CONFIDENTIAL – SUBJECT TO DISCOVERY CONFIDENTIALITY ORDER
`
`UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`______________________________________
`SENJU PHARMACEUTICAL CO., LTD.,
`BAUSCH & LOMB INCORPORATED, and
`BAUSCH & LOMB PHARMA HOLDINGS
`CORP.,
`
`Plaintiffs,
`
`v.
`
`LUPIN, LTD. and LUPIN
`PHARMACEUTICALS, INC.,
`
`Defendants.
`
`INNOPHARMA LICENSING, INC.,
`INNOPHARMA LICENSING, LLC,
`INNOPHARMA, INC., INNOPHARMA,
`LLC,
`
`Defendants.
`______________________________________
`
`
`
`C.A. No.: 1:14-cv-00667-JBS-KMW
`C.A. No.: 1:14:cv-04149-JBS-KMW
`C.A. No.: 1:14-cv-05144-JBS-KMW
`C.A. No.: 1:15-cv-00335-JBS-KMW
`
`C.A. No.: 1:14-cv-06893-JBS-KMW
`C.A. No.: 1:15-cv-03240-JBS-KMW
`
`
`
` ))))))))))))))))))
`
`
`
`OPENING EXPERT REPORT OF
`M. JAYNE LAWRENCE, PH.D.
`
`
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`Page 1 of 270
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`SENJU EXHIBIT 2253
`LUPIN v. SENJU
`IPR2015-01100
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`CONFIDENTIAL – SUBJECT TO DISCOVERY CONFIDENTIALITY ORDER
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`TABLE OF CONTENTS
`
`I.
`QUALIFICATIONS ........................................................................................................ 1
`II.
`COMPENSATION AND PRIOR TESTIMONY ............................................................ 4
`III.
`MATERIALS CONSIDERED ........................................................................................ 4
`IV.
`THE PERSON OF ORDINARY SKILL IN THE ART .................................................. 4
`V.
`THE ASSERTED PATENT CLAIMS ............................................................................ 5
`A.
`The Asserted Claims of the ’431 Patent .......................................................................... 5
`B.
`The Asserted claims of the ’290 Patent ........................................................................... 6
`C.
`The Asserted Claims of the ’131 Patent .......................................................................... 8
`D.
`The Asserted Claims of the ’813 Patent ........................................................................ 10
`E.
`The Asserted Claims of the ’606 Patent ........................................................................ 12
`VI.
`CLAIM CONSTRUCTION ........................................................................................... 14
`VII.
`BACKGROUND ON OPHTHALMIC FORMULATIONS CONTAINING NON-
`STEROIDAL ANTI-INFLAMMATORY DRUGS ..................................................................... 15
`A.
`Non-Steroidal Anti-Inflammatory Drugs Were Widely Used for Ophthalmic Indications
`Prior to 2003 .............................................................................................................................. 16
`B.
`Benzalkonium Chloride was One of the Most Commonly Used Preservative in
`Ophthalmic Formulations as of 2003 ........................................................................................ 19
`C.
`Surfactants Were Known to Prevent the Formation of Insoluble Complexes Between
`NSAIDs and Benzalkonium Chloride ....................................................................................... 20
`VIII. DETAILED DESCRIPTION OF THE PRIOR ART .................................................... 22
`A.
`U.S. Patent No. 4,910,225.............................................................................................. 22
`B.
`EP 0 306 984 A1 ............................................................................................................ 23
`C.
`Schott ............................................................................................................................. 26
`D.
`U.S. Patent No. 5,603,929.............................................................................................. 26
`E.
`U.S. Patent No. 5,891,913.............................................................................................. 27
`IX.
`LEGAL STANDARDS ................................................................................................. 28
`A.
`Legal Standards for Obviousness................................................................................... 28
`B.
`Legal Standard for Anticipation ..................................................................................... 30
`C.
`Legal Standard for Obviousness-Type Double Patenting .............................................. 30
`D.
`Legal Standard for Written Description ......................................................................... 31
`E.
`Legal Standard for Indefiniteness .................................................................................. 31
`F.
`Legal Standard for Improper Dependency ..................................................................... 32
`X.
`ANALYSIS OF THE ASSERTED CLAIMS ............................................................... 32
`A.
`U.S. Patent No. 8,129,431............................................................................................. 32
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`1. The Asserted Claims of the ’431 Patent are Obvious in Light of the ’225 Patent and
`either EP ’984 or the ’913 Patent ................................................................................... 32
`2. The Asserted Claims of the ’431 Patent are Obvious In Light of the ’913 Patent and The
`’225 Patent ..................................................................................................................... 44
`B.
`U.S. Patent No. 8,669,290.............................................................................................. 51
`1. The Asserted Claims of the ’290 Patent are Obvious in Light of the ’225 Patent and
`Either EP ’984 or the ’913 Patent .................................................................................. 51
`2. The Asserted Claims of the ’290 Patent are Obvious in Light of the ’913 Patent and The
`’225 Patent ..................................................................................................................... 72
`3. Asserted Claims 1-3, 8-10, 14-16, 20-22, and 26-30 of the ’290 Patent are Anticipated
`by the ’929 Patent .......................................................................................................... 84
`4. The Asserted Claims of the ’290 Patent are Obvious in Light of the ’929 Patent ......... 86
`C.
`U.S. Patent No. 8,754,131.............................................................................................. 89
`1. The Asserted Claims of the ’131 Patent are Obvious in Light of the ’225 Patent and
`Either EP ’984 or’913 Patent ......................................................................................... 89
`2. The Asserted Claims of the ’131 Patent are Obvious in Light of the ’913 Patent and The
`’225 Patent ................................................................................................................... 109
`3. Asserted Claims 1-3, 7-9, 13-15, 19-21, 25-30 of the ’131 Patent are Anticipated by the
`’929 Patent ................................................................................................................... 122
`4. The Asserted Claims of the ’131 Patent are Obvious in Light of the ’929 Patent ....... 124
`D.
`U.S. Patent No. 8,871,813............................................................................................ 128
`1. The Asserted Claims of the ’813 Patent are Obvious in Light of the ’225 Patent and
`Either EP ’984 or the ’913 Patent ................................................................................ 128
`2. The Asserted Claims of the ’813 Patent are Obvious in Light of the ’913 Patent and The
`’225 Patent ................................................................................................................... 141
`3. The Asserted Claims of the ’813 Patent are Obvious in Light of the ’929 Patent ....... 151
`E.
`U.S. Patent No. 8,927,606............................................................................................ 154
`1. The Asserted Claims of the ‘606 Patent are Obvious in Light of the ’225 Patent and
`Either EP ’984 or the ’913 Patent ................................................................................ 154
`2. The Asserted Claims of the ’606 Patent are Obvious in Light of the ’913 Patent and The
`’225 Patent ................................................................................................................... 174
`3. Asserted Claims 1-4, 11-14, 17, 19-22, 26, 28-30 of the ’606 Patent are Anticipated by
`the ’929 Patent ............................................................................................................. 189
`4. The Asserted Claims of the ’606 Patent are Obvious In Light of the ’929 Patent ....... 190
`F.
`The Asserted Claims of the ’431 Patent Are Not Patentably Distinct From the ’290
`Patent, the ’131 Patent, or the ’544 Patent .............................................................................. 194
`1. The Asserted Claims of the ’431 Patent are Not Patentably Distinct From the ’290
`Patent............................................................................................................................ 194
`
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`2. The Asserted Claims of the ’431 Patent are Not Patentably Distinct from Claims of the
`’131 Patent ................................................................................................................... 198
`3. The Asserted Claims of the ’431 Patent are Not Patentably Distinct From Claims of the
`’544 Patent ................................................................................................................... 202
`G.
`The Asserted Claims of the ’290 Patent Are Not Patentably Distinct From Claims of the
`’131 Patent ............................................................................................................................... 208
`H.
`Objective Indicia of Nonobviousness .......................................................................... 210
`1. No Unexpected Results ................................................................................................ 211
`2. Other Objective Indicia ................................................................................................ 216
`I.
`Documents Produced by Plaintiffs Are Consistent With My Opinions Regarding
`Obviousness ............................................................................................................................ 218
`J.
`All of the Asserted Claims of the ’290, ’131, ’813, and ’606 Patents Are Indefinite . 220
`K.
`Asserted Claims 18-20 of the ’431 Patent Do Not Meet the Written Description
`Requirement ............................................................................................................................ 227
`L.
`Asserted Claims 6 and 18 of the ’131 Patent Do Not Incorporate All of The Limitations
`of the Claims from Which They Depend ................................................................................ 227
`M. Asserted Claim 9 of the ’606 Patent Does Not Incorporate All of The Limitations of the
`Claim from Which It Depends ................................................................................................ 228
`XI.
`MISCELLANEOUS .................................................................................................... 229
`
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`I, Jayne Lawrence, Ph.D., have been asked to render opinions regarding U.S. Patent
`
`8,129,431 (“the ’431 patent”), U.S. Patent 8,669,290 (“the ’290 patent”), U.S. Patent 8,754,131
`
`(“the ’131 patent”), U.S. Patent 8,871,813 (“the ’813 patent”) and U.S. Patent 8,927,606 (“the
`
`’606 patent”) (collectively, “the patents-in-suit”). I hereby submit the following Expert Report
`
`on behalf of Defendants Lupin Limited, Lupin Pharmaceuticals, Inc., InnoPharma Licensing,
`
`Inc., InnoPharma Licensing, LLC, InnoPharma, Inc., and InnoPharma, LLC.
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am an expert in the field of formulation and drug delivery, specifically
`
`pharmaceutical formulation for oral and parenteral use (i.e., non-oral, including intravenous,
`
`intramuscular, nasal, respiratory and ophthalmic), including aqueous liquid preparations. I
`
`have been an expert in this field since prior to 2003.
`
`2.
`
`I received a B.Sc. with first class (top) honors from Liverpool Polytechnic in
`
`1981, and a Ph.D. in Pharmacy from Manchester University in 1985. The subject of my Ph.D.
`
`studies was the design, synthesis and physico-chemical characterization of novel non-ionic
`
`surfactants for use in aqueous pharmaceutical formulations. I performed my Ph.D. studies
`
`under the supervision of Professors P.H. Elworthy and D. Attwood.
`
`3.
`
`From 1984 to the present time I have held full-time, tenured academic positions
`
`of increasing seniority in Pharmacy (Lecturer 1984-1997, Senior Lecturer 1997-1999), Drug
`
`Delivery (Reader 2000-2003) and, most recently Biophysical Pharmaceutics (Professor 2003-
`
`to date) at King’s College London. I note that my professorship at King’s College London is
`
`the United Kingdom equivalent of a full, tenured Professorship in a university in the United
`
`States. In 1993 I spent a 6 month sabbatical working in Respiratory Product Development in
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`
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`Glaxo Group Research (now GSK) concerned with the potential use of surfactants in the new
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`propellant formulations.
`
`4.
`
`I am currently Head of the Pharmaceutical Biophysics Group of The Institute of
`
`Pharmaceutical Science, King’s College London, and I have held this position since 2002. The
`
`Pharmaceutical Biophysics Group of The Institute of Pharmaceutical Science, King’s College
`
`London currently consists of 6 academics and associated post-doctoral fellows and Ph.D.
`
`students. The work of the group is concerned with securing an understanding at the molecular
`
`level of the physicochemical and biological properties of drug and gene delivery systems,
`
`through the combined application of advanced analytical techniques.
`
`5.
`
`Since 2007, I have also held the role of Chief Scientist at the Royal
`
`Pharmaceutical Society on a part-time secondment from King’s College London. At the
`
`present time, I equally divide my time between these two roles. My role at the Royal
`
`Pharmaceutical Society involves my representing it at the highest levels to outside
`
`organisations and key stakeholders (including government and public bodies), acting as its
`
`spokesperson on pharmaceutical sciences in the media and ensuring high quality
`
`pharmaceutical science input to policy development and implementation.
`
`6.
`
`My past and current research has been in relation to pharmaceutical formulation
`
`and drug/gene delivery. I have been a principal or co-investigator on many formulation and
`
`drug/gene delivery studies, recent examples of which include the development of novel
`
`microemulsions for parenteral delivery, including for ocular administration; synthesis and
`
`characterisation of novel, non-ionic and zwitterionic surfactants with enhanced drug
`
`solubilisation capacity; the development of novel polymeric surfactants for pulmonary
`
`
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`delivery; nanoparticles for the targeted delivery of therapeutic agents to the brain; and
`
`development of new injectable composites for gene delivery.
`
`7.
`
`I have co-authored over 120 full scientific publications, with numerous
`
`conference papers and other scientific outputs such as articles for the scientific magazines. I
`
`have given over 150 invited (national and international) presentations. I have also been
`
`involved in the organisation of many pharmaceutical science meetings and conferences
`
`including the annual Academy of Pharmaceutical Sciences conference.
`
`8.
`
`As listed in my curriculum vitae, I have also received numerous awards
`
`pertaining to my research and teaching. For example, in 2013 I became a Faculty Fellow of the
`
`Royal Pharmaceutical Society (“FFRPS”), while in 2012 I was awarded an Eminent
`
`Fellowship of the Royal Pharmaceutical Society (“EFAPS”), one of only about 25 such
`
`Fellowships.
`
`9.
`
`I currently hold senior positions in a number of national and international
`
`scientific committees. For example, I am currently chair of the Formulation and
`
`Pharmaceutical Technology Special Interest Group of the International Pharmaceutical
`
`Federation and vice-chair of the Academy of Pharmaceutical Sciences of Great Britain.
`
`10.
`
`In addition to gaining expertise through educational training, professional
`
`experiences, and research experiences described above, I have kept abreast of the field of
`
`drug/gene delivery and formulation, particularly of aqueous liquid preparations by reading
`
`scientific literature, attending or presenting at scientific conferences, and attending or
`
`presenting at academic symposia. I have also been invited to participate in the peer review
`
`process for various scientific journals, and have reviewed many manuscripts submitted by
`
`other scientists relating to drug delivery, including ocular delivery. Some of the scientific
`
`
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`journals for which I have reviewed scientific manuscripts include: International Journal of
`
`Pharmaceutics, Journal of Pharmaceutical Science, Langmuir, and Biochimica Biophysica
`
`Acta. Furthermore, I have collaborated with, or have communicated with, many researchers in
`
`the field of formulation and drug/gene delivery. Accordingly, I am an expert in the field of
`
`formulation and drug/gene delivery.
`
`11.
`
`In formulating my opinions, I have relied upon my training, knowledge, and
`
`experience in the relevant art. A copy of my current curriculum vitae is provided as Exhibit A,
`
`and it provides a comprehensive description of my academic and employment history.
`
`II.
`
`COMPENSATION AND PRIOR TESTIMONY
`
`12.
`
`I am being compensated for my time spent working on this case at a rate of
`
`GBP300 per hour. My compensation is not at all dependent on the substance of my opinions
`
`or testimony, or on the outcome of this case.
`
`13.
`
`I have not testified in any case in the last four years.
`
`III. MATERIALS CONSIDERED
`
`14.
`
`Attached as Exhibit B is a list of the materials that I considered in forming my
`
`opinions in this report.
`
`IV.
`
`THE PERSON OF ORDINARY SKILL IN THE ART
`
`15.
`
`I have been informed that the relevant time period in which the skilled person
`
`would have analyzed the prior art in this case is up until January 21, 2003.
`
`16.
`
`I provided an opinion as to the person of ordinary skill in the art (“POSA”) in
`
`the August 10, 2015 Declaration of Jayne Lawrence, Ph.D. In Support of Defendants’ Opening
`
`Claim Construction Brief.
`
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`17.
`
`As of January 2003, a person of ordinary skill in the art to which the patents-in-
`
`suit pertain would have been a pharmaceutical scientist involved in the research and
`
`development of pharmaceuticals, and would have a Ph.D. and several years of experience in
`
`the field. The amount of post-graduate level experience would depend upon the level of formal
`
`education and particular experience in the field.
`
`18.
`
`Pharmaceutical scientists involved in the research and development of
`
`pharmaceuticals in the relevant time period were typically involved in the selection of
`
`ingredients, and the amounts of those ingredients, to be included in a pharmaceutical
`
`formulation. Such selections were generally made through routine optimization, whereby the
`
`pharmaceutical scientist would prepare a number of test formulations having different
`
`ingredients, and/or amounts of those ingredients. The pharmaceutical scientist would then
`
`compare certain properties or attributes of those formulations in order to select the optimal
`
`formulation for further development.
`
`V.
`
`THE ASSERTED PATENT CLAIMS
`
`A.
`
`19.
`
`The Asserted Claims of the ’431 Patent
`
`It is my understanding that Plaintiffs claim that Defendants’ drug products for
`
`which they have filed for approval with the FDA will each infringe one or more of claims 1-4,
`
`6-10, and 18-20 of the ’431 patent. The claims of the ’431 patent are directed to aqueous
`
`liquid preparations consisting essentially of 2-amino-3-(4-bromobenzoyl) phenylacetic acid
`
`(“bromfenac”) or a pharmacologically acceptable salt thereof or a hydrate thereof; and
`
`tyloxapol, and when a quaternary ammonium compound is included, the compound is
`
`benzalkonium chloride.
`
`
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`20.
`
`Claims 1 and 18 are independent. Independent claim 1 of the ’431 patent is
`
`reproduced below:
`
`1. An aqueous liquid preparation consisting essentially of the following two components,
`wherein the first component is 2-amino-3-(4-bromobenzoyl)phenylaceticacid or a
`pharmacologically acceptable salt thereof or a hydrate thereof, wherein the hydrate is at least
`one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate and the second component is
`tyloxapol, wherein said liquid preparation is formulated for ophthalmic administration, and
`wherein when a quaternary ammonium compound is included in said liquid preparation, the
`quaternary ammonium compound is benzalkonium chloride.
`
`
`21.
`
`Claims 2-4 and 6-10 depend either directly or indirectly from claim 1 and add
`
`further limitations requiring that the bromfenac is in its salt form, specific concentrations of
`
`tyloxapol and bromfenac, additional excipients, including benzalkonium chloride, and/or a
`
`specific pH range.
`
`22.
`
`Independent claim 18 is reproduced below:
`
`18. An aqueous liquid preparation consisting essentially of: (a) 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`thereof, wherein the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and 3/2
`hydrate, (b) tyloxapol, (c) boric acid, (d) sodium tetraborate, (e) EDTA sodium salt, (f)
`benzalkonium chloride, (g) polyvinylpyrrolidone, (h) sodium sulfite, wherein said liquid
`preparation is formulated for ophthalmic administration, and wherein benzalkonium chloride
`is the only quaternary ammonium compound which is included in said liquid preparation.
`
`
`23.
`
`Claims 19 and 20 depend either directly or indirectly from claim 18 and add
`
`further limitations requiring that the bromfenac is in its salt form, and recite specific
`
`concentrations of bromfenac and tyloxapol.
`
`B.
`
`The Asserted claims of the ’290 Patent
`
`24.
`
` It is my understanding that Plaintiffs claim that Defendants’ drug products for
`
`which they have filed for approval with the FDA will each infringe one or more of claims 1-4
`
`and 6-30 of the ’290 patent. The claims of the ’290 patent are directed to stable aqueous liquid
`
`preparations comprising two components: 2-amino-3-(4-bromobenzoyl) phenylacetic acid
`
`
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`(“bromfenac”) or a pharmacologically acceptable salt thereof or a hydrate thereof; and
`
`tyloxapol.
`
`25.
`
`Claims 1, 8, and 14 are independent . Independent claim 1 of the ’290 patent is
`
`reproduced below.
`
`1. A stable aqueous liquid preparation comprising: (a) a first component; and (b) a second
`component; wherein the first component is 2-amino-3-(4-bromobenzoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a hydrate thereof, wherein the
`hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first
`component is the sole pharmaceutical active ingredient contained in the preparation; the
`second component is tyloxapol and is present in said liquid preparation in an amount
`sufficient to stabilize said first component; and wherein said stable liquid preparation is
`formulated for ophthalmic administration.
`
`
`
`26.
`
`Claims 2-4, 6-7 and 26 depend either directly or indirectly from Claim 1.
`
`Claims 2-4 and 6-7 recite the addition of a quaternary ammonium salt, require that the
`
`bromfenac is in its salt form, concentrations of tyloxapol and/or bromfenac or its sodium salt,
`
`the pH of the preparations, and additional additives. Claim 26 recites a preservative efficacy
`
`standard.
`
`27.
`
`Independent claim 8 is reproduced below:
`
`
`
`
`
`8. A stable aqueous liquid preparation comprising: (a) a first component; and (b) a second
`component; wherein the first component is 2-amino-3-(4-bromobenzoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a hydrate thereof, wherein the
`hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate the first
`component is the sole pharmaceutical active ingredient contained in the preparation; the
`second component is tyloxapol; wherein said stable liquid preparation is formulated for
`ophthalmic administration; and wherein the stable aqueous liquid preparation is
`characterized in that greater than about 90% of the original amount of the first component
`remains in the preparation after storage at about 60°C for 4 weeks.
`
`28.
`
`Claims 9-13 and 27 depend directly or indirectly from claim 8. Claims 9 and 11-
`
`13 recite the addition of a quaternary ammonium salt, concentrations of tyloxapol and/or
`
`
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`bromfenac or its sodium salt, the pH of the preparations, and additional additives. Claim 10
`
`recites an aqueous formulation of claim 8 in which greater than 92% of the original amount of
`
`bromfenac remains in the preparation after 60°C for 4 weeks. Claim 27 recites a preservative
`
`efficacy standard.
`
`Independent claim 14 is reproduced below:
`
`29.
`
`14. A stable aqueous liquid preparation comprising: (a) a first component; and (b) a
`second component; wherein the first component is 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a
`hydrate thereof, wherein the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate,
`and 3/2 hydrate; the first component is the sole pharmaceutical active ingredient
`contained in the preparation; the second component is tyloxapol; wherein said stable
`liquid preparation is formulated for ophthalmic administration; provided that the liquid
`preparation does not include mannitol.
`
`
`
`30.
`
`Claims 15-25 and 28-30 depend directly or indirectly from claim 14. Claims 15-
`
`19, 21, and 23-25 recite the addition of a quaternary ammonium salt, concentrations of
`
`tyloxapol and/or bromfenac or its sodium salt, the pH of the preparations, and additional
`
`additives. Claims 20 and 22 recite a preparation wherein greater than about 90% and 92%,
`
`respectively, of bromfenac remains in the preparation after storage at about 60°C for 4 weeks.
`
`Claims 28-30 recite a preservative efficacy standard.
`
`C.
`
`The Asserted Claims of the ’131 Patent
`
`31.
`
`It is my understanding that Plaintiffs claim that Defendants’ drug products for
`
`which they have filed for approval with the FDA will each infringe one or more of claims 1-30
`
`of the ’131 patent. The claims of the ’131 patent are directed to stable aqueous liquid
`
`preparations comprising two components: 2-amino-3-(4-bromobenzoyl) phenylacetic acid
`
`(“bromfenac”) or a pharmacologically acceptable salt thereof or a hydrate thereof; and
`
`tyloxapol.
`
`
`
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`32.
`
`Claims 1, 7, and 13 are independent. Independent claim 1 of the ’131 patent is
`
`reproduced below.
`
`1. A stable aqueous liquid preparation comprising: (a) a first component; and (b) a second
`component; wherein the first component is 2-amino-3-(4-bromobenzoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a hydrate thereof; wherein the
`hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first
`component is the sole pharmaceutical active ingredient contained in the preparation and
`is present in the preparation at a concentration from about 0.05 w/v % to about 0.2 w/v
`%; the second component is tyloxapol and is present in said liquid preparation in an
`amount sufficient to stabilize said first component; and wherein said stable liquid
`preparation is formulated for ophthalmic administration.
`
`
`Claims 2-6, 25, 26, and 30 depend either directly or indirectly from Claim 1.
`
`33.
`
`Claims 2-6 recite the addition of a quaternary ammonium salt, concentrations of tyloxapol
`
`and/or bromfenac or its sodium salt, the pH of the preparations, and additional additives.
`
`Claims 25 and 26 recite a preservative efficacy standard. Claim 30 recites the addition of one
`
`or more additives.
`
`34.
`
`Independent claim 7 is reproduced below:
`
`7. A stable aqueous liquid preparation comprising: (a) a first component; and (b) a second
`component; wherein the first component is 2-amino-3-(4-bromobenzoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a hydrate thereof; wherein the
`hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first
`component is the sole pharmaceutical active ingredient contained in the preparation and
`is present in the preparation at a concentration from about 0.05 w/v % to about 0.2 w/v
`%; the second component is tyloxapol; wherein said stable liquid preparation is
`formulated for ophthalmic administration; and wherein the stable aqueous liquid
`preparation is characterized in that greater than about 90% of the original amount of the
`first component remains in the preparation after storage at about 60°C for 4 weeks.
`
`
`Claims 8-12, 27, and 28 depend directly or indirectly from claim 7. Claims 8
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`35.
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`and 10-12 recite the addition of a quaternary ammonium salt, concentrations of tyloxapol
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`and/or bromfenac or its sodium salt, the pH of the preparations, and additional additives. Claim
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`9 recites an aqueous formulation of claim 7 in which greater than 92% of the original amount
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`
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`9
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`of bromfenac remains in the preparation after 60°C for 4 weeks. Claims 27 and 28 recite a
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`preservative efficacy standard.
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`36.
`
`Independent claim 13 is reproduced below:
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`13. A stable aqueous liquid preparation comprising: (a) a first component; and (b) a
`second component; wherein the first component is 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a
`hydrate thereof; wherein the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate,
`and 3/2 hydrate; the first component is the sole pharmaceutical active ingredient
`contained in the preparation and is present in the preparation at a concentration from
`about 0.05 w/v % to about 0.2 w/v %; the second component is tyloxapol; wherein said
`stable liquid preparation is formulated for ophthalmic administration; provided that the
`liquid preparation does not include mannitol.
`
`
`Claims 14-24 and 29 depend directly or indirectly from claim 13. Claims 14-18,
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`37.
`
`20, 22, 23, and 24 recite the addition of a quaternary ammonium salt, concentrations of
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`tyloxapol and/or bromfenac or its sodium salt, the pH of the preparations, and additional
`
`additives. Claims 19 and 21 recite a preparation wherein greater than about 90% and 92%,
`
`respectively, of bromfenac remains in the preparation after storage at about 60°C for 4 weeks.
`
`Claim 29 recites a preservative efficacy standard.
`
`D.
`
`The Asserted Claims of the ’813 Patent
`
`38.
`
`It is my understanding that Plaintiffs claim that Defendants’ drug products for
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`which they have filed for approval with the FDA will each infringe one or more of claims 1, 3-
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`5, 7, 9-11, 13, 15-17, and 19-22 of the ’813 patent. The claims of the ’813 patent are directed
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`to stable aqueous liquid preparations consisting essentially of: 2-amino-3-(4-bromobenzoyl)
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`phenylacetic acid (“bromfenac”) or a pharmacologically acceptable salt thereof or a hydrate
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`thereof; tyloxapol; boric acid; sodium tetraborate (“borax”); and water.
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`39.
`
`Claims 1, 7, and 13 are independent. Independent claim 1 of the ’813 patent is
`
`reproduced below.
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`10
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`1. A stable aqueous liquid preparation consisting essentially of: (a) a first component; (b)
`a second component; wherein the first component is 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid or a pharmacological