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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`
`Patent Owner.
`
`__________________
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`__________________
`
`DECLARATION OF STEPHEN G. DAVIES, D.PHIL.
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`U.S. Patent No. 7,041,786
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`Table of Contents
`INTRODUCTION ........................................................................................... 1
`I.
`II. QUALIFICATIONS AND BACKGROUND ................................................. 2
`A.
`Education and Experience ..................................................................... 2
`B. Documents and Information Considered in Forming Opinions ............ 6
`C.
`Scope of Work and Compensation ........................................................ 7
`D.
`Expert Testimony in the Last Four Years ............................................. 8
`INSTITUTED GROUNDS OF UNPATENTABILITY ................................. 8
`III.
`IV. LEGAL STANDARDS ................................................................................... 9
`V. A PERSON OF ORDINARY SKILL IN THE ART ....................................13
`VI. SUMMARY OF OPINIONS .........................................................................14
`VII. TECHNICAL BACKGROUND ...................................................................16
`A.
`The Gastrointestinal Tract ...................................................................18
`B. Naturally Occurring Peptides as Agonists for Guanylate Cyclase
`C Receptors .........................................................................................21
`1.
`Topoisomerism ..........................................................................22
`2.
`Uroguanylin ..............................................................................28
`3.
`Guanylin ....................................................................................40
`4.
`Heat-Stable Enterotoxins ..........................................................41
`C. Development of Therapeutic Peptides Was Unpredictable ................50
`D.
`By January 2002, the Art had Confirmed the Importance of
`Maintaining Asp at Position 3 of Uroguanylin ...................................58
`VIII. PLECANATIDE AND THE ’786 PATENT ................................................60
`A. U.S. Patent No. 7,041,786 ...................................................................60
`
`i
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`IX. GROUND 1: CLAIM 1 WOULD NOT HAVE BEEN OBVIOUS
`OVER CURRIE AND LI ..............................................................................62
`A.
`A Person of Ordinary Skill in the Art Would Have Been
`Disincentivized from Selecting Human Uroguanylin as a Lead
`Compound ...........................................................................................62
`1.
`Human uroguanylin was known
`to suffer
`from
`interconverting topoisomers......................................................63
`a.
`The impact of interconversion on manufacturing
`and formulation ...............................................................64
`Interconversion in vivo ...................................................66
`b.
`Because the heat-stable enterotoxins (STs) did not have
`the drawbacks from topoisomerism, were more stable, and
`had better overall activity profile, they would have been
`the clear lead compound to be selected for further
`development ..............................................................................69
`A Person of Ordinary Skill in the Art Would Not Have Been
`Motivated to Substitute Asp3 with Glu3 with Any Expectation
`of Yielding a Peptide with Improved Properties .................................72
`1.
`Nothing in the art suggested substituting Asp3 for Glu3
`would have stopped human uroguanylin’s interconversion
` ...................................................................................................72
`Nothing in the art suggested that substituting Asp3 for Glu3
`would have reasonably been expected to improve the
`resulting peptide’s activity ........................................................74
`a.
`Conservative substitutions would not have been
`expected to improve activity...........................................75
`As of the priority date, the art taught that Asp at
`positions 2 and 3 was required for clinical effect ...........80
`Protonation would not have been expected to
`improve activity ..............................................................86
`
`B.
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`2.
`
`2.
`
`b.
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`c.
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`ii
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`d.
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`3.
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`Dr. Peterson overstates the benefit of avoiding or
`removing aspartimide formation because the art
`taught other, routinely used means for doing so ............98
`Unexpected Superior Results Underscore the Lack of any
`Reasonable Expectation of Success and Reinforce the
`Nonobviousness of Plecanatide ..............................................100
`a.
`Unexpected stabilization against interconversion ........101
`b.
`Unexpected superior potency for cGMP Production
` ......................................................................................105
`Unexpectedly higher heat stability ...............................114
`Unexpectedly better (and lower) IC50 indicative of
`the claimed invention’s superior activity .....................118
`X. GROUND 2: CLAIMS 2, 4, AND 5 WOULD NOT HAVE BEEN
`OBVIOUS OVER CURRIE, LI, AND NARAYANI .................................120
`XI. GROUND 3: CLAIMS 3-5 WOULD NOT HAVE BEEN OBVIOUS
`OVER CURRIE, LI, NARAYANI, AND CAMPIERI...............................121
`XII. GROUND 4: CLAIM 6 WOULD NOT HAVE BEEN OBVIOUS
`OVER CURRIE, LI, AND EKWURIBE ....................................................122
`XIII. CONCLUSION ............................................................................................122
`
`
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`c.
`d.
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`iii
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`INTRODUCTION
`I have been retained by counsel for Patent Owner Bausch Health
`1.
`
`I.
`
`Ireland Limited (“Bausch”1) as an expert in the fields of organic and medicinal
`
`chemistry, in connection with the above-captioned inter partes review proceeding.
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`2.
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`I have been asked to provide my opinion regarding Petitioner Mylan
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`Pharmaceuticals Inc.’s (“Mylan”) asserted grounds of unpatentability for claims 1-
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`6 of U.S. Patent No. 7,041,786. (Ex. 1001.)2
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`3.
`
`I have also been asked to respond to the Declaration of Blake R.
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`Peterson, Ph.D., submitted in this proceeding on behalf of Mylan. (See Ex. 1002.)3
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`More specifically, I have considered Dr. Peterson’s opinions regarding whether
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`claims 1-6 of the ’786 patent are unpatentable as obvious.
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`4.
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`As explained below, it is my opinion that the inventions of claims 1-6
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`would have been non-obvious to a person of ordinary skill in the art on or before
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`January 17, 2002.
`
`
`1 I understand that Bausch acquired the ’786 patent from Synergy Pharmaceuticals,
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`Inc. In my declaration, I use Bausch to also refer to Synergy Pharmaceuticals, Inc.
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`2 U.S. Patent No. 7,041,786 (“the ’786 patent”).
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`3 Declaration of Blake R. Peterson. (“the Peterson Declaration”).
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`1
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`II. QUALIFICATIONS AND BACKGROUND
`A. Education and Experience
`I am expert in the fields of peptides, organic chemistry, and medicinal
`5.
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`chemistry. My qualifications in these areas, as well as other areas, are established
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`below and by my curriculum vitae. (Ex. 2029.)
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`6.
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`I am the Waynflete Professor of Chemistry Emeritus at the University
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`of Oxford and Extraordinary Lecturer in Chemistry at New College, Oxford,
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`England. I have been employed teaching chemistry at Oxford since 1980. From
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`2006 to 2011, I was Chairman of the Department of Chemistry. In this position, I
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`had full responsibility for all teaching, research, financial and managerial matters
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`in one of the largest chemistry departments in the world. I have also supervised
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`more than 100 graduate students and 100 post-doctoral fellows in the areas of
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`organic, organometallic, and medicinal chemistry.
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`7.
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`In 1973, I earned a B.A. in Chemistry from the University of Oxford.
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`In 1975, I earned a D. Phil. in Chemistry from the University of Oxford. In 1980, I
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`received a D. Sc. in Chemistry from the University of Paris.
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`8.
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`Over the course of my career, I have been a committee member of
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`many professional organizations, a list of which can be found in my curriculum
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`vitae.
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`2
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`I have authored over 600 publications and have given scores of
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`9.
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`research lectures. My research interests include synthetic organic and medicinal
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`chemistry and, in particular, the synthesis and structural studies of various peptides
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`and pseudopeptides as shown in the following publications:
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`• S. G. Davies et al., Resynthesis of Histone Peptide Bonds on a DNA
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`Matrix., in “Chromosomal Proteins and Gene Expression,” Eds. G. R.
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`Reeck, G. H. Goodwin and P. Puigdomenech, NATO-ASI Series
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`Plenum, New York, 1985, 101, 17;
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`• A. J. Burke et al., Asymmetric Synthesis of (2S,3S)- and (2R,3S)-2,3-
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`Diaminobutanoic Acids, Non-Protein Amino-Acid Diastereomers Found
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`in a Number of Peptide Antibiotics, Synlett, 1996, 621;
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`• S. G. Davies et al., Asymmetric synthesis of β-lactams and
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`pseudopeptides via stereoselective conjugate additions of lithium (α-
`
`methylbenzyl)allylamide to α,β-unsaturated iron acyl complexes, J.
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`Chem. Soc., Perkin Trans. 1, 1999, 3105;
`
`• S. G. Davies et al., Double asymmetric induction as a mechanistic probe:
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`conjugate addition for the asymmetric synthesis of a pseudotripeptide,
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`Chem. Commun, 2004, 1128;
`
`• S. G. Davies et al., Asymmetric conjugate reductions with samarium
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`diiodide: asymmetric syntheses of (2S,3R)- and (2S,3S)-[2-2H,3-2H]-
`
`3
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`leucine-(S)-phenylalanine dipeptides and (2S,3R)-[2-2H,3-2H]-
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`phenylalanine methyl ester, Org. Biomol. Chem., 2005, 3, 1435;
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`• E. Abraham et al., A systematic study of the solid state and solution
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`phase conformational preferences of β-peptides derived from
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`transpentacin, Tetrahedron: Asymmetry, 2010, 21, 1797
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`• E. Abraham et al., A systematic study of the solid state and solution
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`phase conformational preferences of β-peptides derived from C(3)-alkyl
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`substituted transpentacin derivatives, Tetrahedron: Asymmetry, 2011, 22,
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`69;
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`• E. Abraham et al., A systematic study of the solid state and solution
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`phase conformational preferences of β-peptides derived from C(3)-alkyl
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`substituted transpentacin derivatives, Tetrahedron: Asymmetry, 2011, 22,
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`69;
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`• E. Abraham et al., Crystal structures of dipeptides derived from (1R,2S)-
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`2-aminocyclopentanecarboxylic acid and (1S,2R,3S)-2-amino-3-
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`methylcyclopentane-carboxylic acid, J. Chem. Crystallogr., 2011, 41,
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`1722; and
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`• S. G. Davies et al., The synthesis and crystal structure of Cbz-[(1R,2S)-
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`ACPC]3-OH: a tripeptide derived from the β-amino acid (1R,2S)-
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`cispentacin, J. Chem. Crystallogr., 2014, 44, 205.
`
`4
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`I have published extensively in peptide chemistry, including the
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`10.
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`synthesis and structural studies of peptides. I have studied peptide conformational
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`isomers and how these conformations affect the properties of these isomers. A list
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`of my publications may be found in my curriculum vitae. (Ex. 2029.)
`
`11.
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`I have also held several editorial appointments. I was the Founding
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`Editor and Editor of Organic Series of “Oxford Chemistry Primers” and “Oxford
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`Chemistry Masters.” I was also the Founding Editor and currently Editor-in-chief
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`of “Tetrahedron: Asymmetry.” (1990-2017.) I am also the Editor of the “On
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`Chemistry” Books, and for many years (1989-2017), I was an Executive Editorial
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`Board Member of the “Tetrahedron” family of Journals.
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`12. Over the course of my career, I have received several awards,
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`including the Hickinbottom Fellowship (1984); Pfizer Award for Chemistry
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`(1985); 1984 Corday Morgan Medal, Royal Society of Chemistry (1986); Royal
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`Society of Chemistry Award for Organometallic Chemistry (1987); Pfizer Award
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`for Chemistry (1988); Royal Society of Chemistry Bader Award (1989); Tilden
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`Lecture Award, Royal Society of Chemistry (1996); Royal Society of Chemistry
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`Award in Stereochemistry (1997); Prize Lectureship of the Society of Synthetic
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`Organic Chemistry, Japan (1998); Distinguished Technopreneur Award, Singapore
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`(2008); Royal Society of Chemistry Perkin Prize for Organic Chemistry (2011);
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`and Doctor Honoris Causa, University of Salamanca, Spain.
`
`5
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`I am also the founder of numerous companies including ones focused
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`13.
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`on the preparation of compounds for potential pharmaceutical use. Along with
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`several others, I founded Oxford Asymmetry, Ltd. in 1992, which became a
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`division of Oxford Asymmetry International plc, with a mission to provide
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`pharmaceutical companies with enantiomerically pure compounds of interest on
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`any desired scale, from small amounts for biological evaluation and research, to
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`commercial quantities. Currently, I am the Founder and Non-executive Chairman
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`of SciInk Ltd. I was also a Non-executive Director of Oxford University
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`Innovation Ltd. I was also the Founder and Non-executive Director of OxStem
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`Ltd., OxStem Neuro Ltd., OxStem Cardio Ltd., OxStem Oncology Ltd., OxStem
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`Ocular Ltd, OxStem Beta Ltd, and OxStem Immuno Ltd. I am also the Founder of
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`Summit Therapeutics plc and Summit Therapeutics Inc., which develops
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`pharmaceutical compounds and has one such compound currently undergoing
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`evaluation after a Phase III clinical trial. I am also the Founder and Non-executive
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`Director of Raphael Laboratories Limited, which is developing prophylactics
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`against airborne respiratory viruses including COVID-19 and all of its variants,
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`one of which successfully completed a Phase II clinical trial.
`
`B. Documents and Information Considered in Forming Opinions
`In forming the opinions expressed in this declaration, I have
`14.
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`considered the Petition (Paper 1), Patent Owner’s Preliminary Response (Paper
`
`6
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`11), the Institution Decision (Paper 16), the Declaration of Dr. Peterson (Ex. 1002),
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`the Declaration of Dr. Shailubhai (Ex. 2023), the Declaration of Dr. Waldman (Ex.
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`2025), the documents cited in this declaration, the exhibits submitted in this
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`proceeding and the publications listed in my curriculum vitae. (Ex. 2029.) I
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`additionally have based my opinions on my professional and academic experience
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`in the areas of peptides, organic chemistry, and medicinal chemistry. The
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`Declaration of Dr. Waldman (Ex. 2025) provides additional support for my
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`opinions. (Ex. 2025.) I reserve the right to testify about these materials and
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`experience.
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`C.
`15.
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`Scope of Work and Compensation
`I will be compensated for my time preparing for and testifying in this
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`matter at the rate of £450 per hour. No part of my compensation is contingent
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`upon the outcome of this matter or any issue in it.
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`16. To the extent I am provided additional documents or information,
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`including any expert declarations or additional documents produced by Mylan, I
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`may offer further opinions. In addition to these materials, I may consider
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`additional documents and information in forming any rebuttal opinions.
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`Additionally, I reserve the right to prepare one or more visual aids or
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`demonstratives to illustrate my opinions, including at trial. I also reserve the right
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`7
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`to provide a technical tutorial to provide additional background information on my
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`opinions.
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`D. Expert Testimony in the Last Four Years
`17. The cases where I have testified at deposition and/or trial in the last
`
`four years are listed in my curriculum vitae. (Ex. 2029.)
`
`III.
`
`INSTITUTED GROUNDS OF UNPATENTABILITY
`I understand that the Patent Trial and Appeal Board (“Board”) has
`18.
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`instituted inter partes review of claims 1-6 of the ’786 patent based on four
`
`grounds of unpatentability.
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`19.
`
`In Ground 1, Mylan asserts that claim 1 of the ’786 patent would have
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`been obvious under 35 U.S.C. § 103 over the combination of Currie (Ex. 1005)4
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`and Li (Ex. 1006)5.
`
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`4 U.S. Patent No. 5,489,670 (Ex. 1005 (“Currie”).)
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`5 Li et al., “Purification, cDNA Sequence, and Tissue Distribution of Rat
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`Uroguanylin”, Regulatory Peptides, Vol. 68, No. 1, 45 (1997) (Ex. 1006 (“Li”).)
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`8
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`In Ground 2, Mylan asserts that claims 2, 4, and 5 of the ’786 patent
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`20.
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`would have been obvious under 35 U.S.C. § 103 over the combination of Currie,
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`Li, and Narayani (Ex. 1007)6.
`
`21.
`
`In Ground 3, Mylan asserts that claims 3-5 of the ’786 patent would
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`have been obvious under 35 U.S.C. § 103 over the combination of Currie, Li,
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`Narayani, and Campieri (Ex. 1008)7.
`
`22.
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`In Ground 4, Mylan asserts that claim 6 of the ’786 patent would have
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`been obvious under 35 U.S.C. § 103 over the combination of Currie, Li, and
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`Ekwuribe (Ex. 1009)8.
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`IV. LEGAL STANDARDS
`I have no formal legal training, but I have been informed by Bausch’s
`23.
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`counsel about the appropriate legal standards as set forth below and have applied
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`these standards in rendering my opinions. I reserve the right to supplement my
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`6 Narayani et al., “Polymer-Coated Gelatin Capsules as Oral Delivery Devices and
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`their Gastrointestinal Tract Behaviour in Humans”, Journal of Biomaterials Science,
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`Polymer Edition, Vol. 7, No.1, 39 (1995) (Ex. 1007 (“Narayani”).)
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`7 Campieri et al., “Oral Budesonide Is as Effective as Oral Prednisolone in Active
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`Crohn’s Disease,” Gut, Vol. 41, No. 2, 209 (1997) (Ex. 1008 (“Campieri”).)
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`8 U.S. Patent No. 5,359,030 (Ex. 1009 (“Ekwuribe”).)
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`9
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`report to take into account any modifications to these standards, if I am informed
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`of such.
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`24.
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`I have been informed and understand that to find a patent claim
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`unpatentable for obviousness, the claimed invention, as a whole, when considered
`
`against the prior art, as a whole, would have been obvious to a person having
`
`ordinary skill in the art at the time the invention was made. I understand that in
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`considering this issue, I must consider 1) the level of skill in the art, 2) scope and
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`content of the prior art, 3) differences between the claimed invention and prior art,
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`and 4) objective evidence of non-obviousness. I have been told by Bausch’s
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`counsel to assume the “time of the invention” mentioned above to be no later than
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`January 17, 2002.
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`25.
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`I have also been informed and understand that the claimed invention
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`and the prior art must each be looked at “as a whole” and that the party alleging an
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`invention is obvious has the burden of establishing that the art as a whole
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`motivates the person of ordinary skill in the art to make the invention as claimed
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`with a reasonable expectation of success in doing so. In this regard, I understand
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`that person of ordinary skill in the art would have considered teachings in the art
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`that may suggest as well as “teach away” from the claimed invention. It is not
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`sufficient to consider an isolated portion of one reference that is similar to what the
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`patent discloses and claims if the reference as a whole, another reference, or the
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`10
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`prior art as a whole teaches or suggests something different than that isolated
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`portion. I also understand that, in resolving whether an invention is obvious based
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`on the teachings of multiple references, one must consider whether the
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`combination yields no more than predictable results or achieves an unexpected
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`result.
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`26. With regard to assessing the inventiveness of a chemical compound, I
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`have also been informed that the law applies a “lead compound” analysis. In this
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`regard, I understand that a compound in the prior art can be considered a lead
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`compound if it would have been promising to modify in order to improve upon
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`its activity and obtain a compound with better activity. I understand that selection
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`of a lead compound is guided by all of the compound’s pertinent properties,
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`including properties that would have discouraged selecting the compound as a lead
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`candidate for further modification and improvement.
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`27.
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`I have also been informed that when objective evidence of non-
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`obviousness is presented, which I understand has been said to often be the best
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`evidence for a compound’s inventiveness, it should not be considered for its
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`“knockdown value” of an initial obviousness assessment based on the prior art but
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`must be collectively considered with all the evidence in assessing motivation and
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`expectation of success in making the claimed invention. I have been informed that
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`some examples of such objective indicia of non-obviousness include: 1) a long-felt
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`11
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`but unsolved need for the claimed invention, 2) the failure of others in the prior art
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`to fill this need, 3) unexpected or surprising results of the claimed invention, 4)
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`skepticism as to the inventor’s chances for success, 5) industry praise for the
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`invention, and 6) commercial success of the claimed invention. Indeed, I
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`understand that when objective evidence of non-obviousness is considered, such as
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`unexpected superior results or benefits, it can undercut a presumption that
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`structurally similar compounds would have been expected to have yield
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`comparable or similar results, leading to a conclusion of nonobviousness for the
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`claimed compound.
`
`28.
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`I have also been informed and understand that, in making an
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`obviousness determination, it is improper to consider the prior art with a hindsight
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`bias based on the teachings of the patent. One must not use the patent as a
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`template to suggest how the elements of the prior art could have been combined.
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`29. Finally, I have also been informed and understand Mylan must
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`demonstrate by a preponderance of the evidence that the asserted claims are
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`unpatentable. I understand that the preponderance of the evidence standard is one
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`characterized as being more likely than not. As each claim is considered a separate
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`invention, I understand that Mylan’s burden is applicable individually to each
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`claim.
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`12
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`V. A PERSON OF ORDINARY SKILL IN THE ART
`I understand that in determining the level of skill of a person of
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`ordinary skill in the field of the invention, the following factors may be considered:
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`(1) the educational level of the named inventor(s), (2) the type of problems
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`encountered in the art, (3) the prior art solutions to those problems, (4) the rapidity
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`with which innovations are made, and (5) the sophistication of the technology and
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`educational level of active workers in the field. I have considered each of these
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`factors in view of my experience in this field and I have applied my understanding
`
`of the level of skill of a person of ordinary skill in forming my opinions.
`
`31.
`
`In my opinion, a person of ordinary skill in the art would have a B.S.
`
`degree in chemistry or a related field and 2-5 years of experience in drug
`
`development that could include experience with peptide chemistry and/or peptide
`
`engineering. The person of ordinary skill in could also include individuals with a
`
`master’s degree or Ph.D. in chemistry or a related field with comparatively less
`
`experience in drug development involving peptide chemistry and/or peptide
`
`engineering. The person of ordinary skill in the art could have worked in
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`consultation with individuals with knowledge and experience with the target drug
`
`receptor and of the disease condition to be treated. In particular, this team could
`
`include a clinical pharmacologist with experience with the target drug receptor
`
`(here, guanylate cyclase-C (“GCC”) receptors), a medical doctor with experience
`
`13
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`in treating GI disorders, who may also have experience designing and running
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`clinical trials, or a pharmaceutical formulator.
`
`32. Dr. Peterson asserts that a person of ordinary skill in the art as of
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`January 17, 2002, “would typically have a Ph.D. in chemistry or protein
`
`engineering or a related field” and “could also include individuals with a master’s
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`degree in one of these fields plus two-to-five years of experience in drug
`
`development.” (Ex. 1002 ¶ 42.) Dr. Peterson further asserts that “[t]his individual
`
`would have worked in consultation with a team including, e.g., a pharmaceutical
`
`chemist or a pharmacist familiar with formulating peptides for administration.”
`
`(Id.) I disagree with Dr. Peterson’s definition of a person of ordinary skill in the
`
`art to the extent that it requires a Ph.D. degree. A person of ordinary skill in the art
`
`could have a B.S. degree in chemistry or a related field with 2-5 years of
`
`experience. My analysis and conclusion, however, would be the same under Dr.
`
`Peterson’s definition of a person of ordinary skill in the art.
`
`VI. SUMMARY OF OPINIONS
`I have been asked to provide my opinion as to whether the peptide
`33.
`
`plecanatide as recited in claim 1 of the ’786 patent is patentable over certain prior
`
`art references. I have also been asked to provide my opinion as to whether the
`
`compositions and peptide conjugates comprising the peptide plecanatide as recited
`
`in claims 2-6 of the ’786 patent are patentable over certain prior art references. It
`
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`is my opinion that the peptide, compositions, and peptide conjugates of claims 1-6
`
`are patentable.
`
`34. Dr. Peterson has failed to establish that any of the cited references
`
`render any of claims 1-6 obvious.
`
`35. First, a person of ordinary skill in the art would not have selected
`
`human uroguanylin as a lead compound because it was known to suffer from
`
`topoisomerism and because heat-stable enterotoxins (STs) did not and were known
`
`to be more stable, have higher binding affinities and cGMP production than human
`
`uroguanylin, and were pH-independent in terms of their activity.
`
`36. Second, a person of ordinary skill in the art would not have
`
`substituted Asp3 with Glu3 with a reasonable expectation of success.
`
`37. Nothing in the art suggested substituting Asp3 for Glu3 would have
`
`addressed human uroguanylin’s interconversion. In fact, the art expressly taught
`
`that the N-terminal region did not affect isomerization of uroguanylin and rather
`
`suggested a third disulfide bond for addressing interconversion.
`
`38. Similarly, nothing in the art suggested that the substitution would
`
`have improved the resulting peptide’s activity. A “conservative substitution,” if
`
`tolerated at all, would not have been expected to improve activity. Further, the art
`
`taught that Asp2 and Asp3 were required and responsible for human uroguanylin’s
`
`activity, and a person of ordinary skill in the art would not have substituted either
`
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`amino acid with an expectation of maintaining activity. Protonation likewise
`
`would not have been expected to improve activity at least because a person of
`
`ordinary skill in the art would have recognized that the side chains of Asp and
`
`Glu—when incorporated into a peptide chain—would remain protonated, and
`
`would deprotonate, at roughly the same pH. Moreover, the “additional benefit” of
`
`eliminating sources of aspartimide formation would not have motivated a person of
`
`ordinary skill in the art, nor does Dr. Peterson assert that it would have.
`
`39. Further, objective evidence of unexpected superior results underscores
`
`the lack of any reasonable expectation of success and reinforces the
`
`nonobviousness of plecanatide. In particular, nothing in the prior art—neither
`
`human uroguanylin nor rat uroguanylin—suggested the particular features of
`
`plecanatide would result in (1) stabilization against interconversion, (2) superior
`
`activity, (3) superior heat stability, and (4) superior binding affinity.
`
`VII. TECHNICAL BACKGROUND
`40. The compound of ’786 patented invention, plecanatide, is a
`
`therapeutic peptide developed and approved by the U.S. FDA for treatment of
`
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`constipation. (Ex. 2031.)9 Prior to January 2002, development of therapeutic
`
`peptides was, and continues to be, unpredictable. The unpredictability of
`
`chemistry is well-recognized, and a person of ordinary skill in the art knows that
`
`even small changes to a chemical compound, like a peptide, can have
`
`unpredictable effects on the resultant compound’s physical and chemical
`
`properties. Absent empirical testing, a person of ordinary skill in the art would not
`
`have any expectation as to the effects of a specific amino acid modification on a
`
`particular peptide, much less an expectation of improving the properties of the
`
`peptide. Indeed, without making and testing each specific peptide, a person of
`
`ordinary skill in the art would not know what properties the peptide would have
`
`had because, as mentioned, small variations in the amino acid chain can result in
`
`drastic changes in activity.
`
`41. This inherent unpredictability becomes even further exacerbated
`
`where, as here, the peptide will be used to bring about the therapeutic effect of
`
`treating constipation inside the human gastrointestinal (“GI”) tract, which is a
`
`complex organ with a myriad of changing conditions (such as pH) and endogenous
`
`
`9 “FDA approves Trulance for Chronic Idiopathic Constipation”, FDA News
`
`Release
`
`(January
`
`19,
`
`2017),
`
`https://www.fda.gov/news-events/press-
`
`announcements/fda-approves-trulance-chronic-idiopathic-constipation. (Ex. 2031.)
`
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`enzymes that can unpredictably impact and undermine how a particular therapeutic
`
`might be expected to behave.
`
`A. The Gastrointestinal Tract
`42. The GI tract includes the or