UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`Patent Owner
`
`Case IPR20 15-01100
`Patent 8,927,606
`
`DECLARATION OF WILLIAM B. TRATTLER, M.D.
`
`Page 1 of26
`
`1
`
`SENJU EXHIBIT 2116
`LUPINv. SENJU
`IPR2015-01100
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`Patent Owner
`
`Case IPR20 15-01100
`Patent 8,927,606
`
`DECLARATION OF WILLIAM B. TRATTLER, M.D.
`
`Page 1 of26
`
`1
`
`SENJU EXHIBIT 2116
`LUPINv. SENJU
`IPR2015-01100
`
`
`
`I, William B. Trattler, M.D., under penalty of perjury, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by Finnegan, Henderson, Farabow, Garrett &
`
`Dunner, LLP on behalf of Patent Owner Senju Pharmaceutical, Co., Ltd. ("Senju"),
`
`Bausch + Lomb Incorporated and Bausch + Lomb Pharma Holdings Corp. in
`
`connection with four inter partes review ("IPR") proceedings (IPR2015-01099,
`
`IPR2015-01097, IPR2015-01105, and IPR2015-01100) before the United States
`
`Patent and Trademark Office Patent Trial and Appeal Board as a medical expert in
`
`the field of ophthalmology, including cataract, corneal and refractive surgery.
`
`A.
`
`2.
`
`Qualifications
`
`I am an ophthalmologist specializing in refractive, corneal and
`
`cataract eye surgery at the Center for Excellence in Eye Care in Miami, FL, where
`
`I have practiced since July 1997.
`
`I perform a wide variety of cataract and
`
`refractive surgeries, including photorefractive keratectomy ("PRK"), all laser
`
`LASIK, and no-injection sutureless cataract surgery as well as laser cataract
`
`surgery.
`
`In connection with these surgeries, I administer various medications,
`
`including Prolensa® (bromfenac ophthalmic solution 0.07%), to patients to treat
`
`post-operative inflammation and pain.
`
`3.
`
`I received my Bachelor of Arts degree in biology from Dartmouth
`
`College in 1988 and my M.D. degree, with research distinction~ from the
`
`Page 2 of26
`
`2
`
`
`
`University of Miami School of Medicine in 1992.
`
`I completed an internal
`
`medicine
`
`internship at Mount Sinai Medical Center
`
`in June 1993, an
`
`ophthalmology residency at the University of Pennsylvania Scheie Eye Institute in
`
`July 1996, and a cornea and external disease fellowship from the University of
`
`Texas-Southwestern Medical Center in 1997.
`
`I received board certification in
`
`ophthalmology in October 1998, and in January 2009 I was recertified through
`
`2018.
`
`4. While practicing at the Center for Excellence in Eye Care, I also
`
`served on the surgical staff of the V .A. Hospital in Miami from July 1997 through
`
`July 2001, supervising University of Miami ophthalmology residents in surgery
`
`and in the clinic. I additionally assisted at the Bascom Palmer Eye Institute on a
`
`part-time basis trom July 2002 through July 2006, supervising residents in the eye
`
`emergency department and instructing residents in cataract and corneal surgery.
`
`From 2002 to the present, I also have worked as a volunteer for the Good News
`
`Care Center in Miami, which provides free medical services to uninsured low(cid:173)
`
`income patients regardless of race, occupation, national origin or immigrant status.
`
`In this role, I have provided between 50 and 100 free examinations and 5 to 10 free
`
`surgeries to low-income patients each year.
`
`5.
`
`I also have held two academic appointments during my career as an
`
`ophthalmologist. From July 2000 through the present, I have been a Volunteer
`
`Page 3 of26
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`3
`
`
`
`Assistant Professor of Ophthalmology at the Bascom Palmer Eye Institute. From
`
`January 2012 through the present, I have been a volunteer faculty member in the
`
`Department of Ophthalmology at the Herbert Wertheim College of Medicine at
`
`Florida International University.
`
`6.
`
`I have received numerous awards and honors over the course of my
`
`professional career, including an Achievement Award and Senior Achievement
`
`Award from the American Academy of Ophthalmology, the Curtis D. Benton, Jr.,
`
`M.D. Outstanding Young Ophthalmologist Leadership Award presented by the
`
`Florida Society of Ophthalmology, and the Scheie Eye Institute Teaching Award
`
`on two separate occasions. I have been qualified and listed as a Trusted LASIK
`
`Surgeon, a LASIK directory service that screens surgeons based on experience,
`
`premier patient care and professional credentials.
`
`I also have been voted by
`
`'
`readers of the publication Cataract and Refractive Surgery Today as a top 50
`
`opinion leader in the field of cataract and refractive surgery.
`
`I have received a
`
`Patient Choice Award and, for the past several years, have been elected to Best
`
`Doctors in America. I also have been selected by my peers as a Florida Super
`
`Doctor for South Florida, a distinction bestowed upon the top 5% of South Florida
`
`doctors, based on peer nominations as well as a panel review process and
`
`independent research on candidates. A full list of awards and honors I have
`
`received can be found in my curriculum vitae. (EX2051 at 1-2.)
`
`Page 4 of26
`
`4
`
`
`
`7.
`
`I have conducted research in the field of ophthalmology for over 30
`
`years and have been an investigator on nearly 70 clinical trials for ophthalmic
`
`products, a full list of which can be found in my curriculum vitae. (EX2051 at 2-
`
`6.) I have conducted clinical trials for bromfenac formulations, including clinical
`
`trials for Xibrom® and Bromday® that led to their approval by the U.S. Food and
`
`Drug Administration ("FDA").
`
`8.
`
`I have authored scores of publications in both peer-reviewed and non-
`
`peer reviewed journals, and I have co-authored four textbooks and two chapters in
`
`textbooks. I also have co-authored chapters in four different online textbooks. A
`
`full list of my publications can be found in my curriculum vitae. (EX2051 at 6-8.)
`
`9.
`
`I regularly attend a variety of scientific meetings in the field of
`
`ophthalmology and have given hundreds of presentations at these meetings. I also
`
`have served on a number of scientific panels, as both a panelist and moderator. I
`
`have given numerous lectures to local ophthalmology and medical groups. A full
`
`list of these activities can be found in my curriculum vitae. (EX2051 at 8-11, 19-
`
`34.)
`
`10.
`
`I have served as a reviewer for
`
`the American Academy of
`
`Ophthalmology, and I currently serve as a peer reviewer for five journals:
`
`Ophthalmology, Journal of Cataract and Refractive Surgery, Cornea, American
`
`Journal of Ophthalmology, and Ophthalmic Research. I also have served on the
`
`Page 5 of26
`
`5
`
`
`
`editorial boards for several publications, which are listed in my curriculum vitae.
`
`(EX2051 at 34.)
`
`11.
`
`I have been a member of several professional associations for many
`
`years. I have been a member of the American Academy of Ophthalmology since
`
`1996 and have served in various capacities, including on the Annual Meeting
`
`Program Committee for Refractive Surgery, on the Ophthalmic Technology
`
`Assessment Committee Refractive Surgery Panel, and as Chairperson of the
`
`Refractive Management/Intervention Panel. Since 1997 I have been a member of
`
`the American Society of Cataract and Refractive Surgery, as well as the Miami
`
`Ophthalmology Society, for which I served as Secretary in 2004, Treasurer in 2005
`
`and President in 2006. Since 2000 I have been a member of the Florida Society of
`
`Ophthalmology, and since 2007 I have been a member of The Cornea Society. I
`
`also have been a member of the International Society of Refractive Surgery since
`
`2007 and was appointed to the Executive Board in 2011. I am a founding board
`
`member of the American-European Congress of Ophthalmic Surgery and a
`
`founding member of CEDARS, which stands for Cornea, External Disease and
`
`Refractive Surgeons. A full list of these activities can be found in my curriculum
`
`vitae. (EX2051 at 34-35.)
`
`Page 6 of26
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`6
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`
`
`12.
`
`I have consulted for numerous pharmaceutical companies over the
`
`years. I also have served as an expert witness in the field of ophthalmology, and
`
`my testimony has been credited in court.
`
`13. On the basis of my education and experience, I believe I am qualified
`
`to express the opinions provided below.
`
`B. Materials Considered
`
`14.
`
`In forming my opinions, I had available the documents cited herein as
`
`well as the publications listed on my curriculum vitae. (EX2051 at 6-8.) I have
`
`also reviewed Dr. Jayne Lawrence's declaration, including some of the references
`
`cited therein.
`
`(EX1005.)
`
`I have also reviewed the declaration of Robert 0.
`
`Williams, III.
`
`(EX2082.) For reasons discussed below, I disagree with Dr.
`
`Lawrence's conclusions that the claims of the patents at issue are invalid based on
`
`obviousness.
`
`C.
`
`The Patents at Issue
`
`15.
`
`I understand that Lupin has challenged Senju's U.S. Patent Nos.
`
`8,669,290 ("the '290 patent"), 8,754,131 ("the '131 patent"), 8,871,813 ("the '813
`
`patent"), and 8,927,606 ("the '606 patent"). I further understand that January 21,
`
`2003, is the filing date of the applications to which the '290, '131, '813, and '606
`
`patents claim priority.
`
`Page 7 of26
`
`7
`
`
`
`16.
`
`I also understand that Prolensa® (bromfenac ophthalmic solution
`
`0.07%) is an embodiment of the aqueous liquid preparations disclosed and claimed
`
`in the '606 patent. (EX2082 at~~ 175-76.) I understand that the aqueous liquid
`
`preparations of the claimed methods of the '606 patent require at least bromfenac
`
`and tyloxapol. (!d.)
`
`•
`
`I understand that the inclusion of tyloxapol resulted in unexpectedly superior
`
`stability of bromfenac formulations.
`
`(!d. at ~~ 187-96.) As discussed further
`
`below, the formulation of bromfenac with tyloxapol and tyloxapol's unexpected
`
`stabilization effect led to several beneficial improvements manifested in the
`
`commercial formulation of Prolensa ®.
`
`II.
`
`STATEMENT OF OPINIONS EXPRESSED AND BASES AND
`REASONS THEREFOR
`
`A.
`
`General Background of Cataract Surgery
`
`17. A cataract is a clouding of the patient's natural lens in the eye that
`
`reduces quality of vision and causes visual aberrations, including glare and
`
`blurring. (EX2067 at 606.) If left untreated, cataracts can grow larger and denser,
`
`and they can lead to severe loss of vision and even blindness. (EX2052 at 447.) In
`
`fact, cataracts are one of the most common causes of blindness worldwide. (!d.)
`
`Even where cataracts have not yet caused blindness, cataracts may interfere with a
`
`patient's daily activities including, for example, the ability to work, read, drive a
`
`car, and engage in social and leisure activities. (EX2067 at 607.)
`
`Page 8 of26
`
`8
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`
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`18. A common cause of cataracts is age-related changes to the lens of the
`
`eye. (ld. at 606.) Other factors, however, such as diabetes, exposure to radiation
`
`and trauma to the eye can also contribute to cataracts. (Id.) Once cataracts have
`
`progressed to a point where vision is impaired, surgery is required to remove the
`
`lens and replace it with a new lens. (!d. at 606-607.)
`
`19. One of the first modem surgical techniques developed for cataract
`
`extraction was intracapsular cataract extraction, or "ICCE."
`
`(EX2069 at S5.)
`
`ICCE was first performed in the 1700s, and it required a large incision and removal
`
`of the entire lens capsule. (ld. at S7; EX2067 at 607.)
`
`20. Another major improvement to cataract surgery was extracapsular
`
`cataract extraction, or "ECCE." (EX2069 at S6.) ECCE allowed for removing the
`
`lens without removing the lens capsule, but required a "ripe" lens, or a lens that
`
`had become so hardened with advanced cataract that it would not break during
`
`removal. (!d. at S7.) Leaving the capsule intact prevents material from falling into
`
`the vitreous cavity of the eye. (Id. at S11.)
`
`21.
`
`In 1967, Dr. Charles Kelman developed phacoemulsification surgery
`
`for cataract extraction.
`
`(!d. at S11.)
`
`Phacoemulsification surgery uses
`
`ultrasonography to break the lens into minute fragments that can be aspirated,
`
`allowing for a small incision. (ld.; EX2067 at 607.) A smaller incision heals more
`
`quickly and has a decreased risk of complications. (EX2052 at 448; EX2067 at
`
`Page 9 of26
`
`9
`
`
`
`607.) Phacoemulsification techniques have continued to progress, and they remain
`
`the standard of care today. (EX2052 at 448; EX2067 at 607.)
`
`22. Although cataract surgery techniques have advanced considerably
`
`over the last three centuries, incisions into the eye are still required. (EX2069 at
`
`S13; EX2067 at 607.) This results in pain and inflammation in virtually all
`
`patients, thereby necessitating medicinal treatment.
`
`B.
`
`Other NSAID Therapies
`
`23. Despite continuing improvement in cataract surgery techniques in the
`
`20111 century, no topical non-steroidal anti-inflammatory drug ("NSAID") was
`
`approved until the 1990s for treatment of pain and inflammation in patients after
`
`surgery. NSAIDs are a structurally diverse group of compounds that treat
`
`inflammation by a different mechanism in the cyclooxygenase ("COX") enzyme
`
`pathway than steroidal compounds such as corticosteroids.
`
`(EX2117 at 41.)
`
`Corticosteroids inhibit only COX-2 whereas NSAIDs inhibit both COX-I and
`
`COX-2. (Jd.) Prostaglandin synthesis, which is the major inflammatory response
`
`following surgical trauma, is mediated differently by corticosteroids and NSAIDs:
`
`corticosteroids act on the enzyme phospholipase A2, whereas NSAIDs act on the
`
`enzymes cyclo-oxygenase and lipoxygenase.
`
`(Jd.) Moreover, based on their
`
`different mechanisms of action, NSAIDs and corticosteroids have different side
`
`effect profiles. (Id. at 44.)
`
`Page 10 of26
`
`10
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`
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`24. NSAID eye drop technology for reduction in pain and inflammation
`
`following cataract surgery was developed and approved in the 1990s, but as
`
`discussed below, these therapies continued to have various drawbacks.
`
`25.
`
`The first NSAID eye drop approved commercially in the United States
`
`was flurbiprofen sodium ophthalmic solution, marketed under the name Ocufen ®.
`
`(EX2053 at 1-3). The FDA approved Ocufen® in 1986, but only for the inhibition
`
`of intraoperative miosis. (EX2054 at 1; EX2053 at 1.) Intraoperative miosis refers
`
`to the constriction of the eye pupil during cataract surgery, and inhibition of this
`
`constriction phenomenon helps improve surgical outcomes. Thus, Ocufen® was
`
`approved for use prior to surgery, but not for post-surgical use to
`
`treat
`
`inflammation and pain. (EX2053 at 1, 3.) Adverse reactions to Ocufen® included
`
`transient burning and stinging upon instillation and other symptoms of ocular
`
`irritation. (Id. at 3.)
`
`26. A few years later, in 1988, the NSAID suprofen, marketed under the
`
`name Profenal®, was also approved for inhibition of intraoperative miosis, the
`
`same indication as Ocufen®.
`
`(EX2055 at 1; EX2056 at 1.) Profenal® exhibited
`
`similar adverse ocular reactions as Ocufen ®, including burning and stinging.
`
`(EX2056 at 3.) Instances of discomfort, itching and redness were also reported.
`
`(Id.) Other adverse reactions associated with Profenal® include allergy, iritis, pain,
`
`chemosis, photophobia, irritation and punctuate epithelia staining. (I d.)
`
`Page 11 of26
`
`11
`
`
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`27.
`
`In 1991, the first NSAID eye drop approved for treatment of
`
`postoperative inflammation in patients undergoing cataract surgery was diclofenac
`
`sodium, marketed as Voltaren®. (EX2057 at 3-7; EX2044 at 1.) Voltaren® was
`
`approved for treatment of postoperative inflammation in patients who have
`
`undergone cataract extraction and temporary relief of pain and photophobia in
`
`patients undergoing corneal refractive surgery.
`
`(EX2057 at 4.)
`
`For its
`
`postoperative inflammation indication, Voltaren ® requires application 4 times daily
`
`beginning 24 hours after cataract surgery and continuing through the first 2 weeks
`
`of the post-operative period. (Jd. at 6.) Similar to Suprofen® and Profenal®, with
`
`Voltaren® transient burning and stinging were reported in approximately 15% of
`
`patients across studies. (Id.)
`
`28.
`
`In 1992, a 0.5% solution of the NSAID ketorolac tromethamine, or
`
`Acular®, was approved for treatment of postoperative inflammation in patients who
`
`have undergone cataract extraction. (EX2059 at 1; EX2060 at 5.) Acular® was
`
`additionally approved for temporary relief of ocular itching due to seasonal allergic
`
`conjunctivitis.
`
`(EX2060 at 5.) Like Voltaren® and all other commercially
`
`available ophthalmic NSAIDs to that date, adverse events reported included
`
`transient stinging and burning on instillation.
`
`(Jd. at 7-8.) Notably, for Acular®,
`
`these side effects were reported by up to 40% of patients participating in clinical
`
`trials.
`
`(Jd. at 7.) For treatment of postoperative inflammation, Acular® requires
`
`Page 12 of26
`
`12
`
`
`
`application 4 times daily beginning 24 hours after surgery and continuing for 2
`
`weeks of the post-operative period. (Id. at 8.)
`
`29. A preservative free version of Acular®, marketed under the name
`
`Acular® PF, was approved in 1997. (EX2060 at 9-13; EX2061 at 1.) Acular® PF
`
`was sold in single use vials for administration 4 times per day for 2 weeks
`
`following incisional refractive surgery. (EX2060 at 12.) Unlike Acular®, Acular®
`
`PF was not indicated for the treatment of postoperative inflammation in patients
`
`who have undergone cataract extraction. (!d. at 1 0.) Rather, it was approved for
`
`the reduction of ocular pain and photophobia following incisional refractive
`
`surgery. (!d.) Even without inclusion of a preservative in the formulation, adverse
`
`events for Acular® PF still included transient burning and stinging upon instillation
`
`in approximately 20% of patients participating in clinical trials. (!d. at 12.)
`
`30.
`
`In 2000, Bronuck, a 0.1% bromfenac sodium NSAID ophthalmic
`
`formulation, was first approved in Japan.
`
`(EX2111 at 2; EX2112 at 1.)
`
`I
`
`understand that because Bronuck was only sold in Japan and not in the United
`
`States, sales of Bronuck are not "prior art" to the '290, '131, '813, and '606
`
`patents.
`
`31. Bronuck was approved in Japan for the treatment of inflammatory
`
`ailments of the external eye and anterior eye (blepharitis, conjunctivitis, scleritis
`
`(including, episcleritis), and postoperative inflammation). Bronuck exhibited
`
`Page 13 of26
`
`13
`
`
`
`vanous adverse events, including ocular pain, stinging and burning sensation.
`
`(EX2111 at 2, column 2; EX2112 at 2, column 2.) These events were reported in
`
`0.1% to less than 5% of patents. (EX2111 at 2, column 2; EX2112 at 2, column 2.)
`
`32.
`
`In 2005, the FDA approved Xibrom®, a 0.09% bromfenac sodium
`
`NSAID ophthalmic formulation. (EX2062 at 1.) As discussed above, I understand
`
`that January 21,2003, is the filing date of the applications to which the '290, '131,
`
`'813, and '606 patents claim priority. I thus understand that Xibrom ® is not "prior
`
`art" to the '290, '131, '813, and '606 patents.
`
`33. Xibrom® was approved
`
`for
`
`the
`
`treatment of postoperative
`
`inflammation in patients who have undergone cataract extraction. (EXl 008 at 1.)
`
`Xibrom ® exhibited various adverse events, including abnormal sensation in eye,
`
`conjunctival hyperemia, eye irritation (including burning/stinging), eye pain, eye
`
`pruritus, eye redness, headache and iritis. (!d. at 3 .) These events were reported in
`
`2-7% of patients. (!d.)
`
`34.
`
`In 2010, the FDA approved Bromday®, a 0.09% bromfenac sodium
`
`NSAID ophthalmic formulation identical to Xibrom ® except indicated for once
`
`daily usage instead of twice daily usage.
`
`(EX2063 at 1; EX1009 at 4.) As
`
`discussed above, I understand that January 21, 2003, is the filing date of the
`
`applications to which the '290, '131, '813, and '606 patents claim priority. I thus
`
`Page 14 of26
`
`14
`
`
`
`understand that Bromday® is not "prior art" to the '290
`'
`
`'131
`'
`
`'813 and '606
`'
`
`patents.
`
`3 5. Bromday® was approved
`
`for
`
`the
`
`treatment of postoperative
`
`inflammation and reduction of ocular pain in patients who have undergone cataract
`
`extraction. (EX1009 at 4.) Bromday® exhibited various adverse events, including
`
`abnormal sensation in eye, conjunctival hyperemia, eye irritation (including
`
`burning/stinging), eye pain, eye pruritus, eye redness, headache and iritis. (Id. at
`
`6.) These events were reported in 2-7% ofpatients. (Id.)
`
`36. Unfortunately, each of Voltaren®, Acular®, Bronuck, Xibrom® and
`
`Bromday® are
`
`limited by
`
`their side effects when
`
`treating postoperative
`
`inflammation in patients who have undergone cataract extraction. (EX2057 at 6;
`
`EX2060 at 7-8; EX2111 at 2, column 2; EX1 008 at 3; EX1009 at 6.) For example,
`
`each causes burning and stinging upon administration in a significant proportion of
`
`patients. (EX2057 at 6; EX2060 at 7-8; EX2111 at 2, column 2; EX1008 at 3;
`
`EX1009 at 6.) These complaints are typical of what I have observed from patients
`
`whom I have treated in my practice. Burning and stinging are significant side
`
`effects because they are painful and impact patient compliance, resulting in
`
`patients not using their medication. (EX2119 at 928.) When patients avoid using
`
`available therapies and thus do not treat inflammation after undergoing cataract
`
`surgery, they have a higher risk of developing cystoid macular edema ("CME"),
`
`Page 15 of26
`
`15
`
`
`
`which is a senous post-operative complication, among other complications.
`
`(EX2068 at 568; EX2113 at 966.) Not treating inflammation also leads to greater
`
`post-surgical pain and dissatisfaction with the surgery.
`
`C.
`
`Development of Prolensa® as a Safe and Effective Treatment of
`Pain and Inflammation Following Cataract Surgery
`
`3 7.
`
`In light of the shortcomings, including burning and stinging, of
`
`available NSAID eye drops for treating postoperative inflammation in patients who
`
`have undergone cataract extraction, researchers continued to develop other
`
`formulations.
`
`38.
`
`In 2013, the FDA approved Prolensa®, 0.07% bromfenac sodium, for
`
`the treatment of postoperative inflammation and reduction of ocular pain in
`
`patients who have undergone cataract surgery.
`
`(EX2014 at 1; EX1049 at 4.)
`
`Reported adverse events included anterior chamber inflammation, foreign body
`
`sensation, eye pain, photophobia and vision blurred.
`
`(EX1049 at 6.) These
`
`reactions were reported in 3 to 8% of patients. (I d.)
`
`39. Notably, and unlike all other approved NSAID ophthalmic eye drops,
`
`Prolensa® was not reported to cause burning and stinging upon administration.
`
`(Id.) This comports with what I observe from patients whom I treat in my practice,
`
`who describe Prolensa® as very comfortable to administer and well-tolerated. As
`
`discussed above, this is a major benefit of Prolensa®, and it increases patient
`
`Page 16 of26
`
`16
`
`
`
`compliance, which in tum minimizes the potential for pain and complications such
`
`as post-operative CME. (EX2068 at 568; EX2113 at 966; EX2119 at 928.)
`
`40. Moreover, I understand that Prolensa® is formulated at a lower pH of
`
`7 .8, closer to that of natural tears (pH 7.4\ as compared to the higher pH of 8.3 at
`
`which Xibrom® and Bromday® were formulated. (EX2082 at~ 201; EX2113 at
`
`966; compare EX1049 at 7 with EX1008 at 5 and EX1009 at 7.)
`
`m Prolensa® eliminated the burning and stinging
`
`The reduced pH
`
`sensation, making it more comfortable and ensuring greater patient compliance.
`
`(EX2113 at 966; EX2119 at 928)
`
`41.
`
`Prolensa®'s lower pH also led to improved ocular penetration, even at
`
`a lower concentration of bromfenac (0.07%) as compared to Xibrom® and
`
`Bromday® (0.09%).
`
`(EX2033 at 1722 ("Even at a lower concentration, the
`
`bromfenac 0.07%, pH 7.8 solution exhibited similar, 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 EX1049 at 7 with
`
`EXl 008 at 3 and EXI 009 at 7 .) In addition, the lower concentration of bromfenac
`
`in Prolensa® places less drug in contact with surgically compromised ocular tissue
`
`1 Dr. Lawrence states that "[i]deally, the pH of the formulation should be 7.4, i.e., the
`same as tear fluid." (EXl 005 at~ 66(b ).)
`
`Page 17 of26
`
`17
`
`
`
`without a reduction in efficacy.
`
`(EX2033 at 1718; compare EX1049 at 4 with
`
`EX1008 at 3 and EX1009 at 4.) These additional benefits of Prolensa® are
`
`substantial for patients undergoing cataract surgery, and further make Prolensa®
`
`my drug of choice in treating post-operative pain and inflammation in my patients.
`
`42.
`
`Furthermore, Prolensa® exhibits these significant patient benefits,
`
`including a remarkably safe adverse event profile, despite containing the
`
`preservative benzalkonium chloride ("BAK") in its formulation. (EX1049 at 7.)
`
`BAK has long been known to be toxic to the eye, 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
`
`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 ophthalmic drug Lumigan®, the Court of Appeals
`
`for the Federal Circuit noted that the patent 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.)
`
`43. 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.) This finding led the author to urge that a
`
`Page 18 of26
`
`18
`
`
`
`preservative-free ketorolac formulation may be a better postoperative ocular
`
`analgesic than the preserved ketorolac formulation. (!d.)
`
`44. Accordingly, as of 2003, researchers were actively researching
`
`formulations avoiding BAK.
`
`(EX2089 and EX2091.)
`
`In September 2001,
`
`Noecker et al. published results comparing several preservatives, including
`
`stabilized oxychloro complex ("SOC," also known as Purite®) and BAK,
`
`recognized by Noecker as having significant cytotoxic effects in animals and
`
`humans. (EX2089 at Abstract.) Noecker indicated a better approach to using toxic
`
`preservatives, such as BAK, was to use more tolerated preservatives and
`
`specifically described the benefits observed by replacing BAK with SOC in an
`
`ophthalmic formulation of brimonidine, which the FDA approved in March 2001
`
`as Alphagan® P (EX2092 (indicating approval date); EX2093 at 2 (Purite®
`
`included as a preservative)), stating as follows:
`
`in patients with
`A 12-month clinical comparison
`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 lOP-lowering
`efficacy.
`
`(EX2089 at 211, ~ 2.)
`
`45.
`
`Similarly, in 2002, Katz (EX2091) published additional studies of
`
`brimonidine-SOC showing a 41% relative reduction in ocular allergy and superior
`
`satisfaction and comfort ratings compared to brimonidine-BAK, leading Katz to
`
`Page 19 of26
`
`19
`
`
`
`conclude that that brimonidine-Purite 0.15% is "an effective, safe, and well(cid:173)
`
`tolerated therapy for the long-term treatment of high lOP." (Id at 126.)
`
`46.
`
`I agree that BAK is toxic and should be eliminated from ophthalmic
`
`formulations wherever possible. For example, Acular®, which contained BAK,
`
`was later made available in a preservative-free formulation, Acular® PF, described
`
`above. (EX2060 at 4; 9-13.) Yet even with 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 EX1049 at 6
`
`with EX2060 at 12.) Prolensa® exhibits this superior adverse event profile despite
`
`that the frequency of symptoms and objective signs of irritation are reported to be
`
`higher with eye drops containing preservatives, particularly BAK, as compared to
`
`preservative-free eye drops. (EX2080 at 422.)
`
`D.
`
`Objective Evidence of Non-Obviousness
`
`47.
`
`I understand that certain objective evidence, including, for example,
`
`unexpected results, teaching away and acclaim, is relevant to the non-obviousness
`
`of a patented invention. I provide below my opinions concerning certain objective
`
`evidence that the development ofProlensa® would not have been obvious.
`
`48. As discussed above, I understand that Prolensa® embodies the
`
`patented subject matter by formulating bromfenac with tyloxapol. (EX2082 at ~~
`
`Page 20 of26
`
`20
`
`
`
`175-76.) It is my understanding that Prolensa® falls within the scope of at least
`
`claims 1-7 and 9-30 ofthe '606 patent. (!d.)
`
`49.
`
`I am informed that tyloxapol is unexpectedly effective at chemically
`
`stabilizing bromfenac, which has permitted formulating Prolensa® at the lower pH
`
`of 7.8
`
`(!d. at~~ 201-03.) Not only did this
`
`eliminate burning and stinging sensation, making it more comfortable and helping
`
`to ensure greater patient compliance (EX2113 at 966; EX2119 at 928), but the
`
`lower pH also improved ocular penetration. (EX2033 at 1722.) That led to the
`
`ability to reduce Prolensa®'s bromfenac concentration to 0.07%, down from 0.09%
`
`in Xibrom® and Bromday®. (EX2033 at 1722; compare EX1049 at 7 with EX1008
`
`at 3 and EX1009 at 7.) A lower bromfenac concentration advantageously places
`
`less drug in contact with surgically compromised ocular tissue without a reduction
`
`in efficacy. (EX2033 at 1718; EX2113 at 971; compare EX1049 at 4 with EX1008
`
`at 3 and EX1 009 at 4.)
`
`1.
`
`Unexpected Results Leading to Significant Medical
`Benefits, Where the Prior Art Taught Away
`
`50.
`
`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
`
`eliminated burning and
`
`stinging. (See~~ 38-42 above.) As of 2003, a topical ophthalmic NSAID that did
`
`Page 21 of26
`
`21
`
`
`
`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.
`
`Lawrence contends represents an embodiment of the Ogawa patent (EXl 005 at ,-r
`
`266), caused both burning and stinging.
`
`(EX2111 at 2; EX2112 at 2.) Even
`
`Xibrom® and Bromday®, which Dr. Lawrence also contends
`
`represent
`
`embodiments of the Ogawa patent, published in 1990 (EXl 005 at ,-r 81 ), exhibited
`
`burning and stinging. (EX1008 at 3; EX1009 at 6.)
`
`51. 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.
`
`(EX1049 at 6.) As discussed above, making the 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
`
`Page 22 of26
`
`22
`
`
`
`Prolensa® would exhibit this highly favorable side effect profile while providing
`
`efficacious treatment of post-operative pain and inflammation, especially in light
`
`of the side effect profiles of other ophthalmic NSAID formulations, including
`
`bromfenac formulations Bronuck, Xibrom ® and Bromday®. Based on this benefit,
`
`despite the fact that less expensive generic versions of each of Voltaren ®, Acular®
`
`and Bromday® are currently available, I routinely prescribe Prolensa® because,
`
`among other reasons, its lack of burning and stinging makes it more comfortable to
`
`patients, which fosters patient compliance.
`
`52. Lowering the pH also improved ocular penetration, leading to a
`
`reduction of bromfenac on surgically damaged tissue without sacrificing anti(cid:173)
`
`inflammatory efficacy. (Jd. at 7; EX2033 at 1718.) Constituting much more than a
`
`difference in degree, these significant benefits have made Prolensa® an effective
`
`and
`
`safe ophthalmic pharmaceutical
`
`formulation compared
`
`to previous
`
`formulations having significant side effects that c
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