`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC, INNOPHARMA
`INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS INC. and MYLAN INC.
`Petitioners
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INCORPORATED, and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner
`
`
`Case IPR2015-00902
`Patent 8,669,290
`
`
`
`DECLARATION OF WILLIAM B. TRATTLER, M.D.
`
`
`1
`
`
`
`
`
`
`
`
`
`
`
`
`
`SENJU EXHIBIT 2116
`INNOPHARMA v SENJU
`IPR2015-00902
`
`PAGE 1 OF 20
`
`
`
`
`
`
`
`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 two inter partes
`
`review (“IPR”) proceedings (IPR2015-00902 and IPR2015-00903) 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 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.
`
`
`
`2
`
`PAGE 2 OF 20
`
`
`
`
`
`
`
`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 from 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-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 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
`
`
`
`3
`
`PAGE 3 OF 20
`
`
`
`
`
`
`
`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.)
`
`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
`
`
`
`4
`
`PAGE 4 OF 20
`
`
`
`
`
`
`
`also have served on the 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.)
`
`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. Paul
`5
`
`
`
`PAGE 5 OF 20
`
`
`
`
`
`Laskar’s declaration, including some of the references cited therein.
`
`(EX1003.)
`
`I have also
`
`reviewed the declaration of Robert 0. Williams, III. EX2082.) For reasons discussed below, I
`
`disagree with Dr. Laskar’s conclusions that the claims of the patents at issue are invalid based on
`
`obviousness.
`
`C.
`
`The Patents at Issue
`
`15.
`
`I understand that InnoPharma has challenged Senj11’s U.S. Patent Nos. 8,129,431
`
`(“the ’43l patent”) and 8,669,290 (“the ’290 patent”).
`
`I further understand that January 21,
`
`2003, is the filing date of the applications to which the ’431 and ’290 patents claim priority.
`
`16.
`
`I also understand that Prolensa® (bromfenac ophthalmic solution 0.07%) is an
`
`embodiment of the aqueous liquid preparations disclosed and claimed i11 the ’290 patent.
`
`(EX2082 at 1|1] 142-43.)
`
`I understand that the claimed aqueous liquid preparations of the ’290
`
`patent require at least bromfenac and tyloxapol.
`
`(Id.)
`
` - I understand that the inclusion of tyloxapol resulted in
`
`unexpectedly superior stability of bromfenac formulations.
`
`(Id. at 1|‘|] 154-63.) 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. O3X2052 at 447.)
`
`In fact, cataracts are one of the most common causes of
`
`PAGE 6 OF 20
`
`
`
`
`
`blindness worldwide. (Id.) 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.)
`
`18.
`
`A common cause of cataracts is age-related changes to the lens of the eye. (Id. 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. (Id. at 606-607.)
`
`19.
`
`One of the first modern 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. (Id. 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. (Id. 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. (Id. at S11.) Phacoemulsification surgery uses ultrasonography to break the lens into
`
`minute fragments that can be aspirated, allowing for a small incision. (Id.; EX2067 at 607.) A
`
`smaller incision heals more quickly and has a decreased risk of complications. (EX2052 at 448;
`
`EX2067 at 607.) Phacoemulsification techniques have continued to progress, and they remain
`
`the standard of care today. (EX2052 at 448; EX2067 at 607.)
`
`
`
`7
`
`PAGE 7 OF 20
`
`
`
`
`
`
`
`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.
`
`23.
`
`Other NSAID Therapies
`
`Despite continuing improvement in cataract surgery techniques in the 20th
`
`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-1 and
`
`COX-2. (Id.) 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. (Id.) Moreover, based on their different mechanisms of action, NSAIDs and
`
`corticosteroids have different side effect profiles. (Id. at 44.)
`
`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
`8
`
`
`
`PAGE 8 OF 20
`
`
`
`
`
`
`
`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. (Id.)
`
`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. (Id. 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
`
`
`
`9
`
`PAGE 9 OF 20
`
`
`
`
`
`
`
`transient stinging and burning on instillation. (Id. at 7-8.) Notably, for Acular®, these side
`
`effects were reported by up to 40% of patients participating in clinical trials. (Id. at 7.) For
`
`treatment of postoperative inflammation, Acular® requires 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. (Id. at 10.) Rather, it was
`
`approved for the reduction of ocular pain and photophobia following incisional refractive
`
`surgery. (Id.) 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. (Id. 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
`
`’431 and ’290 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 various 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.)
`
`
`
`10
`
`PAGE 10 OF 20
`
`
`
`
`
`
`
`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 ’431 and ’290 patents claim priority. I
`
`thus understand that Xibrom® is not “prior art” to the ’431 and ’290 patents.
`
`33.
`
`Xibrom® was approved for the treatment of postoperative inflammation in patients
`
`who have undergone cataract extraction. (EX2026 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. (Id. at 3.) These
`
`events were reported in 2-7% of patients. (Id.)
`
`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; EX2027 at 4.) As discussed above, I understand that January
`
`21, 2003, is the filing date of the applications to which the ’431 and ’290 patents claim priority.
`
`I thus understand that Bromday® is not “prior art” to the ’431 and ’290 patents.
`
`35.
`
`Bromday® was approved for the treatment of postoperative inflammation and
`
`reduction of ocular pain in patients who have undergone cataract extraction. (EX2027 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% of patients. (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; EX2026 at
`
`3; EX2027 at 6.) For example, each causes burning and stinging upon administration in a
`
`
`
`11
`
`PAGE 11 OF 20
`
`
`
`
`
`
`
`significant proportion of patients. (EX2057 at 6; EX2060 at 7-8; EX2111 at 2, column 2;
`
`EX2026 at 3; EX2027 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”), which is a serious 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
`
`37.
`
`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. (EX2015 at 1; EX2013 at 4.) Reported adverse events included
`
`anterior chamber inflammation, foreign body sensation, eye pain, photophobia and vision
`
`blurred. (EX2013 at 6.) These reactions were reported in 3 to 8% of patients. (Id.)
`
`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
`
`
`
`12
`
`PAGE 12 OF 20
`
`
`
`
`
`
`
`Prolensa®, and it increases patient compliance, which in turn minimizes the potential for pain and
`
`complications such as post-operative CME. (EX2068 at 568; EX2113 at 966; EX2119 at 928.)
`
`40.
`
`Dr. Laskar acknowledges that Prolensa®’s package insert does not identify
`
`burning or stinging as an adverse event, but then states that the inclusion of eye pain as an
`
`adverse event in the Prolensa® package insert connotes or is equivalent to burning and stinging.
`
`(EX2114 at 38:14 - 39:3.) I disagree. Eye pain is a separate and distinct adverse event from
`
`burning or stinging a patient may experience. For example, ocular pain is a separate adverse
`
`event from burning and stinging associated with Bronuck. (EX2111 at 2, column 2; EX2112 at
`
`2, column 2.) Similarly, eye pain is listed separately from burning and stinging in both the
`
`Xibrom® and Bromday® package inserts. (EX2026 at 3; EX2027 at 6.) Thus, the inclusion of
`
`eye pain as an adverse event in the Prolensa® package insert does not in any way indicate that it
`
`connotes or is equivalent to burning and stinging.
`
`41. 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 ¶ 168; EX2113 at 966; compare EX2013 at 7 with
`
`EX2026 at 5 and EX2027 at 7.) Prolensa® also contains far less surfactant, 0.02 w/v% tyloxapol
`
`compared to 0.15 w/v% polysorbate 80 in Xibrom® and Bromday®. (EX2082 at ¶ 168.) The
`
`reduced pH and amount of surfactant in Prolensa® eliminated the burning and stinging sensation,
`
`making it more comfortable and ensuring greater patient compliance. (EX2113 at 966; EX2119
`
`at 928)
`
`42.
`
`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%). (EX2030
`
`at 1722 (“Even at a lower concentration, the bromfenac 0.07%, pH 7.8 solution exhibited similar,
`
`
`
`13
`
`PAGE 13 OF 20
`
`
`
`
`
`
`
`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
`
`at 3 and EX2027 at 7.) In addition, the lower concentration of bromfenac in Prolensa® places
`
`less drug in contact with surgically compromised ocular tissue without a reduction in efficacy.
`
`(EX2030 at 1718; compare EX2013 at 4 with EX2026 at 3 and EX2027 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.
`
`43.
`
`Furthermore, Prolensa® exhibits these significant patient benefits, including a
`
`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,
`
`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.)
`
`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.)
`
`This finding led the author to urge that a preservative-free ketorolac formulation may be a better
`
`postoperative ocular analgesic than the preserved ketorolac formulation. (Id.)
`
`
`
`14
`
`PAGE 14 OF 20
`
`
`
`
`
`
`
`45.
`
`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:
`
`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-
`
`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.
`
`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 EX2013
`
`at 6 with EX2060 at 12.) Prolensa® exhibits this superior adverse event profile despite that the
`
`
`
`15
`
`PAGE 15 OF 20
`
`
`
`
`
`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
`
`48.
`
`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 of
`
`Prolensa® would not have been obvious.
`
`49.
`
`As discussed above, I understand that Prolensa
`
`embodies the patented subject
`
`®
`
`matter by formulating bromfenac with tyloxapol.
`
`(EX2082 at
`
`1|1[ 142-43.) ‘
`
`50.
`
`I am informed that tyloxapol is unexpectedly effective at chemically stabilizing
`
`bromfenac, which has permitted formulating Prolensa® at the lower pH of 7.8 with a reduced
`
`amount of surfactant.
`
`(Id. at 1|1I 168-70.) Not only did this eliminate burning and stinging
`
`sensation, making it more comfortable and helping to ensure greater patient compliance
`
`GIX21 13 at 966; EX2119 at 928), but 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 EX2013 at 4 with EX2026 at 3 and EX2027 at 4.)
`
`16
`
`PAGE 16 OF 20
`
`
`
`
`
`1.
`
`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
`
`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
`
`
`
`17
`
`PAGE 17 OF 20
`
`
`
`
`
`
`
`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