UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
`
`v.
`
`COSMO TECHNOLOGIES LIMITED,
`Patent Owner.
`
`U.S. Patent No. 9,320,716 to Villa et al.
`Issue Date: April 26, 2016
`Title: Controlled Release and Taste Masking Oral Pharmaceutical Compositions
`
`Inter Partes Review No.: IPR2018-00080
`
`DECLARATION OF HARTMUT DERENDORF, PH.D
`
`Exhibit 1006
`ARGENTUM
`IPR2018-00080
`
`000001
`
`

`

`Declaration of Hartmut Derendorf, Ph.D.
`
`Table of Contents
`
`I.
`
`INTRODUCTION ................................................................................ 1
`
`II. MY EXPERIENCE AND QUALIFICATIONS .................................. 2
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`LIST OF MATERIALS CONSIDERED ............................................. 6
`
`LEGAL STANDARD ........................................................................ 10
`A. Anticipation .............................................................................. 10
`B.
`Obviousness ............................................................................. 11
`
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”) ............ 13
`
`THE VILLA PATENTS ..................................................................... 14
`
`VII. CLAIM CONSTRUCTION ............................................................... 18
`
`VIII. SCOPE AND CONTENT OF THE PRIOR ART .............................. 20
`A.
`Controlled Release Oral Compositions .................................... 20
`B.
`Budesonide ............................................................................... 24
`
`IX.
`
`B.
`
`INVALIDITY OF THE ’716 PATENT ............................................. 24
`A.
`The ’584 Patent Anticipates Claims 1-29 of the ’716 Patent ... 24
`1.
`Independent Claims ........................................................ 24
`2.
`Dependent Claims .......................................................... 34
`The ’584 Patent Renders Obvious Claims 1-29 of the ’716 Patent
` .................................................................................................. 38
`Claim 1 ........................................................................... 39
`1.
`2.
`Claims 6, 12, and 22: “at least one amphiphilic
`compound” ..................................................................... 46
`Claims 2 and 13: “wherein the gastro-resistant coating is
`.
`.
`. methacrylic acid polymers and cellulose
`derivatives” .................................................................... 48
`Claims 3-5 and 14-16: “wherein the at least one
`hydrophilic compound is . . . a hydroxyalkyl cellulose” 49
`Claims 7, 8, 17 and 18: “wherein the at least one
`amphiphilic compound . . . lecithin” .............................. 50
`
`3.
`
`4.
`
`5.
`
`i
`
`000002
`
`

`

`Declaration of Hartmut Derendorf, Ph.D.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claims 9, 10, 19 and 20: “wherein the at least one
`lipophilic compound is selected from the group consisting
`of an unsaturated or hydrogenated alcohol or fatty acid,
`salt, ester, or amide thereof . . .”/”lipophilic compound is
`stearic acid” .................................................................... 51
`Claims 11, 21 and 23: “The controlled release oral
`pharmaceutical composition . . . further comprising . . . an
`acrylic acid polymer” ..................................................... 52
`Claims 24, 25 and 26: “wherein the macroscopically
`structure
`comprises microcrystalline
`homogenous
`cellulose” ........................................................................ 53
`Claims 27, 28 and 29: “A method for treating intestinal
`inflammatory disease comprising administering to a
`patient
`the controlled
`release oral pharmaceutical
`composition according to claim [1/12/22]” ................... 53
`10. Reasonable Expectation of Success ............................... 54
`The ’388 Patent Anticipates Claims 1-7, 9, 11-17, 19, and 21-29
`of the ’716 Patent ..................................................................... 54
`1.
`Independent Claims ........................................................ 54
`2.
`Dependent Claims .......................................................... 64
`The ’388 Patent Renders Obvious Claims 1-29 of the ’716 Patent
` .................................................................................................. 67
`1.
`Claim 1 ........................................................................... 68
`2.
`Claims 6, 12, and 22: “at least one amphiphilic
`compound” ..................................................................... 72
`Claims 2 and 13: “wherein the gastro-resistant coating is
`.
`.
`. methacrylic acid polymers and cellulose
`derivatives” .................................................................... 73
`Claims 3-5 and 14-16: “wherein the at least one
`hydrophilic compound is . . . a hydroxyalkyl cellulose” 73
`Claims 7, 8, 17 and 18: “wherein the at least one
`amphiphilic
`compound
`is
`....[phosphatidylcholines/lecithin]” ................................ 74
`Claims 9, 10, 19 and 20: “wherein the at least one
`lipophilic compound is selected from the group consisting
`of an unsaturated or hydrogenated alcohol or fatty acid,
`salt, ester, or amide thereof . . . “/”lipophilic compound is
`stearic acid” .................................................................... 75
`
`C.
`
`D.
`
`3.
`
`4.
`
`5.
`
`6.
`
`ii
`
`000003
`
`

`

`Declaration of Hartmut Derendorf, Ph.D.
`
`7.
`
`8.
`
`9.
`
`Claims 11, 21 and 23: “The controlled release oral
`pharmaceutical composition . . . further comprising . . . an
`acrylic acid polymer” ..................................................... 76
`Claims 24, 25 and 26: “wherein the macroscopically
`structure
`comprises microcrystalline
`homogenous
`cellulose” ........................................................................ 77
`Claims 27, 28 and 29: “A method for treating intestinal
`inflammatory disease comprising administering to a
`patient
`the controlled
`release oral pharmaceutical
`composition according to claim [1/12/22]” ................... 78
`10. Reasonable Expectation of Success ............................... 78
`The ‘388 Patent in View of the ’584 Patent Renders Obvious
`Claims 8, 10, 18, and 20 of the ’716 Patent ............................. 79
`1.
`Claims 8 and 18: wherein the at least one amphiphilic
`compound is . . . . lecithin” ............................................ 79
`Claims 10 and 20: “wherein the at least one lipophilic
`compound is stearic acid” .............................................. 80
`
`E.
`
`2.
`
`X.
`
`[Intentionally blank] ........................................................................... 81
`
`[Paragraphs 129-195 intentionally omitted] ................................................. 81
`
`XI.
`
`SECONDARY CONSIDERATIONS ................................................ 81
`
`iii
`
`000004
`
`

`

`I, Hartmut Derendorf, Ph.D., do hereby declare and state as follows:
`
`1.
`
`I understand that Petitioner Argentum is seeking to join IPR2017-
`
`01035, in which the petitioner, Mylan, relies on the expert testimony of Dr. Palmieri.
`
`For that reason, my testimony below repeats verbatim Dr. Palmieri’s declaration
`
`testimony from IPR2017-01035, with the exception of omitting testimony related to
`
`a second patent not the subject of this IPR petition, and reciting my own background
`
`and qualifications instead of those of Dr. Palmieri. I provide this testimony below:
`
`I.
`
`INTRODUCTION
`
`2.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this Declaration.
`
`3.
`
`My services have been retained on behalf of Petitioner for the above-
`
`captioned inter partes reviews (“IPRs”). Our consulting company is being
`
`compensated for my time in connection with this IPR at my standard consulting rate,
`
`which is $600 per hour for all work conducted in this matter and $6000 per day for
`
`deposition. This compensation does not depend in any way on the outcome of any
`
`of the IPRs.
`
`4.
`
`It is my understanding that the Petition for Inter Partes Review in this
`
`matter involves U.S. Patent No. 9,320,716 (“the ’716 patent”) (EX1001).
`
`5.
`
`The ’716 Patent names Roberto Villa, Massimo Pedrani, Mauro Ajani,
`
`and Lorenzo Fossati as the purported inventors. I understand that the ’716 patent is
`
`1
`
`000005
`
`

`

`a continuation of U.S. Patent No. 8,784,888 (“the ’888 patent”) (collectively the
`
`“Villa Patents”).
`
`6.
`
`It is also my understanding that the priority date of the ’716 patent is
`
`June 9, 2000, the filing date of the International Patent Application No.
`
`PCT/EP00/05356. I further understand that the ’716 patent is assigned to Cosmo
`
`Technologies Limited (“Cosmo,” “Patentee,” or “Patent Owner”).
`
`7.
`
`As explained below, my opinion is that all claims of the ’716 patent
`
`would have been invalid for anticipation and/or obviousness. Budesonide oral
`
`compositions were known and all the purported inventors did was use known
`
`excipients in known ways to create a budesonide oral tablet composition. See, e.g.,
`
`infra ¶¶ 49-56.
`
`II. MY EXPERIENCE AND QUALIFICATIONS
`
`8.
`
`I received my bachelor’s degree in Pharmacy from the University of
`
`Münster, Germany, in 1976. I received my Ph.D. in Pharmacy, summa cum laude,
`
`from the University of Münster in 1979. My dissertation titled “Biopharmaceutical
`
`investigations of weak analgesics” was awarded best dissertation for 1979. From
`
`1979 to 1980, I was an Assistant Scientist at the Institute for Pharmaceutical
`
`Chemistry at the University of Münster. My research involved pharmacokinetics and
`
`pharmacodynamics of analgesics and corticosteroids. From 1981 to 1982, I was a
`
`Postdoctoral Fellow with E.R. Garrett at the University of Florida, College of
`
`2
`
`000006
`
`

`

`
`
`Pharmacy. My post-doctoral
`
`research
`
`involved pharmacokinetics
`
`and
`
`pharmacodynamics of opiates and antibiotics.
`
`9.
`
`I became an Assistant Professor in the Department of Pharmaceutics at
`
`the University of Florida’s Department of Pharmacy in 1983, Associate Professor in
`
`1987, and Professor in 1993. Today I am a Distinguished Professor and I have served
`
`as Chairman of the Department since 1998. I previously served as Chairman of the
`
`Department from 1987 to 1995.
`
`10. My
`
`research
`
`interests
`
`include
`
`the
`
`pharmacokinetics
`
`and
`
`pharmacodynamics of corticosteroids, analgesics, and antibiotics, as well as drug
`
`interactions. My corticosteroid research
`
`includes preclinical and clinical
`
`investigations with oral, inhaled and injected drug formulations that focus on model
`
`development for dose optimization of new drug products. My pharmacokinetic
`
`studies investigate new and established compounds in animal and clinical studies,
`
`with particular emphasis on measuring the drug concentration in tissues using
`
`microdialysis. My group is one of the leading groups in pharmacokinetics and
`
`pharmacodynamics. My pharmacodynamic studies with corticosteroids investigate
`
`the both desired and undesired effects of drug concentrations typically observed in
`
`patients. My group evaluates this type of pharmacokinetic and pharmacodynamic
`
`data using mathematical models to help assess useful doses and dosing regimens for
`
`the compounds we study.
`
`3
`
`000007
`
`

`

`
`
`11.
`
`I have taught graduate and undergraduate courses in biopharmaceutics
`
`as well as basic and clinical pharmacokinetics, and pharmacodynamics. In my
`
`clinical pharmacokinetics course, I teach the appropriate dosing of several drug
`
`classes including corticosteroids. In my graduate class, I teach how to find
`
`therapeutic doses (dose finding) and how to confirm that these doses work (dose
`
`justification) in drug development.
`
`12.
`
`I often teach professionals in the pharmaceutical industry, at national
`
`and international workshops, conferences and through educational programs at
`
`pharmaceutical companies.
`
`13. For example, I cofounded the International Drug-Drug Interaction
`
`Workshop series, which is held annually in Marbach Castle, Germany and focuses
`
`on the evaluation of drug-drug interactions in the laboratory (in-vitro) as well as in
`
`animal and clinical studies (in-vivo). I was also the program chair for the 20th North
`
`American International Society for the Study of Xenobiotics held in Orlando in
`
`October, 2015. My workshops for the pharmaceutical industry typically review
`
`current developments in the pharmacokinetics and pharmacodynamics as it relates
`
`to drug development
`
`14. My professional awards include: the Mentorship Award of the
`
`American College of Clinical Pharmacology (2015), the ISOP Leadership Award
`
`from the International Society of Pharmacometrics (2013), the Distinguished
`
`4
`
`000008
`
`

`

`
`
`Investigator Award from the American College of Clinical Pharmacology (2010),
`
`the Volwiler Research Achievement Award from the American Association of
`
`Colleges of Pharmacy (AACP, 2010), Howard Hughes Medical Institute
`
`Distinguished Mentor Award (2008), the Faculty Award in Pharmaceutical Sciences
`
`from the University of Utrecht (2005), the Research Achievement Award in Clinical
`
`Science of the American Association of Pharmaceutical Sciences (AAPS, 2003), the
`
`Nathaniel T. Kwit Distinguished Service Award of the American College of Clinical
`
`Pharmacology (ACCP, 2003), the McKeen-Cattell Award for the best publication in
`
`Journal of Clinical Pharmacology (1994), and the Rottendorf Award for
`
`Pharmaceutical Sciences (1983).
`
`15.
`
`I am the past President (2006-2008) of the American College of Clinical
`
`Pharmacology (ACCP) and serve as a Fellow, Honorary Regent and also served as
`
`Secretary for the organization. I served as President (2004-2005) of the International
`
`Society of Antiinfective Pharmacology (ISAP), an organization focused on PK/PD
`
`of antiinfectives. I am a Fellow of the American Association of Pharmaceutical
`
`Sciences (AAPS), and a member of the American Pharmacists Association (APhA),
`
`the American Society for Clinical Pharmacology and Therapeutics (ASCPT), the
`
`Florida Pharmacists Association (FPA), American Society of Microbiology (ASM),
`
`and Deutsche Pharmazeutische Gesellschaft (German Pharmaceutical Society). I
`
`5
`
`000009
`
`

`

`
`
`was also a member of the Nutrition and Therapeutics Committee of the NASA Space
`
`Medicine Program, and the FDA Clinical Pharmacology Advisory Committee.
`
`16.
`
`I have published over 460 scientific publications and given over 880
`
`presentations at national or international meetings. I have published ten textbooks in
`
`English and German. I am an inventor on one patent.
`
`17.
`
`I am an editor for the International Journal of Clinical Pharmacology &
`
`Therapeutics, International Journal of Antiinfective Agents, Journal of Clinical
`
`Pharmacology (associate editor), European Journal of Pharmaceutical Sciences
`
`(associate editor), and Pharmazie (U.S. editor). I serve on the editorial board of
`
`Journal of Pharmacokinetics & Pharmacodynamics, Journal of Pharmaceutical
`
`Sciences; Planta Medica; Clinical Research & Regulatory Affairs; and Clinical
`
`Pharmacokinetics.
`
`18. A copy of my curriculum vitae, which includes a complete description
`
`of my education and experience, is attached hereto as EX1007.
`
`III. LIST OF MATERIALS CONSIDERED
`19.
`In formulating my opinions, I have considered the materials referenced
`
`in this Declaration and those referenced in the Petition for Inter Partes Review of
`
`the ’716 Patent. I also have reviewed the ’716 Patent and its prosecution history as
`
`well as each of the documents cited herein in light of the general knowledge in the
`
`state of the art as of June 9, 2000.
`
`6
`
`000010
`
`

`

`
`
`Petitioner
`Exhibit #
`1001
`
`1002
`
`1009
`
`1010
`
`1011
`
`1003
`1004
`1005
`1006
`1007
`1008
`
`Description
`U.S. Patent No. 9,320,716 to Villa et al., “Controlled Release and
`Taste Masking Oral Pharmaceutical Compositions”
`U.S. Patent No. 8,784,888 to Villa et al., “Controlled Release and
`Taste Masking Oral Pharmaceutical Composition”
`Reserved
`Reserved
`Reserved
`Declaration of Anthony Palmieri III, Ph.D., R.Ph.
`Curricula Vitae of Hartmut Derendorf, Ph.D.
`U.S. Patent No. 5,681,584 to Savastano et al., “Controlled Release
`Drug Delivery Device”
`U.S. Patent No. 5,811,388 to Friend et al., “Delivery of Drugs to the
`Lower GI Tract”
`U.S. Patent No. 6,239,120 to Hallgren et al., “Method and Means for
`Treating Glomerulonephritis”
`U.S. Patent Appl. Pub. No. 2006/0134208 to Villa et al., “Controlled
`Release and Taste Masking Oral Pharmaceutical Composition”
`1012 Markman Opinion and Order in Cosmo Technologies Limited v.
`Alvogen Pine Brook, LLC., C.A. No. 15-193-LPS, ECF Nos. 167, 168
`(D. Del. Sept. 7, 2016).
`Amendment and Response to Advisory Action filed on February 21,
`2014 in U.S. Patent Appl. No. 13/617,138
`Substitute Specification (Clean Copy) filed on April 29, 2013 in U.S.
`Patent Appl. No. 13/617,138
`Amendment After Final filed on April 29, 2013 in U.S. Patent Appl.
`No. 13/617,138
`Amendment and Response to Office Action filed on July 1, 2013 in
`U.S. Patent Appl. No. 13/617,138
`U.S. Patent No. 6,607,751 to Odidi et al., “Controlled Release
`Delivery Device for Pharmaceutical Agents Incorporating Microbial
`Polysaccharide Gum”
`Campieri et al., Oral Budesonide is as Effective as Oral Prednisolone
`in Active Crohn’s Disease, Gut, 41:209-214 (1997)
`Reserved
`Reserved
`Reserved
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`1020
`1021
`
`7
`
`000011
`
`

`

`1022
`
`1023
`
`1024
`
`1025
`1026
`
`1027
`1028
`1029
`1030
`
`1031
`1032
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`
`
`PCT International Publication No. WO 96/36318, “Three-Phase
`Pharmaceutical Form With Constant and Controlled Release of
`Amorphous Active Ingredient for Single Daily Application”
`U.S. Patent No. 5,342,625 to Hauer et al., “Pharmaceutical
`Compositions Comprising Cyclosporins”
`PCT International Publication No. WO 99/39700, “Pharmaceutical
`compositions in form of nanoparticles comprising lipidic substances
`and amphiphilic substances and related preparation process”
`FDA Inactive Ingredient Guide 1996/1997
`Handbook of Pharmaceutical Excipients (Wade and Weller, eds., 2d
`ed. 1994)
`Reserved
`Remington: The Science and Practice of Pharmacy, Vol. 1 (1995)
`Reserved
`Hawley’s Condensed Chemical Dictionary (John Wiley & Sons, Inc.,
`13th ed. 1997)
`Reserved
`Entocort® EC Highlights of Prescribing Information
`Svensson et al., Hydration of an Amphiphilic Excipient, Gelucire
`44/14, 2004, <hal-00015990>
`U.S. Patent No. 6,395,300 to Straub et al., “Porous Drug Matrices and
`Methods of Manufacture Thereof”
`Flanders et al., The Control of Drug Release From Conventional Melt
`Granulation Matrices, Drug Development & Industrial Pharmacy,
`13(6):1001-1022 (1987)
`Gandhi et al., Extrusion and Spheronization in the Development of
`Oral Controlled-Release Dosage Forms, Pharmaceutical Sci. & Tech.
`Today 2(4):160 (1999)
`US Patent No. 4,880,830
`Formulation”
`Daly et al., The Effect of Anionic Surfactants on the Release of
`Chlorpheniramine from a Polymer Matrix Tablet, Int’l J. of
`Pharmaceutics, 18:201-05 (1984)
`S.S. Davis, The Design and Evaluation of Controlled Release Dosage
`Forms for Oral Delivery, S.T.P. Pharma 3(5):412-417 (1987)
`U.S. Patent No. 5,849,327 to Berliner et al., “Delivery of Drugs to the
`Lower Gastrointestinal Tract”
`U.S. Patent No. 5,643,602 to , “Oral Composition for the Treatment
`of Inflammatory Bowel Disease”
`
`to Alan Rhodes, “Slow Release
`
`8
`
`000012
`
`

`

`
`
`1042
`1043
`
`1044
`
`1045
`
`1047
`
`1048
`
`1049
`1050
`
`1051
`
`1052
`
`U.S. Provisional Application No. 60/080,274 filed on April 1, 1998
`Gliko-Kabir et al., Low Swelling, Crosslinked Guar and Its Potential
`Use as a Colon-Specific Drug Carrier, Pharm. Research 15(7):1019-
`1025 (1998)
`See A Blume, B Arnold, HU Weltzien, Effects of a synthetic
`lysolecithin analog on
`the phase
`transition of mixtures of
`phosphatidylethanolamine and phosphatidylcholine, FEBS Letters
`(1976)
`Qiu et al., Design of sustained-release matrix systems for a highly
`water-soluble compound, ABT-089, Int’l J. of Pharmaceutics 157:43-
`52 (1997)
`1046 M. Efentakis et al., The Influence of Surfactants on Drug Release from
`a Hydrophobic Matrix, Int’l J. Pharm. 70:153-58 (1991)
`Uceris® website, https://www.uceris.com/tablet/ (accessed on March
`5, 2017)
`Santarus’ CEO Discusses FDA Approval Of UCERIS (Budesonide)
`For The Induction Of Remission In Patients With Active, Mild To
`Moderate Ulcerative Colitis (Transcript) (Jan. 15, 2013)
`Uceris® Instant Savings Program
`Transcript of the Second Quarter 2014 Earnings Conference Call of
`Salix Pharmaceuticals, Ltd.
`L.W. Doner, Determining Sugar Composition of Food Gum
`Polysaccharides by HPTLC, Chromatographia 2001, 53, May (No.
`9/10)
`Amendment filed on January 15, 2013 in U.S. Patent Appl. No.
`13/617,138
`Specification of U.S. Patent Application No. 10/009,532
`Specification of 12/210,969 application
`Specification of 13/249,839 application
`Specification of 13/462,409 application
`Final Office Action of March 6, 2013 in U.S. Patent Appl. No.
`13/617,138
`Applicant-Initiated Interview Summary of April 23, 2013 in U.S.
`Patent Appl. No. 13/617,138
`Original Specification as field on September 14, 2012 in U.S. Patent
`Appl. No. 13/617,138
`Orange Book Listing of Uceris® (accessed on March 8, 2017)
`Hawley’s Condensed Chemical Dictionary (John Wiley & Sons, Inc.,
`13th ed. 1997)
`
`1053
`1054
`1055
`1056
`1057
`
`1058
`
`1059
`
`1060
`1061
`
`9
`
`000013
`
`

`

`
`
`1062
`
`N. Robinson, Surface Interaction of Lecithin and Lysolecithin, J. of
`Pharmacy and Pharmacology, 12(1) 609-616 (1960)
`
`
`IV. LEGAL STANDARD
`20. Although I am not a lawyer, I provide my general understanding of the
`
`anticipation and obviousness analysis, and I used these principles in conducting my
`
`analysis and drawing any conclusions.
`
`21.
`
`I understand that the first step in determining whether a patent claim
`
`would have been anticipated or obvious is to construe the claims to determine claim
`
`scope and meaning. I understand that in Inter Partes Review proceedings the claim
`
`terms are generally given the broadest reasonable interpretation, i.e., their ordinary
`
`and customary meaning as would have been understood by a POSA at the time, in
`
`the context of the entire patent disclosure.
`
`A. Anticipation
`22.
`I understand that anticipation requires that each and every element of
`
`the claimed invention be disclosed expressly or inherently in a single prior art
`
`reference.
`
`23.
`
`I also understand that an element may be inherent in the prior art where
`
`the prior art necessarily functions in accordance with or includes the claimed
`
`limitations. I am also informed that inherency may exist even if a POSA would not
`
`appreciate or recognize the inherent characteristics of the prior art, as the discovery
`
`10
`
`000014
`
`

`

`
`
`of a previously-unappreciated property does not make an old composition
`
`patentable.
`
`24.
`
`I also understand that a prior art reference must enable a POSA to make
`
`and use a claimed invention in order to anticipate a patent claim.
`
`25.
`
`I understand that it is appropriate to consider additional references in
`
`the context of analyzing anticipation where a reference is silent about an inherent
`
`characteristic and to determine whether the reference gives possession of the
`
`invention to a POSA.
`
`B. Obviousness
`26.
`I understand that a patent claim is invalid if the differences between the
`
`claimed invention and prior art are such that the subject matter as a whole would
`
`have been obvious at the time the invention was made to a POSA.
`
`27.
`
`I have been told the following factors are used in making an
`
`obviousness determination: a) the scope and content of the prior art; b) the
`
`differences between the prior art and the claimed invention; c) the level of ordinary
`
`skill in the pertinent art; and d) any secondary considerations evidencing
`
`nonobviousness.
`
`28.
`
`I also understand that obviousness can be established by combining or
`
`modifying the teachings of the prior art. A claimed invention can be obvious when,
`
`for example, there is some teaching, suggestion, or motivation in the prior art that
`
`11
`
`000015
`
`

`

`would have led a POSA to modify the prior art reference or to combine prior art
`
`reference teachings to arrive at the claimed invention.
`
`29.
`
`I also understand that the prior art references themselves do not have to
`
`provide an explicit teaching, suggestion, or motivation to combine prior art
`
`teachings; rather, the analysis may rely on interrelated teachings, market demands,
`
`the background knowledge possessed by a POSA, and/or common sense. Put
`
`another way, the motivation to combine or modify prior art references can come
`
`from any reason to do so, and is not limited to the reasons that may have motivated
`
`the patentee.
`
`30.
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`I am also informed that a combination of familiar elements according
`
`to known methods is likely to be obvious when it does no more than yield predictable
`
`results. I also understand that when a person of ordinary skill would have reached
`
`the claimed invention through routine experimentation, the invention may be
`
`deemed obvious.
`
`31.
`
`I understand that various rationales are utilized to determine whether a
`
`claim
`
`is obvious,
`
`including, among others:
`
` (i) simple substitution or
`
`interchangeability of one known element for another to obtain predictable results;
`
`(ii) use of known techniques to improve similar methods or products in the same
`
`way; (iii) applying a known technique to a known method or product ready for
`
`improvement to yield predictable results; (iv) “obvious to try”—choosing from a
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`finite number of identified, predictable solutions, with a reasonable expectation of
`
`success; and (v) known work in one field of endeavor may prompt variations of it
`
`for use in either the same field or a different one based on design incentives or other
`
`market forces if the variations would have been predictable to one of ordinary skill
`
`in the art.
`
`32. As stated above, I understand that secondary considerations of non-
`
`obviousness are part of the obviousness inquiry. I understand that these secondary
`
`considerations may include failure of others, copying, unexpectedly superior results,
`
`perception in the industry, commercial success, and long-felt but unmet need. I also
`
`understand that in order for secondary considerations of non-obviousness to be
`
`applicable, they must have a nexus to the claimed subject matter. I understand that
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`this nexus (i.e., link) includes a connection between the subject matter of the claim
`
`and the secondary considerations alleged.
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”)
`33.
`
`In arriving at my opinions, I have relied on my experience in the
`
`relevant art and have considered the point of view of a person of ordinary skill in the
`
`art.
`
`34. With respect to the Villa Patents, a POSA in the relevant field would
`
`have had education or experience in the field of drug delivery systems, including
`
`controlled release compositions.
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`35. The education and experience levels may vary between POSAs, with
`
`some having a bachelor’s degree in the chemical or pharmaceutical arts (e.g.,
`
`pharmacy or pharmaceutics) plus five years of relevant work experience, or with
`
`others holding more advanced degrees—e.g., Ph.D. or Pharm.D.—while having
`
`fewer years of experience.
`
`36.
`
`In determining the qualifications of a POSA, I considered, among other
`
`factors, the field of the alleged invention and use thereof described in the Villa
`
`Patents, and my experience with the educational level of practitioners in related
`
`fields. In addition, my opinion is based upon my background, education, and
`
`personal experience.
`
`37. Based on my experience, I have the understanding and capabilities of a
`
`person of ordinary skill as defined above prior to and on June 9, 2000.
`
`VI. THE VILLA PATENTS
`38.
`I have reviewed and considered the Villa Patents in view of general
`
`knowledge in the relevant field measured from the time of the earliest possible
`
`priority date for the Villa Patents. I understand Patent Owner contends that Villa
`
`Patents purportedly cover the Uceris® product. See EX1060.
`
`39. At a high level, the challenged claims of the Villa Patents are directed
`
`to a “controlled release oral composition” containing budesonide and certain classes
`
`of excipients. The ’716 patent has three independent claims (Claims 1, 12 and 22).
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`Independent Claim 1 recites a controlled release oral pharmaceutical composition
`
`comprising: (i) budesonide in an amount effective to treat intestinal inflammatory
`
`disease; (ii) a macroscopically homogenous structure comprising: (a) at least one
`
`lipophilic compound and (b) at least one hydrophilic compound, wherein the
`
`macroscopically homogenous structure controls the release of the budesonide; and
`
`(iii) a gastro-resistant coating on the macroscopically homogenous structure that
`
`prevents release of budesonide in the stomach, wherein the macroscopically
`
`homogenous structure is a tablet. EX1001 at 10:12–26. Claims 12 and 22 are similar
`
`to Claim 1 except that Claim 12 requires “at least one amphiphilic compound” rather
`
`than the “at least one lipophilic compound” of Claim 1, whereas Claim 21 requires
`
`“at least one amphiphilic compound” and “at least one lipophilic compound.”
`
`EX1001 at 11:4-15; 12:9-25.
`
`40. The ’888 patent has one independent claim (Claim 1). Independent
`
`Claim 1 recites a controlled release oral pharmaceutical composition consisting
`
`essentially of: (1) a tablet core consisting essentially of: (a) budesonide in an
`
`amount effective to treat intestinal inflammatory disease; and (b) a macroscopically
`
`homogeneous composition comprising at least one lipophilic excipient, at least one
`
`amphiphilic excipient, and at least one hydrogel-forming hydrophilic excipient other
`
`than a gum, wherein said budesonide is dispersed in said macroscopically
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`homogeneous composition; and (2) a coating on said tablet core, said coating
`
`consisting essentially of a gastro-resistant film. EX1002 at 10:20–32.
`
`41. Generally speaking, the claims of the Villa Patents recite classes of
`
`excipients based on a recited property (e.g., lipophilic, hydrophilic, or amphiphilic
`
`excipients) rather than specific compounds. Alternatively, they may recite a class
`
`of excipients (e.g., “methacrylic acid polymers,” “cellulose derivatives” or
`
`“hydroxyalkyl cellulose”), or a group of classes of excipients. Only in some
`
`instances do the claims recite a specific compound (e.g., dependent Claim 10 of the
`
`’716 patent (stearic acid) and dependent Claim 7 of the ’888 patent (lecithin)) but
`
`even then, the specific compound is coupled with, e.g., any hydrophilic and/or
`
`lipophilic compound (’716 patent) or excipients (’888 patent).
`
`42. The specification of the Villa Patents states the following:
`
`The present invention relates to controlled release and
`taste-masking compositions containing one or more active
`principles incorporated in a three-component matrix
`structure,
`i.e. a structure
`formed by successive
`amphiphilic, lipophilic or inert matrices and finally
`incorporated or dispersed in hydrophilic matrices. The use
`of a plurality of systems for the control of the dissolution
`of the active ingredient modulates the dissolution rate of
`the active ingredient in aqueous and/or biological fluids,
`thereby controlling
`the
`release kinetics
`in
`the
`gastrointestinal tract . . . .
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`EX1001 at 1:24-33.1
`
`43. After discussing other prior art controlled release compositions using
`
`lipophilic/hydrophilic/bioerodible matrices, reservoir structures, and/or gastro-
`
`resistant film (EX1001 at 1:47-2:55), the Villa Patents state the following:
`
`When preparing sustained-, controlled-release dosage
`forms of a medicament
`topically active
`in
`the
`gastrointestinal tract, it is important to ensure a controlled
`release from the first phases following administration, i.e.
`when the inert matrices have the maximum release rate
`inside the logarithmic phase, namely the higher deviation
`from linear release.
`Said object has been attained according to the present
`invention, through the combination of an amphiphilic
`matrix inside an inert matrix, the latter formulated with a
`lipophilic polymer in a superficial hydrophilic matrix. The
`compositions of the invention are characterized by the
`absence of a first phase in which the medicament
`superficially present on the matrix is quickly solubilized,
`and by the fact the amphiphilic layer compensate the lack
`
`
`1 I understand that