`the benefits observed by replacing BAK with SOC in an ophthalmic formulation of brimonidine,
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`which the FDA approved in March 2001 as Alphagan® P (EX2092 (indicating approval date);
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`EX2093 at 2 (Purite® included as a preservative)), stating as follows:
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`A 12-month clinical comparison in patients with glaucoma or
`ocular hypertension showed that brimonidine-SOC was well
`tolerated and produced a significantly lower incidence of allergic
`conjunctivitis than brimonidine, as well as equivalent IOP-
`lowering efficacy.
`
`(EX2089 at 211, ¶ 2.)
`
`46.
`
`Similarly, in 2002, Katz (EX2091) published additional studies of brimonidine-
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`SOC showing a 41% relative reduction in ocular allergy and superior satisfaction and comfort
`
`ratings compared to brimonidine-BAK, leading Katz to conclude that that brimonidine-Purite
`
`0.15% is “an effective, safe, and well-tolerated therapy for the long-term treatment of high IOP.”
`
`(Id. at 126.)
`
`47.
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`I agree that BAK is toxic and should be eliminated from ophthalmic formulations
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`wherever possible. For example, Acular®, which contained BAK, was later made available in a
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`preservative-free formulation, Acular® PF, described above. (EX2060 at 4; 9-13.) Yet even with
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`BAK, Prolensa® exhibits a superior adverse event profile to Acular® PF and in particular is not
`
`associated with the painful burning and stinging associated with Acular® PF. (Compare EX2013
`
`at 6 with EX2060 at 12.) Prolensa® exhibits this superior adverse event profile despite that the
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`frequency of symptoms and objective signs of irritation are repoited to be higher with eye drops
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`containing preservatives, particularly BAK, as compared to preservative-free eye drops.
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`(EX2080 at 422.)
`
`D.
`
`Objective Evidence of Non-Obviousness
`
`48.
`
`I tmderstand that certain objective evidence, including, for example, unexpected
`
`results, teaching away and acclaim, is relevant to the non-obviousness of a patented invention. I
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`provide below my opinions conceming certain objective evidence that the development of
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`P1'olensa® would not have been obvious.
`
`49-
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` 1) the formulation of bromfenac with tyloxapol
`
` (E39082 at
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`11"" 151-529 2
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`50.
`
`I am infonned that tyloxapol is unexpectedly effective at chemically stabilizing
`
`bromfenac, which has permitted formulating Prolensa® at the lower pH of 7.8 with a reduced
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`amount of s1u'factant.
`
`(Id. at 11] 178-80.) Not only did this eliminate burning and stinging
`
`sensation, making it more comfortable and helping to ensure greater patient compliance
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`(EX2113 at 966; EX2119 at 928), b11t the lower pH also improved ocular penetration.
`
`(EX2030
`
`at 1722.) That led to the ability to reduce Prolensa®’s bromfenac concentration to 0.07%, down
`
`from 0.09% in Xibrom® and Bromday®.
`
`(EX2030 at 1722; compare EX2013 at 7 with EX2026
`
`at 3 and EX2027 at 7.) A lower bromfenac concentration advantageously places less drug in
`
`contact with surgically compromised ocular tissue without a reduction in efficacy.
`
`(EX2030 at
`
`1718: EX2113 at 971; compare EX20l3 at 4 with EX2026 at 3 and EX2027 at 4.)
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`
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`1.
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`Unexpected Results Leading to Significant Medical Benefits,
`Where the Prior Art Taught Away
`
`51.
`
`For the reasons I have explained above, tyloxapol’s unexpected ability to stabilize
`
`bromfenac has led to a number of significant improvements in the formulation of Prolensa® that
`
`have substantially benefited patients. For example, lowering pH and reducing the amount of
`
`surfactant eliminated burning and stinging. (See ¶¶ 39-42 above.) As of 2003, a topical
`
`ophthalmic NSAID that did not exhibit burning and stinging upon instillation was not available
`
`to physicians or their patients to treat post-operative inflammation after cataract surgery.
`
`(EX2053 at 3; EX2056 at 3; EX2057 at 6; EX2060 at 7-8, 12.) Indeed, as of 2003, the two
`
`NSAID formulations, Voltaren® and Acular®, that had received FDA approval for treatment of
`
`post-operative inflammation both caused burning and stinging, thus decreasing patient
`
`compliance. (EX2057 at 6; EX2060 at 7-8; EX2119 at 928.) Moreover, Bronuck, a 0.1%
`
`bromfenac sodium NSAID ophthalmic formulation approved in 2000 in Japan for treatment of
`
`postoperative inflammation, which Dr. Laskar contends represents an embodiment of the Ogawa
`
`patent (EX1003 at ¶ 29), caused both burning and stinging. (EX2111 at 2; EX2112 at 2.) Even
`
`Xibrom® and Bromday®, which Dr. Laskar also contends represent embodiments of the Ogawa
`
`patent, published in 1990 (EX1003 at ¶ 42), exhibited burning and stinging. (EX2026 at 3;
`
`EX2027 at 6.)
`
`52.
`
`The development of Prolensa® was highly significant
`
`to
`
`the field of
`
`ophthalmology and cataract surgery, because it represented a new therapy for effectively treating
`
`postoperative inflammation after cataract surgery with a favorable side effect profile, without
`
`burning or stinging upon administration. (EX2013 at 6.) As discussed above, making the
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`formulation more comfortable to patients increases patient compliance and thus reduces the
`
`potential for CME and other serious complications to develop. It was by no means expected that
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`Prolensa® would exhibit this highly favorable side effect profile while providing efficacious
`
`treatment of post-operative pain and i