`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`APOTEX INC.,
`
`Petitioner
`
`v.
`
`Patent of ALCON PHARMACEUTICALS LTD.,
`
`Patent Owner.
`
`Case IPR2013-00012
`
`U.S. Patent No. 6,716,830
`
`DECLARATION OF SOUMYAJIT MAJUMDAR, Ph.D.
`
`
`
`
`
`
`
`
`
`ALCON 2275
`Apotex Inc. v. Alcon Pharmaceuticals, Ltd.
`Case IPR2013-00012
`
`
`
`
`
`I.
`
`II.
`
`Table of Contents
`
`Overview .......................................................................................................... 1
`
`Background ...................................................................................................... 2
`
`IV. Person of Ordinary Skill in the Art .................................................................. 5
`
`V. Opinions ........................................................................................................... 6
`
`A.
`
`Summary of Opinions ................................................................. 6
`
`B. Ocular Pharmacokinetics of a Topical Ophthalmic
`Composition ................................................................................ 9
`
`C. Ocular Pharmacokinetics of Moxifloxacin ............................... 14
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`Precorneal Factor: Tear-Protein Binding ........................ 16
`
`Passive Transport through Corneal Layers..................... 19
`
`Lipophilicity ................................................................... 34
`
`Carrier Mediated Absorption .......................................... 46
`
`Transport Out of the Eye ................................................ 48
`
`Active Transport Out ...................................................... 49
`
`g. Melanin Binding ............................................................. 51
`
`D.
`
`Summary of Moxifloxacin’s Predicted Pharmacokinetic
`Properties .................................................................................. 53
`
`VI. The Ocular Pharmacokinetics of the Claimed Topical Ophthalmic
`Moxifloxacin Formulation Are Unexpected ................................................. 55
`
`
`
`i
`
`
`
`
`
`I, Soumyajit Majumdar, do declare as follows:
`
`I.
`
`Overview
`
`1.
`
` I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Alcon
`
`Pharmaceuticals Ltd. (“Alcon”) for the above-captioned inter partes review
`
`(“IPR”). I am being compensated for my time at my usual rate of $300 per hour.
`
`My compensation is in no way dependent on the outcome of this IPR.
`
`3.
`
`I understand that the Patent Trial and Appeal Board has granted
`
`Apotex’s petition to institute this IPR regarding claim 1 of United States Patent
`
`No. 6,716,830 (the “’830 patent”) on the ground that the claim is allegedly obvious
`
`over a combination of (i) United States Patent No. 5,607,942 (the “’942 patent”);
`
`(ii) Petersen, et al., “Synthesis and in Vitro Activity of BAY-12-8039, a New 8-
`
`Methoxy-Quinolone,” Abstracts of the 36th Interscience Conference on
`
`Antimicrobial Agents and Chemotherapy 100, American Society for Microbiology,
`
`New Orleans, LA, on Sept. 15-18, 1996 (the “Petersen Abstract”); and (iii)
`
`Physicians’ Desk Reference, p. 481, 50th ed. (the “Ocuflox® PDR”). I also
`
`understand that the Patent Trial and Appeal Board denied all other alleged grounds
`
`
`
`1
`
`
`
`
`
`of invalidity raised in Apotex’s petition with regard to this claim, and hence those
`
`grounds of invalidity are not at issue in this IPR.
`
`4.
`
`In formulating my opinions regarding the validity of claim 1 of the
`
`’830 patent, I have considered the materials cited herein, my training and
`
`experience, and the knowledge and information available to a person of ordinary
`
`skill in the art as of September 30, 1998. The list of documents I have considered
`
`in forming my opinions is Ex. 2281.
`
`5.
`
`As discussed in detail below, claim 1 of the ’830 patent would not
`
`have been obvious to the person of ordinary skill in the art as of September 30,
`
`1998. To the contrary, the person of ordinary skill in the art would have had no
`
`reasonable expectation of success in arriving at the claimed invention. Moreover,
`
`the topical ophthalmic moxifloxacin compositions of claim 1 of the ’830 patent
`
`demonstrate unexpectedly superior properties compared to the closest prior art.
`
`II. Background
`
`6.
`
`I am an expert in the area of drug delivery and disposition, in
`
`particular ocular drug delivery and disposition. I have over twelve years of
`
`experience, in addition to my graduate studies and research, in the fields of topical
`
`ophthalmic formulation, ocular penetration, drug delivery, and disposition. I have
`
`performed and become familiar with numerous experiments involving solubility,
`
`stability, and lipophilicity testing. My recent research activities have focused
`2
`
`
`
`
`
`
`
`primarily on the development of drug delivery methods to enhance ocular
`
`bioavailability of poorly permeating compounds. In this research, I focus on,
`
`among other things, biopharmaceutical and pharmacokinetic considerations, drug
`
`design, and novel drug delivery platforms. My CV is attached as Exhibit 2276.
`
`7.
`
`Based on my education, background, experience, and expertise, I am
`
`qualified to provide an opinion as to what a person of ordinary skill in the art
`
`would have understood, known or concluded as of September 30, 1998.
`
`8.
`
`I am currently an Associate Professor of Pharmaceutics at the
`
`University of Mississippi in Oxford, Mississippi. In addition to my position at the
`
`University of Mississippi, I am also a Research Associate Professor at the Research
`
`Institute of Pharmaceutical Sciences, and an Associate Director of the Pii Center
`
`for Pharmaceutical Technology at the University of Mississippi’s Department of
`
`Pharmaceutics. As Associate Director of the Pii Center for Pharmaceutical
`
`Technology, I help develop novel methods of drug delivery.
`
`9.
`
`I received a Ph.D. from the University of Missouri-Kansas City in
`
`Pharmaceutical Sciences and Pharmacology. Prior to receiving a Ph.D., I worked
`
`for Sandoz India Ltd. and Novartis Enterprises Pvt. Ltd., formulating drugs. In
`
`those roles, I formulated multiple topical ophthalmic formulations.
`
`10. Over the years, I have authored and co-authored 41 peer-reviewed
`
`articles, published in, among other journals: Current Eye Research, Molecular
`3
`
`
`
`
`
`
`
`Pharmaceutics, AAPS PharmSci, Clinical Research and Regulatory Affairs,
`
`International Journal of Pharmaceutics, Journal of Ocular Pharmacology and
`
`Therapeutics, Expert Opinion on Drug Delivery, Journal of Ocular Pharmacology
`
`and Therapeutics, Drug Development and Industrial Pharmacy, Pharmaceutical
`
`Research, Drug Metabolism and Disposition, Journal of Pharmaceutical Sciences,
`
`and The Journal of Pharmacy and Pharmacology. Many of these publications have
`
`dealt with the investigation of ocular pharmacokinetic properties of various drugs.
`
`I have authored two book chapters, both dealing with ocular drug delivery.
`
`11.
`
`In addition to writing and publishing numerous articles, I am also a
`
`reviewer (by invitation) for numerous journals, including: Current Eye Research,
`
`Expert Opinion on Drug Delivery, International Journal of Pharmaceutics, Journal
`
`of Ocular Pharmacology and Therapeutics, Journal of Pharmaceutical Sciences,
`
`and Molecular Pharmaceutics. In this role, I have reviewed manuscripts submitted
`
`by other scientists relating to ophthalmic pharmaceuticals and pharmacology. I
`
`also keep myself familiar with the latest research in the field of ophthalmic
`
`pharmaceuticals and pharmacology through attending and presenting at scientific
`
`conference and academic symposia, and reading scientific literature.
`
`12.
`
`I teach numerous university courses on pharmaceutical sciences,
`
`including Basic Pharmaceutics, Industrial Pharmacy, and Advanced
`
`Pharmacokinetics which covers Biopharmaceutics and Pharmacokinetics. As a
`4
`
`
`
`
`
`
`
`professor, I have also advised numerous graduate students, some of whom have
`
`received awards and fellowships on the basis of their research.
`
`13.
`
`I myself have received numerous awards and honors for my work as a
`
`researcher and a teacher. These awards include the University of Mississippi’s
`
`Pharmaceutical Sciences Teacher of the Year, and Faculty Research Fellowship
`
`Award, the American Association of Indian Pharmaceutical Scientists’ (“AAiPS”)
`
`Research Award, and the University of Missouri-Kansas City’s School of Graduate
`
`Studies Distinguished Dissertation Fellowship Award.
`
`III. Person of Ordinary Skill in the Art
`
`14.
`
`I understand that the person of ordinary skill in the art is a
`
`hypothetical person who may possess the combined skills of more than one actual
`
`person. I have formed an opinion as to the qualifications of the person of ordinary
`
`skill in the art to whom the invention of the ’830 patent, Ex. 1001, is directed, as is
`
`applicable to my opinions as expressed in this Declaration. In my opinion, the
`
`person of ordinary skill in the art would have expertise in the topical treatment and
`
`prevention of ophthalmic bacterial infections. In particular, as is relevant to my
`
`opinions, this expertise would include knowledge regarding ocular
`
`pharmacokinetics and delivery. While the person of ordinary skill in the art would
`
`also have relevant expertise in other areas relating to active and prophylactic
`
`treatment of ophthalmic bacterial infections, I have not been asked to address those
`5
`
`
`
`
`
`
`
`topics. I understand that those issues will be addressed by other experts in this
`
`IPR.
`
`15.
`
`I have also considered the definition of a person of ordinary skill in
`
`the art offered by Drs. Barza and Fiscella. If I were to apply that definition, it
`
`would not change my opinions as they are laid out in this Declaration.
`
`16.
`
`I have undertaken to determine the knowledge a person of ordinary
`
`skill in the art would have regarding ocular pharmacokinetics and delivery of
`
`fluoroquinolones, and moxifloxacin in particular, as of September 30, 1998 (the
`
`“priority date”). Counsel for Alcon has informed me that September 30, 1998 is
`
`the relevant date for making this determination. When I refer to a “person of
`
`ordinary skill in the art” in this Declaration, I am referring to a person of ordinary
`
`skill in the art as of that date.
`
`IV. Opinions
`
`A.
`
`17.
`
`Summary of Opinions
`
`I have considered literature publicly available as of the priority date
`
`that is relevant to my opinions, including literature concerning the ocular
`
`pharmacokinetics of topical ophthalmic formulations containing fluoroquinolones,
`
`the physiochemical properties of fluoroquinolones (including moxifloxacin), and
`
`other aspects of ocular pharmacokinetics, such as tear-protein binding, carrier-
`
`mediated absorption and elimination, carrier-mediated efflux, and melanin binding,
`6
`
`
`
`
`
`
`
`as well as my education, background, and experience.
`
`18.
`
`It is my opinion that, in assessing the potential efficacy of a topical
`
`ophthalmic composition containing moxifloxacin, a person of ordinary skill would
`
`not have expected the invention of claim 1 of the ’830 patent to exhibit ocular
`
`pharmacokinetic properties and achieve active ingredient tissue concentrations in
`
`relevant ocular tissues that are superior to topical ophthalmic formulations
`
`containing ofloxacin and ciprofloxacin. It is also my opinion that those
`
`formulations containing ofloxacin and ciprofloxacin were the closest prior art to
`
`the invention claimed in the ’830 patent. In particular, a person of ordinary skill in
`
`the prior art would know that ofloxacin was considered to have superior ocular
`
`penetration when compared to other relevant fluoroquinolones, like ciprofloxacin.
`
`Ex. 1016 at 904 (Donnenfeld et al., Penetration of Topically Applied
`
`Ciprofloxacin, Norfloxacin, and Ofloxacin into the Aqueous Humor, The J. of the
`
`Am. Academy of Ophthalmology, 101(5):902-05 (1994)). Thus, a person of
`
`ordinary skill in the art would compare moxifloxacin’s1 predicted pharmacokinetic
`
`
`1 For convenience and brevity throughout this report, I refer to moxifloxacin’s
`
`properties, but a person of ordinary skill in the art would have understood that they
`
`are properties of a topical ophthalmic formulation containing moxifloxacin.
`
`
`
`7
`
`
`
`
`
`properties to those of ofloxacin, as it was the prior state-of-the-art fluoroquinolone
`
`with regard to pharmacokinetic properties. Based upon the literature available as
`
`of September 30, 1998, the person of ordinary skill would not have been able to
`
`predict or reasonably expect the superior pharmacokinetic properties of the
`
`claimed invention. Instead, to the extent the person of ordinary skill in the art
`
`would have attempted to form any expectation regarding the ocular
`
`pharmacokinetic properties of the claimed invention, the person of ordinary skill in
`
`the art would have expected that those properties would likely have been inferior to
`
`those of ofloxacin and not significantly superior to ciprofloxacin ophthalmic
`
`formulations.
`
`19. These superior pharmacokinetic properties are features of the claimed
`
`invention of the ’830 patent. These properties are found after administration of
`
`moxifloxacin topical ophthalmic pharmaceutical composition, as is described in
`
`claim 1 of the ’830 patent.
`
`20. Contrary to the person of ordinary skill’s expectations, topical
`
`ophthalmic moxifloxacin has been shown to have superior ocular pharmacokinetic
`
`properties when compared to topical ophthalmic formulations of other
`
`fluoroquinolones, including ofloxacin and ciprofloxacin. The unexpectedly
`
`superior ocular pharmacokinetic properties of the claimed topical ophthalmic
`
`moxifloxacin compositions include enhanced penetration and retention in ocular
`8
`
`
`
`
`
`
`
`tissues.
`
`21. Finally, it is my opinion that a person of ordinary skill in the art would
`
`understand the limitation “pharmaceutically acceptable vehicle” (or
`
`“pharmaceutically acceptable vehicle therefor,” as the limitation is properly read)
`
`of the claim-at-issue to mean pharmaceutically acceptable excipient components of
`
`a composition comprising moxifloxacin suitable for topical application to
`
`ophthalmic tissue. I disagree that saline constitutes a pharmaceutically acceptable
`
`vehicle for an ophthalmic pharmaceutical composition containing moxifloxacin.
`
`B. Ocular Pharmacokinetics of a Topical Ophthalmic Composition
`
`22. The ocular pharmacokinetics of a topical ophthalmic composition
`
`refers to the ocular absorption, distribution, metabolism, and elimination of the
`
`active ingredient after the composition is administered. The ocular
`
`pharmacokinetics of a topical ophthalmic composition containing an active
`
`compound (or “active ingredient”), such as moxifloxacin, is based on a
`
`combination of factors that determines its penetration into and elimination from the
`
`ocular tissues. Along with its intrinsic potency, the therapeutic activity of the
`
`active ingredient is dependent on the duration and extent (how long and how
`
`much) of exposure to the active molecule at the site of infection. Exposure at the
`
`sites of infection, where the vision-threatening infections of keratitis and
`
`endophthalmitis occur, depends on the penetration of the active ingredient in a
`9
`
`
`
`
`
`
`
`topical ophthalmic formulation across the corneal layers and on the accumulation
`
`and retention at these sites without rapid diffusion out or removal from the target
`
`tissues.
`
`23. The eye contains numerous complex structures, and the ability of a
`
`formulation to deliver the drug to the site of infection is influenced by a number of
`
`factors, which interact in complicated ways. Because of this complexity, the
`
`effectiveness of a formulation cannot be predicted based on an assessment of only
`
`a few properties of the active ingredient of the formulation, such as the active
`
`ingredient’s aqueous solubility or lipophilicity.
`
`24. Ocular tissues are protected from exposure to substances from outside
`
`the eye by a variety of mechanisms that resists a substance’s penetration into the
`
`eye and expels foreign substances from the eye. These same mechanisms make it
`
`difficult for an active molecule to penetrate to the ocular tissues in sufficient
`
`concentrations and to maintain adequate concentrations at those ocular tissues to
`
`treat an infection. As is relevant to the ocular pharmacokinetics of a topical
`
`ophthalmic composition, the composition facilitates delivery of the active
`
`ingredient, such that the active ingredient reaches the anterior segment of the eye
`
`and is not expelled rapidly, so that sufficient concentrations are maintained in the
`
`ocular tissues.
`
`25.
`
`I review the factors that influence the drug delivery into the eye in
`10
`
`
`
`
`
`
`
`detail later in this Declaration. In brief, these factors include:
`
`i.
`
`Precorneal Factors: These are factors that influence the
`
`penetration of a formulation into the eye even before the
`
`formulation reaches the corneal surface and includes factors
`
`such as binding of the active ingredient to proteins in the tears,
`
`solubility in the tear film, tear flow and penetration across the
`
`tear film.
`
`ii.
`
`Passive Transport Through Corneal Layers. For an active
`
`molecule to permeate across the cornea it has to penetrate
`
`through each individual layer of the cornea. The three main
`
`layers of the cornea are the epithelium (the outermost layer), the
`
`stroma (the middle layer), and the endothelium (the innermost
`
`layer). While the corneal epithelium and endothelium are both
`
`lipophilic, the middle stroma layer is hydrophilic. Lipophilicity
`
`refers to the extent that a substance is soluble in lipids, while
`
`hydrophilicity refers to the extent a substance is soluble in
`
`water. The ability of a compound to passively diffuse (move
`
`from a region of higher concentration to a region of lower
`
`concentration) through the corneal layers is determined by
`
`factors such as its solubility, lipophilicity, and molecular
`11
`
`
`
`
`
`
`
`
`
`weight.
`
`iii. Carrier Mediated Absorption. Unlike passive diffusion or
`
`passive transport, carrier mediated absorption involves a carrier
`
`or transport system that can facilitate absorption of the active
`
`ingredient through the cornea. The carrier or transporter is a
`
`cellular protein that binds to the active ingredient and transports
`
`it through the corneal cell membranes. Carrier mediated
`
`absorption and passive diffusion processes occur in parallel and
`
`thus transcorneal permeation of an active ingredient involving
`
`both carrier mediated and passive diffusion mechanisms is
`
`greater than that involving passive diffusion alone. Carrier
`
`mediated absorption is not uniform across molecules. The
`
`binding of a molecule to the carrier protein and induction of a
`
`configurational change in the protein, so as to induce transport,
`
`depends on the chemical structure and configuration of the
`
`active and its binding affinity to the protein. Thus, carrier
`
`mediated transport may facilitate the absorption of different
`
`active ingredients into the eye at different rates.
`
`iv. Carrier Mediated Transport Out of the Eye. Carrier
`
`proteins can also act as efflux systems to remove molecules
`12
`
`
`
`
`
`from
`
`the
`
`eye,
`
`influencing
`
`a
`
`compound’s maximum
`
`concentration and duration of exposure (half-life) in the ocular
`
`tissues. Examples of transport systems that expel drug from the
`
`ocular tissues include organic anionic transporters and efflux
`
`pumps
`
`v.
`
`Passive Diffusion Out of the Eye. Like with passive diffusion
`
`into the eye, molecules also passively diffuse out of the eye
`
`(move from the ocular tissues into the lymphatics or systemic
`
`circulation),
`
`thus
`
`influencing a compound’s maximum
`
`concentration and half-life in the ocular tissues.
`
`vi. Binding to Iris and Ciliary Bodies. The iris and ciliary bodies
`
`consist of tissues inside the eye, to which compounds may be
`
`bound. When a molecule binds to the iris and ciliary bodies,
`
`the duration of the drug’s intraocular exposure is extended as
`
`the iris and ciliary bodies act as a slow release mechanism for
`
`the active ingredient thus slowing its elimination from the eye.
`
`26. Attached as Exhibits 2266 and 2267 are diagrams of the eye and the
`
`cornea. These diagrams are accurate illustrations that I have selected to
`
`demonstrate the anatomical arrangement of the ocular tissues. See also Ex. 1032
`
`(Remington’s) (containing illustrations of the eye’s anatomy).
`13
`
`
`
`
`
`
`
`C. Ocular Pharmacokinetics of Moxifloxacin
`
`27. As of September 30, 1998, there was no reported study on the ocular
`
`pharmacokinetics of a topical ophthalmic formulation of moxifloxacin. In such a
`
`circumstance, given the complexities and unpredictability in this field, a person of
`
`ordinary skill would not have known the ocular pharmacokinetics of an ophthalmic
`
`moxifloxacin formulation. Based on the limited data available as of this date, a
`
`person of ordinary skill in the art would also not have had a reasonable expectation
`
`that an ophthalmic moxifloxacin formulation would penetrate into and achieve
`
`higher concentrations in ocular tissues when compared to formulations of
`
`ciprofloxacin and ofloxacin.
`
`28. Because a person of ordinary skill in the art could not look to a study
`
`of topical ophthalmic moxifloxacin formulation’s pharmacokinetics, a person of
`
`ordinary skill in the art would consider other information to attempt to predict the
`
`properties of a topical ophthalmic moxifloxacin formulation. This is a difficult
`
`task, because a formulation’s pharmacokinetic properties depend on a number of
`
`factors that do not operate independently or predictably, and cannot be predicted
`
`either independently or in the aggregate. To the extent data were available, a
`
`person of ordinary skill in the art would predict that the pharmacokinetic
`
`characteristics of a moxifloxacin ophthalmic composition would not be
`
`significantly different from those containing ciprofloxacin or norfloxacin, and
`14
`
`
`
`
`
`
`
`would be inferior to those containing ofloxacin.
`
`29. We now know, however, that the pharmacokinetic properties of a
`
`topical ophthalmic composition of moxifloxacin are in fact superior to the prior art
`
`fluoroquinolone ophthalmic formulations. These superior pharmacokinetic
`
`properties of the claimed topical ophthalmic moxifloxacin compositions and the
`
`claimed methods of using such compositions would have been unexpected to the
`
`person of ordinary skill in the art.
`
`30.
`
`In the following section of this Declaration, I will review the various
`
`pharmacokinetic factors that determine whether an active ingredient, in this case
`
`moxifloxacin, will penetrate and be retained in the relevant ocular tissue upon
`
`topical ophthalmic administration. Each of the factors I discuss below is relevant
`
`to such a determination. Dr. Fiscella discounts some of these factors (such as tear-
`
`protein binding, passive transport, and the rate of diffusion and efflux out of
`
`relevant ocular tissues), saying instead that aqueous solubility and lipophilicity are
`
`the most influential. Ex. 1012 ¶¶ 32-33. The single source cited by Dr. Fiscella
`
`for this proposition, Donnenfeld, Ex. 1016, does not support his conclusion. While
`
`Donnenfeld stated that the lipophilicity and aqueous solubility of a drug influences
`
`its penetration into the aqueous humor, Donnenfeld does not discuss or compare
`
`the importance of other pharmacokinetic factors. While aqueous solubility and
`
`lipophilicity do influence a topical ophthalmic composition’s pharmacokinetic
`15
`
`
`
`
`
`
`
`properties, other factors are also important. As discussed below, a person of
`
`ordinary skill in the art would have considered all of the pertinent factors if
`
`attempting to predict the pharmacokinetic properties of topical moxifloxacin
`
`formulations.
`
`a.
`
`Precorneal Factor: Tear-Protein Binding
`
`31.
`
` Tear-protein binding is one factor a person of ordinary skill in the art
`
`would consider in evaluating topical ophthalmic moxifloxacin’s pharmacokinetic
`
`properties. When a topical ophthalmic formulation is placed on a person’s eye, the
`
`active ingredient is diluted in the tear film, where it can bind to tear-proteins.
`
`Because a topical ophthalmic formulation must first pass through the tear film
`
`before even reaching the cornea, tear-protein binding occurs before the active
`
`compound reaches the outermost layer of the cornea, the corneal epithelium. If the
`
`active ingredient binds to the protein in tears, less of the active ingredient will be
`
`available to penetrate the cornea, and therefore less active ingredient will
`
`ultimately reach the site of infection in the eye.
`
`32. The eye’s lacrimal fluid (commonly known as tears) has a protein
`
`content of approximately 0.7%. Ex. 2234 at 62-63 (Vincent H.L. Lee, “Precorneal,
`
`Corneal, and Postcorneal Factors” in Ophthalmic Drug Delivery Systems (Ashim
`
`K. Mitra ed. 1993)). Pathological conditions (i.e., diseases) that affect the eye can
`
`cause the protein content of lacrimal fluid to increase substantially. Id. at 63.
`16
`
`
`
`
`
`
`
`33. A person of ordinary skill in the art would know that fluoroquinolones
`
`bind to proteins in lacrimal fluid, and do so at varying rates. Albumin is one
`
`protein that is common to both blood serum and tear film. Ex. 2235 at 263 (J.U.
`
`Prause, Serum Albumin, Serum Antiproteases and Polymorphonuclear Leucocyte
`
`Neutral Collagenolytic Protease in the Tear Fluid of Normal Healthy Persons,
`
`Acta Opthalmologica, 61: 261-71 (1983)). Studies of the blood serum had shown
`
`that some fluoroquinolones bind to albumin. Thus, the person of ordinary skill in
`
`the art would expect that there would be protein binding in the tear film, as the tear
`
`film contains the same protein, albumin, as the blood serum. To the extent a drug
`
`binds to the albumin in tears, there is a reduced amount of the free drug to
`
`penetrate into the eye and exert the desired pharmacological effect. As of
`
`September 30, 1998, a person of ordinary skill in the art would have known that
`
`fluoroquinolones bind to albumin, and that the extent of albumin binding varied
`
`among fluoroquinolones, with more lipophilic fluoroquinolones binding to the
`
`protein present in tears to a greater extent than less lipophilic fluoroquinolones.
`
`Ex. 2236 at 505 (Eiichi Okezaki et al., Serum Protein Binding of Lomefloxacin, a
`
`New Antimicrobial Agent, and Its Related Quinolones, J. of Pharm. Sci., 78(6):
`
`504-07 (1989)); Ex. 2237 at 1421 (Weiguo Liu et al., Pharmacokinetics of
`
`Sparfloxacin in the Serum and Vitreous Humor of Rabbits: Physicochemical
`
`Properties that Regulate Penetration of Quinolone Antimicrobials, Anti. Agents &
`17
`
`
`
`
`
`
`
`Chem., 42(6):1417-23 (1998)); see also Ex. 2234 at 63 (Lee) (protein content
`
`increases in certain conditions that affect the eye). For reasons I explain more fully
`
`below, a person of ordinary skill in the art could not have assessed or formed a
`
`reasonable expectation regarding the relative lipophilicity of moxifloxacin
`
`compared to other fluoroquinolones. Accordingly, a person of ordinary skill in the
`
`art could not have predicted or formed a reasonable expectation regarding the
`
`extent of binding to tear film protein that would occur upon topical ophthalmic
`
`administration of moxifloxacin. However, if a person of ordinary skill had
`
`expected that moxifloxacin’s lipophilicity is greater than the lipophilicity of other
`
`fluoroquinolones (as Dr. Fiscella erroneously asserts), then the person of ordinary
`
`skill in the art also would have expected that the rate of tear-protein binding for
`
`moxifloxacin would be greater than that of other fluoroquinolones, leaving less
`
`moxifloxacin available to penetrate into the eye.
`
`34.
`
`In his deposition, Dr. Fiscella asserted that fluoroquinolones generally
`
`do not bind to tear protein. Ex. 2044 (Fiscella Deposition (5/13/2013) Tr. 219-21).
`
`Dr. Fiscella’s conclusion is not supported by any prior art. Instead, a person of
`
`ordinary skill in the art would have considered the literature which showed that
`
`fluoroquinolones did bind to protein present in tear film. In a study by Okezaki et
`
`al., the researchers performed an experiment to determine the extent of serum
`
`protein binding of ofloxacin, norfloxacin, and lomefloxacin and determined that
`18
`
`
`
`
`
`
`
`those fluoroquinolones did bind to albumin, a protein present in tear film. Ex.
`
`2236 at 505. A person of ordinary skill in the art would consider the amount of
`
`tear protein binding a relevant factor, because it decreases the amount of active
`
`ingredient available for transport through the corneal layers, and ultimately
`
`available to treat infections at the relevant ocular tissues.
`
`b.
`
`Passive Transport through Corneal Layers
`
`35. A person of ordinary skill in the art would also evaluate the
`
`characteristics of moxifloxacin that would influence its ability to pass through the
`
`corneal layers. Many factors influence whether a formulation can passively
`
`transport through the corneal layers, including solubility, lipophilicity, and the
`
`molecular weight of the active ingredient.
`
`36. A person of ordinary skill in the art would have evaluated each of the
`
`factors that would influence moxifloxacin’s passive transport through the corneal
`
`layers. As to moxifloxacin’s solubility, a person of ordinary skill in the art would
`
`not have known moxifloxacin’s aqueous solubility at a physiologically relevant pH
`
`based on the data available as of September 30, 1998. As to moxifloxacin’s
`
`lipophilicity, a person of ordinary skill in the art would have had difficulty
`
`comparing moxifloxacin’s lipophilicity to those of other fluoroquinolones due to a
`
`lack of data to which it could be meaningfully compared. To the extent a person of
`
`ordinary skill predicted moxifloxacin’s lipophilicity based on the available data, he
`19
`
`
`
`
`
`
`
`or she would predict that moxifloxacin is less lipophilic, or at best equally
`
`lipophilic, when compared to ofloxacin. Because a person of ordinary skill in the
`
`art would have difficulty determining moxifloxacin’s aqueous solubility and
`
`lipophilicity as of September 30, 1998, a person of ordinary skill in the art would
`
`not have expected that topical ophthalmic moxifloxacin would display superior
`
`ocular pharmacokinetic properties when compared to prior art ophthalmic
`
`formulations.
`
`37. As to molecular weight, a person of ordinary skill in the art would
`
`have known that moxifloxacin’s molecular weight was higher than other relevant
`
`fluoroquinolones. Generally, the higher a compound’s molecular weight, the lower
`
`its corneal penetration. Thus, to the extent that molecular weight exerted an effect
`
`on moxifloxacin’s transport through the corneal layers, a person of ordinary skill in
`
`the art would conclude that moxifloxacin’s penetration into the cornea should be
`
`lower than other fluoroquinolones.
`
`i. Solubility
`
`38. High aqueous solubility allows a high percentage of the active
`
`ingredient to dissolve in the solution, which allows formulators to create a
`
`pharmaceutical composition containing a higher concentration of the active
`
`ingredient. The eye is at physiological pH, and a solution, once applied to the eye,
`
`quickly reaches physiological pH. Thus, the relevant pH to evaluate an active
`20
`
`
`
`
`
`
`
`ingredient’s solubility is physiological pH. Physiological pH is 7.4, which is close
`
`to neutral pH of 7.0. If an active ingredient has high solubility at physiological pH,
`
`less of the active ingredient will precipitate out of the composition upon
`
`application and more of the active ingredient will remain in solution in the tear
`
`film. Thus, the higher the solubility of an active ingredient at physiological pH,
`
`the more active ingredient will be available for penetration into the eye.
`
`39. Dr. Fiscella stated in his Declaration that a person of ordinary skill in
`
`the art would have known that the “aqueous solubility of moxifloxacin at 25ºC at
`
`neutral pH is reported to be 24 mg/ml.” Ex. 1012 ¶ 30; see also id. (“This aqueous
`
`solubility of moxifloxacin at neutral pH exceeds the solubility of ofloxacin at
`
`neutral pH, the most soluble fluoroquinolone known prior to moxifloxacin, by
`
`about 8-fol
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
