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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`APOTEX INC.,
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`Petitioner
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`v.
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`Patent of ALCON PHARMACEUTICALS LTD.,
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`Patent Owner.
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`Case IPR2013-00012
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`U.S. Patent No. 6,716,830
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`DECLARATION OF EDUARDO C. ALFONSO, M.D.
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`ALCON 2271
`Apotex Inc. v. Alcon Pharmaceuticals, Ltd.
`Case IPR2013-00012
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`Table of Contents
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`OVERVIEW .................................................................................................... 1
`I.
`BACKGROUND AND QUALIFICATIONS ................................................. 2
`II.
`III. LIST OF DOCUMENTS CONSIDERED ...................................................... 5
`IV. SUMMARY OF OPINIONS ........................................................................... 5
`V.
`PERSON OF ORDINARY SKILL IN THE ART ........................................ 10
`VI. BACKGROUND ........................................................................................... 12
`A.
`The Anatomy of the Eye and Ocular Penetration ............................... 12
`B. Ophthalmic Bacterial Infections in September 1998 .......................... 15
`The State of the Art in the Treatment of Ophthalmic Infections
`C.
`in September 1998 ............................................................................... 19
`VII. OBVIOUSNESS ............................................................................................ 25
`A.
`The Invention of the ’830 Patent ......................................................... 25
`B.
`The Invention of Claim 1 of the ’830 Patent Would Not Have
`Been Obvious to the Person of Ordinary Skill in the Art. .................. 26
`1.
`Overview of the References at Issue ......................................... 26
`2.
`The Claimed Invention Would Not Have Been Obvious
`over the ’942 Patent, the Ocuflox® PDR, and the
`Petersen Abstract. ...................................................................... 43
`C. Objective Indicia of Non-Obviousness ............................................... 75
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`
`
`i
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`I, Eduardo C. Alfonso, do declare as follows:
`I.
`I am over the age of eighteen (18), and am otherwise competent to
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`OVERVIEW
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`1.
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`make this declaration.
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`2.
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`I have been retained as an expert witness on behalf of Alcon for the
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`above-captioned inter partes review (“IPR”). I am being paid at my usual hourly
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`consulting fee, at a rate reflected in Exhibit 2278. My compensation does not
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`depend on the outcome of this case.
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`3.
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`I understand that the Patent Trial and Appeal Board (“the Board”) has
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`granted Apotex’s petition to institute this IPR regarding claim 1 of United States
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`Patent No. 6,716,830 (the “’830 patent”) on the ground that that claim is allegedly
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`obvious over a combination of (i) United States Patent No. 5,607,942 (the “’942
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`patent”) (Ex. 1002); (ii) Peterson, et al., “Synthesis and in Vitro Activity of BAY-
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`12-8039, a New 8-Methoxy-Quinolone,” Abstracts of the 36th Interscience
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`Conference on Antimicrobial Agents and Chemotherapy 100, American Society
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`for Microbiology, New Orleans, LA, on Sept. 15-18, 1996 (“the Petersen
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`Abstract”) (Ex. 1005);1 and (iii) Physician’s Desk Reference, p. 481, 50th ed.
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`(“Ocuflox® PDR”) (Ex. 1006).
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`1 While Exhibit 1005 contains five separate abstracts (F1 through F5), I understand
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`that the Ground on which this IPR was instituted specifically pertains to the
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`1
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`4.
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`I also understand that the Patent Trial and Appeal Board denied all
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`other alleged grounds of invalidity raised in Apotex’s Petition with regard to these
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`claims, and hence those grounds of invalidity are not at issue in this IPR. I further
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`understand that the priority date of the ’830 patent is September 30, 1998.
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`5.
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`Claim 1 of the ’830 patent recites:
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`6.
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`In formulating my opinions regarding the validity of claim 1 of the
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`’830 patent, I have considered the materials cited herein, my training and
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`experience, and the knowledge and information available to a person of ordinary
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`skill in the art as of September 30, 1998.
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`II. BACKGROUND AND QUALIFICATIONS
`I am the Chairman and Director, Professor, and the Kathleen and
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`7.
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`Stanley Glaser Distinguished Chair of the Department of Ophthalmology at the
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`Bascom Palmer Eye Institute, University of Miami, in Miami, Florida. I formerly
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`held the Edward WD Norton Chair in Cornea and External Diseases at the same
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`institution. I graduated from Yale University Medical School in 1980, after which
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`abstract labeled F1 in Exhibit 1005, which was the only portion of that document
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`discussed in Apotex’s Petition and the Declarations of Drs. Barza and Fiscella.
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`2
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`I was an intern at Mt. Sinai Hospital, a resident in Ophthalmology at Bascom
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`Palmer Eye Institute, and a fellow in Cornea and External Diseases, Ophthalmic
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`Pathology at Harvard Medical School and the Massachusetts Eye and Ear
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`Infirmary. My curriculum vitae, which describes in detail my educational
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`background and the highlights of my career, is submitted as Ex. 2272.
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`8. My work at Bascom Palmer involves treating patients who have
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`complicated ophthalmic infections, including mis-diagnosed and/or post-operative
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`bacterial infections that can cause sight loss. In addition, I consult on difficult
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`cases of bacterial infections. I also perform ophthalmic surgeries, and an important
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`component of my surgical work involves the prevention of infection during and
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`after surgery. I am familiar with the products that have been used to prevent and
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`treat ophthalmic bacterial infections over the last two decades, including products
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`containing fluoroquinolone antibiotics, such as Ciloxan®, Ocuflox®, Zymar®, and
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`Vigamox®. I have used each of these products to treat and prevent bacterial
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`infections in patients.
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`9.
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`In addition to my work treating patients and performing surgery, I
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`conduct research relating to the treatment and prevention of ophthalmic infections.
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`I have served as the Medical Director of the Bascom Palmer Ocular Microbiology
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`Laboratory for more than 20 years. In this capacity, I train post-doctoral research
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`fellows in ocular microbiology. Among other topics, my research has focused on
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`3
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`the ability of various ophthalmic formulations (both marketed and non-marketed)
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`to treat and prevent ophthalmic bacterial infections, as well as the properties of
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`those formulations. This research in microbiology includes the use of standard
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`techniques used to evaluate the activity, the ability to kill bacteria (often measured
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`by minimum inhibitory concentration, or “MIC”), and efficacy of compounds and
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`formulations against ocular pathogens (disease causing organisms). For this
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`purpose, I maintain a library of clinical isolates of ocular pathogens that are used to
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`evaluate potential antimicrobial treatments. The evaluation of the properties of
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`formulations containing fluoroquinolones for ophthalmic use has been a significant
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`area of my research. I have authored hundreds of book chapters, monographs, and
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`peer-reviewed publications, many of which relate to ophthalmic infections and the
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`treatment and/or prevention thereof. A list of my publications is included in my
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`CV. See Ex. 2272.
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`10.
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`In connection with my microbiological research, I have consulted with
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`various companies in obtaining and assessing data regarding topical ophthalmic
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`antibiotic formulations, including for the purpose of advising whether to pursue (or
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`to continue to pursue) development of a product. I served on the advisory board
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`for ophthalmic antibiotic development for several companies and for more than a
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`decade have advised companies as to whether and why topical ophthalmic
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`4
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`antibiotic formulations (including those containing fluoroquinolones) should be
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`made, pursued, and used.
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`11.
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`I frequently serve as a peer-reviewer for articles relating to ophthalmic
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`infections for numerous journals and have served on several editorial boards of
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`peer-reviewed journals, including Archives of Ophthalmology, Ocular Surgery
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`News, and Eye World ALACCSA.
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`12. For nearly three decades, I have taught ophthalmology to medical
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`school students, residents, interns, and fellows, including instruction regarding the
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`treatment and prevention of ophthalmic bacterial infections, as well as the
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`properties and uses of ophthalmic formulations containing fluoroquinolones. I
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`have served on the faculty of numerous national and international meetings relating
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`to the diagnosis and treatment of ocular infections and the properties and uses of
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`ophthalmic formulations containing fluoroquinolones.
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`III. LIST OF DOCUMENTS CONSIDERED
`In formulating the opinions set forth herein, I have considered the
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`13.
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`documents in Exhibit 2280.
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`IV. SUMMARY OF OPINIONS
`In my opinion, based on the state of the art as of September 30, 1998,
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`14.
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`a person of ordinary skill would not have had an interest in making or using a
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`topical ophthalmic formulation containing moxifloxacin for the treatment and
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`5
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`prevention of bacterial infections. Based on the then-available information, such a
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`person of ordinary skill would have expected such a formulation to be inferior to
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`current therapies such as Ciloxan®, especially as to the treatment of sight-
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`threatening Pseudomonas aeruginosa infections that were a major focus of
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`ophthalmic anti-infective therapy.
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`15. Moreover, a person of ordinary skill would have been concerned
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`about the potential toxicity of a topical ophthalmic formulation containing
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`moxifloxacin, because of both the toxicity of quinolone molecules as a class and
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`the lack of sufficient published toxicity data relating to moxifloxacin, and would
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`have been dissuaded from developing such a formulation on this basis as well.
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`16.
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`In addition, there was a concern amongst practitioners in the field that
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`important ocular pathogens were increasingly resistant to the existing
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`fluoroquinolone therapies, and that this resistance would extend to new quinolone
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`therapies.
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`17. A person of ordinary skill in the art would have expected
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`moxifloxacin to kill bacteria through the same pathway as ciprofloxacin, ofloxacin,
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`and other fluoroquinolones. Accordingly, the skilled artisan would have
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`considered moxifloxacin unlikely to be suitable to treat infections caused by
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`certain strains that had become resistant to existing quinolone therapies and would
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`have expected ocular strains to quickly become resistant to moxifloxacin upon its
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`6
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`use in patients. As a result, skilled persons were, and a person of ordinary skill in
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`the art would have been, less interested in fluoroquinolones as a class for new
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`ophthalmic formulations than other classes of antibiotics, including (for example)
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`oxazolidones, carbapenems, and cephalosporins, and streptogramins.
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`18. Surprisingly, topical ophthalmic formulations containing
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`moxifloxacin have numerous clinically beneficial properties that could not have
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`been predicted based on information that was publicly known in September 1998.2
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`By way of example, moxifloxacin ophthalmic formulations have desirable
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`pharmacokinetic properties in the eye that demonstrate a substantial and entirely
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`unexpected improvement over the therapies in use at the September 30, 1998
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`priority date. The ability of a quinolone ophthalmic formulation to treat or prevent
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`an infection was known to depend on the concentration of the compound at the site
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`2 Vigamox®, like most topical ophthalmic formulations, is an eyedrop. Though
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`other forms of topical ophthalmic formulations (such as ointments) exist for other
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`purposes, in the area of treating and preventing bacterial infections in the cornea
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`and aqueous humor, the products are predominately, if not exclusively, eyedrops.
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`Topical ophthalmic formulations other than eyedrops (such as ointments) are not as
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`practical in the treatment of corneal infections or the prevention of infections after
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`intraocular surgery. For that reason, I will use the terms “topical ophthalmic
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`formulation” and “eyedrop” synonymously in this report.
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`7
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`of the infection. Moxifloxacin is able to penetrate and achieve high concentrations
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`in the cornea and in the aqueous humor—two areas of the eye where infections are
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`traditionally most sight-threatening and difficult to treat.
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`19. Among the infections that can be prevented using topical ophthalmic
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`moxifloxacin as a result of its surprising pharmacokinetic properties are infections
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`inside the eye, including infections caused by Pseudomonas aeruginosa that a
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`person of ordinary skill in the art in 1998 would have considered among the most
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`important for a new therapy to prevent, and for which topical ophthalmic
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`moxifloxacin would have appeared unsuitable based on the available literature. In
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`short, the desirable and unexpected pharmacokinetic properties of topical
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`formulations of moxifloxacin in the eye compensate for the compound’s reduced
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`activity in vitro against Pseudomonas aeruginosa as compared to ciprofloxacin and
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`contribute to its clinical utility.
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`20.
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`In addition, the surprising penetration of topical ophthalmic
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`formulations of moxifloxacin contributes to an enhanced ability to treat corneal
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`infections (keratitis), including those caused by Pseudomonas aeruginosa and
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`ciprofloxacin-resistant strains of methycillin-resistant Staphylococcus aureus
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`(MRSA), both of which are important pathogens.
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`21. Also, because moxifloxacin upon topical ophthalmic administration
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`surprisingly kills bacteria in a different way than expected—by binding both in the
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`8
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`expected manner but also to an additional bacterial enzyme to which ciprofloxacin
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`and ofloxacin do not bind—resistance to moxifloxacin has not developed as
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`expected. Moreover, topical ophthalmic administration of moxifloxacin
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`surprisingly is able to prevent mycobacterial infections, which are commonly
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`associated with LASIK surgery, more effectively than ciprofloxacin. The topical
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`ophthalmic administration of moxifloxacin also surprisingly has been found since
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`the priority date to be useful in treating fungal infections, which have been
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`implicated in infections caused by contact lenses. A person of ordinary skill in the
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`art could not have predicted in 1998 that a topical ophthalmic formulation of
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`moxifloxacin could treat such fungal infections.
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`22. Alcon’s commercial topical moxifloxacin ophthalmic formulation,
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`Vigamox®, which I understand is an embodiment of claim 1, has fulfilled a long-
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`felt need in the field for a product that could help prevent intraocular bacterial
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`infections and treat corneal infections, including those caused by Gram-positive
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`pathogens such as Staphylococcus aureus and Gram-negative pathogens such as
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`Pseudomonas aeruginosa, including quinolone-resistant pathogens. Because of its
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`properties, the ophthalmologic community quickly adopted Vigamox®, which has
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`become the standard of care for prevention of potentially dangerous intraocular
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`infections, as well as for the prevention and treatment of corneal and other ocular
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`infections. Vigamox® has provided a significant clinical benefit to numerous
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`9
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`patients in whom it has been used for the treatment and prevention of ophthalmic
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`infections and has received significant praise from practitioners in the field.
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`23. The literature cited by Apotex and its experts Drs. Barza and Fiscella
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`does not disclose or suggest a topical ophthalmic formulation containing
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`moxifloxacin. Nor does the literature cited by Apotex and Drs. Barza and Fiscella
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`suggest that moxifloxacin topical ophthalmic formulations would have the
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`desirable properties discussed above, without many of which a person of ordinary
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`skill in the art would not have wanted to pursue such formulations. Likewise, the
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`available literature I have reviewed does not provide any information from which a
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`person of ordinary skill in the art could conclude that topical ophthalmic
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`formulations of moxifloxacin would have such properties. On the contrary, the
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`literature as a whole discloses that moxifloxacin has significantly lower activity
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`against Pseudomonas aeruginosa than ciprofloxacin and other fluoroquinolones
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`known in September 1998, which provided a significant reason not to pursue such
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`formulations. Moreover, the literature provides no reason to believe that resistance
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`to moxifloxacin would not arise, as it did for the quinolones that previously had
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`been developed into topical ophthalmic formulations.
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`PERSON OF ORDINARY SKILL IN THE ART
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`V.
`I have been asked to describe the qualifications of a “person of
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`24.
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`ordinary skill in the art” as of September 1998 with respect to the patent at issue.
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`10
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`Such a person would have an M.D., O.D. (Optometric Doctor) and/or Ph.D. degree
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`and training and several years of experience in the area of treating and preventing
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`bacterial infections, including infections in the eye, and/or research concerning
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`these subjects. In addition, such a person would be familiar with the available
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`options for the treatment and prevention of ophthalmic infections and would be
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`familiar with the quinolone class of antibiotics, their history, their properties, and
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`the microbiological techniques and parameters used to assess those properties
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`(such as activity, pharmacokinetics in the eye, and toxicity). Such a person of
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`ordinary skill in the art would appreciate the shortcomings of the existing therapies
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`in September 1998 for the treatment and prevention of ophthalmic bacterial
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`infections, as well as the nature of the infections—including the pathogenic species
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`and location of the infections—that any new topical ophthalmic formulation would
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`have to treat. In addition, such a person of ordinary skill would have experience
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`working or consulting with companies interested in developing products to treat
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`ophthalmic infections and would be familiar with the clinical and scientific
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`considerations relevant to the decision of whether or not to pursue development of
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`a topical ophthalmic antibiotic. A person of ordinary skill in the art also would
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`have been familiar with the manner and frequency in which topical ophthalmic
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`antibiotic formulations were used, and would have training and experience in
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`preparing formulations for topical ophthalmic use. Unless otherwise indicated,
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`11
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`references to a person of ordinary skill refer to such a person as of September 30,
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`1998.
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`25.
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`I have also considered the alternative definition of the person of
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`ordinary skill in the art offered by Drs. Barza and Fiscella. The opinions expressed
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`in this declaration would not change if that definition of a person of ordinary skill
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`in the art were applied.
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`VI. BACKGROUND
`A. The Anatomy of the Eye and Ocular Penetration
`26. Set forth below is a summary of additional background information
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`pertaining to the opinions I will express in this case.
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`27. The eye is designed to keep foreign bodies and compounds (including
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`pharmaceutical compounds) from entering through the ocular surface. This
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`includes microorganisms that can cause dangerous infections and interfere with
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`vision. This important function is achieved, in large measure, by multiple
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`heterogeneous, protective layers on the surface of the eye. Beginning on the
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`periphery and moving inward, the surface of the eye is coated by a tear film that
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`has three layers: the oil, aqueous, and mucus layers. The first such layer is oily,
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`and compounds (or any other foreign specimens) that are hydrophilic (water-
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`loving) will have difficulty surviving in and penetrating through this layer.
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`Beneath this oily layer of the tear film is a watery layer—an environment that is
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`12
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`difficult for hydrophobic (water-hating) compounds to survive in and penetrate.
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`Beneath this layer is a third layer of the tear film, which contains mucus and other
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`materials that can interfere with the penetration of foreign compounds.
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`28. Beneath this three-layer tear film is an epithelial cell layer on the
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`surface of the eye, which is a hydrophobic layer that hydrophilic compounds will
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`have difficulty penetrating. Beneath this epithelial layer is a hydrophilic stromal
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`cell layer (which hydrophobic compounds will have difficulty penetrating),
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`beneath which is a hydrophobic endothelial cell layer (which hydrophilic
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`compounds will have difficulty penetrating). In any of these layers, compounds
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`unpredictably may be highly bound (and thus not available to exert effects on
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`pathogens or continue to penetrate into deeper structures). In addition to these
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`multiple protective layers and mechanisms, the movement of the eyelids (blinking)
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`promotes the rapid efflux of foreign bodies or compounds from the surface of the
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`eye to the oropharynx (nose and mouth), where they are absorbed into the blood
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`circulation. In addition, the eye has efflux mechanisms that actively pump
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`compounds that do penetrate into the eye back out of the eye through the
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`membrane. This protective system—a portion of which I have summarized here—
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`is unique among the organs of the human body; I am aware of no other organ that
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`13
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`contains an analogous mechanism for preventing penetration and accumulation of
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`foreign compounds.3
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`29.
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`In short, in order to both penetrate the ocular surface and then remain
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`present and accumulate in ocular tissue, the topical formulation applied to the
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`ocular surface must strike the ideal balance of size, hydrophobicity/hydrophilicity,
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`avoidance of efflux mechanisms, and numerous other parameters (such as binding
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`to a various substances and tissues) that are not well understood. Absent any data
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`relating to ocular penetration of a compound in an ophthalmic formulation, a
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`3 Compounds that penetrate through the cornea and conjunctiva enter the aqueous
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`humor. The aqueous humor is turned over, i.e., removed and replaced, frequently
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`(approximately every five hours), thus resulting in the removal of certain
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`compounds that enter the aqueous humor into the circulation. However,
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`compounds such as moxifloxacin that achieve high concentrations in the aqueous
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`humor upon topical administration can accumulate in other intraocular structures
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`(like the iris) and thereby continue to remain inside the eye despite the frequent
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`turnover of the aqueous humor. Compounds that achieve high concentrations in
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`the aqueous humor can continue to penetrate into the deeper structures of the eye,
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`including the lens, the vitreous humor, the retina, and the choroid. Compounds
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`transported out of the aqueous humor (by the turnover of the aqueous humor) enter
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`the bloodstream via blood vessels.
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`14
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`person of ordinary skill in 1998 could not predict whether a particular ophthalmic
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`formulation containing a particular compound would strike this balance; most
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`compounds do not penetrate the ocular surface well—a result that is not surprising,
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`given the numerous protective, heterogeneous layers that must be navigated in
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`order to do so.4
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`B. Ophthalmic Bacterial Infections in September 1998
`30. Despite this complex and efficient system that protects against the
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`penetration and accumulation of foreign compounds in the cornea and interior
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`ocular tissues, bacterial infections often are found, and must be treated, in these
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`tissues. These infections can arise as a result of an injury, abrasion (for example,
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`from contact lenses), or surgical incision in the ocular surface, which permit
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`bacteria to infect the cornea and intraocular tissues. Indeed, after cataract surgery
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`for example, it is virtually inevitable that certain pathogens present on the surface
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`of the eye, as well as pathogens introduced during the surgery will be present in the
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`4 For this reason, one alternative to topical treatment of interior ocular infections is
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`intravitreal injection, in which the formulation is introduced into the interior
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`vitreous humor by way of a needle. Needless to say, this is not an attractive
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`alternative, but one that may be employed if a topical formulation cannot penetrate
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`and accumulate at the site of infection at a sufficient concentration to kill the
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`bacteria.
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`15
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`aqueous humor and cornea. If not properly treated or prevented, certain pathogens
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`in the aqueous humor or cornea can cause serious infection in one of those areas or
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`migrate into areas even deeper into the eye and cause endophthalmitis (an infection
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`in or near the retina that causes inflammation of the inner coating of the eye and
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`can result in sight loss).
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`31.
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`Irrespective of whether these infections remain in the cornea or
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`aqueous humor or migrate internally into the eye and cause endophthalmitis, such
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`infections were considered at the priority date (and still are considered) the most
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`important infections for a topical ophthalmic antibiotic formulation to treat and
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`prevent. That is because infections on the surface of the eye (conjunctivitis) had
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`been treated successfully by existing therapies for decades, while infections in the
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`cornea and interior ocular tissues (for example, in the aqueous humor) were not
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`sufficiently treated and prevented by existing therapies. Ex. 2018 (Chaudhry
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`1998); Ex. 2019 (Chaudhry 1999); Ex. 2047 (Hwang 1997); Ex. 2049 (Forster
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`1998); Ex. 2055 (Goldstein 1999); Ex. 2056 (Baum 2000); Ex. 2061 (Garg 1999);
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`Ex. 2062 (Goldstein 1998); Ex. 2067 (Snyder 1992); Ex. 2068 (Knauf 1996); Ex.
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`2069 (Hodge 1995); Ex. 2070 (Maffett 1993); Ex. 2071 (Alexandrakis 2000); Ex.
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`2072 (Kunimoto 1999); Ex. 2073 (Hwang 2004); Ex. 2074 (Blondeau 2004); Ex.
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`2077 (Steinert 1991); Ex. 2080 (Javitt 1991); Ex. 2083 (Syed 1996); Ex. 2084
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`(Barza 1993); Ex. 2190 (Endophthalmitis Vitrectomy Study Group 1995); Ex.
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`16
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`2193 (Lohr 1988); Ex. 2196 (Montan 1998); Ex. 2198 (Olson 2004). Infections in
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`interior ocular tissues, if not adequately treated or prevented, can cause permanent
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`impairment of vision, complete loss of vision, and even loss of an eye. See Ex.
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`2081 (Donnenfeld 2005); Ex. 2077 (Steinert 1991); Ex. 2049 (Forster 1998).
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`Conjunctivitis, on the other hand, is considered a minor infection that is self-
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`limited (i.e., it typically resolves on its own without the need for any medication).
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`Ex. 2056 (Baum 2000); Ex. 2083 (Syed 1996); Ex. 2084 (Barza 1993). I
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`understand that this is not disputed by Apotex. Ex. 2045 (Barza Depo.) at 243:11-
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`16; Ex. 2044 (Fiscella Depo.) at 107:22-108:7. Compounds in use well before
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`1998, such as polymyxin-trimethoprim, were successfully treating surface
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`infections. See, e.g., Ex. 2193 (Lohr 1988); Ex. 2198 (Olson 2004) at S53 (“The
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`more common surface infections, such as conjunctivitis, fortunately do not often
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`lead to serious consequences and may even resolve on their own in the absence of
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`specific anti-microbial therapy.”); Ex. 2085 (Jensen 2006) at 1639 (“[B]acterial
`
`conjunctivitis can be effectively treated by a multitude of ophthalmic antibiotics.
`
`Fluoroquinolones are often considered excessive . . . .”)); Ex. 2050 (Fiscella 2007)
`
`at 2072 (“Bacterial conjunctivitis should be treated with a cost-effective, well-
`
`tolerated, broad-spectrum topical ophthalmic antibiotic, such as polymyxin-
`
`trimethoprim or polymyxin-bacitracin ointment.”). Thus, it was the treatment and
`
`prevention of bacterial infections beneath the surface of the eye that was the goal
`
`
`
`17
`
`
`
`
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`of a person of ordinary skill and the ability to treat surface infections such as
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`conjunctivitis would not have been sufficient for the person of ordinary skill to
`
`have been interested in pursuing an ophthalmic formulation containing a particular
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`compound. See, e.g., Ex. 2080 (Javitt 1991); Ex. 2190 (Endophthalmitis
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`Vitrectomy Study Group 2004); Ex. 2196 (Montan 1998); Ex. 2077 (Steinert
`
`1991).
`
`32. Though various species of pathogens may infect the cornea and
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`interior tissues of the eye, among the most important and sight-threatening is
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`Pseudomonas aeruginosa. Ex. 2063 (Fiscella 1993); Ex. 2053 (Eifrig 2003); Ex.
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`2054 (Alfonso 1986); Ex. 2055 (Goldstein 1999); Ex. 2061 (Garg 1999); Ex. 2071
`
`(Alexandrakis 2000). Pseudomonas aeruginosa is one of the common causes of
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`keratitis, it can cause rapid necrosis, and therefore Pseudomonal infections must be
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`treated quickly. See Ex. 2063 (Fiscella 1993) at 1585 (“Pseudomonas causes rapid
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`necrosis and . . . may cause corneal perforation within 1 to 2 days if not treated
`
`promptly.”); see also Ex. 2064 (Leibowitz 1991). As Dr. Barza correctly explained
`
`shortly after the priority date: “[t]he treatment of a putative P. aeruginosa keratitis
`
`has presented a clinical challenge since the beginning of the antibiotic era, and
`
`even before” and Pseudomonas is “an important pathogen” due to “its ability to
`
`rapidly destroy the corneal stroma and because of its increased prevalence since
`
`the introduction of soft contact lens wear in the 1970s.” Ex. 2056 (Baum 2000) at
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`
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`18
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`
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`663; see also Ex. 1027 (Brodovsky 1997). I understand that Apotex’s experts did
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`not dispute these points in their deposition testimony. Ex. 2044 (Fiscella Depo.) at
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`101; Ex. 2045 (Barza Depo.) at 202-205.
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`C. The State of the Art in the Treatment of Ophthalmic Infections in
`September 1998
`33. Generally, when a topical ophthalmic antibiotic formulation is
`
`administered, the pathogenic species to be treated or prevented is unknown. This
`
`is because waiting to determine a particular pathogen responsible for the infection
`
`before beginning treatment could prove catastrophic if the pathogen is a
`
`particularly virulent one; by the time its identity is known, irreparable damage to
`
`the eye may have already resulted. Ex. 2048 (Bower 1996); Ex. 2049 (Forster
`
`1998); Ex. 2086 (Masket 1998). This empirical approach to treatment applies to
`
`severe conditions such as keratitis, which are typically treated empirically at the
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`outset of the infection, and in some cases throughout the infection. Ex. 2050
`
`(Fiscella 2007). Accordingly, ocular infections are generally treated with
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`antibiotics with a broad spectrum of activity, in the hopes of covering all likely and
`
`important pathogens. A person of ordinary skill considering whether to pursue
`
`development of a topical ophthalmic formulation in September 1998 therefore
`
`would have been concerned with the formulation’s ability to treat and prevent
`
`infections in the cornea and intraocular tissues caused by all important ocular
`
`
`
`19
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`
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`pathogens, including those caused by Pseudomonas aeruginosa. See, e.g., Ex.
`
`2055 (Goldstein 1999); Ex. 2071 (Alexandrakis 2000).
`
`34. A topical ophthalmic formulation’s ability to treat and/or prevent
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`infection generally depends on two factors: (1) the activity of the active ingredient
`
`against the infective bacterial strain (often measured by its minimum inhibitory
`
`concentration) and (2) the amount of active ingredient present at the site of
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`infection.5 In addition, the formulation must not cause unacceptable toxicity in the
`
`course of treating or preventing the infection. The acceptability of a level of
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`toxicity depends on the benefit provided by the treatment and the risk to benefit
`
`ratio of other available options for treatment and prevention.
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`35. The state of the art products for the treatment and prevention of
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`bacterial infections in September 1998 were Ocuflox® and Ciloxan®, topical
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`ophthalmic formulations containing (respectively) ofloxacin and ciprofloxacin as
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`the active ingredient at concentrations of 0.3%.6 Ciprofloxacin is not very soluble
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`5 The amount of drug at the site of infection may be measured by various
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`pharmacokinetic parameters, including maximum concentration (Cmax), area of
`
`the compound under the curve (AUC), or simply the concentration of compound
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`present at various timepoints.
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`6 The other
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