UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner,
`
`V.
`
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`
`
`IPR2022-00722
`Patent No. 7,041,786
`
`
`DECLARATION OF BLAKER. PETERSON,PH.D.
`
`MSN Exhibit 1002 - Page 1 of 129
`MSNv. Bausch - IPR2023-00016
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`

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`TABLE OF CONTENTS
`
`Page
`
`I.
`
`Hl.
`
`QUALIFICATIONS. ...... oc. cc ccececcceseescecceceeseeceessccucseceeececeesesesssceeseeeceseeeeeesesseseeeeecs ]
`
`S@OPE OP WORK csssssssssccsvecsnvsosnacwvonss.-......--csececoncsecsecceecceseeceececceeeeceeecensoaesonees 4
`
`II].©LEGAL STANDARDS .00...eeeeceseeecceeceeseeeeceseeeeceseeeeecaecaeceseeeeeesecaecaecteeeeeeneesteneees 5
`
`TV.
`
`OVERVIEW OF SHAILUBHAL. 000.22... .0cccceeee ccc ccccc cee cceeeeeeeecccceccecueeuseseecececeeceeassenens 7
`
`A. Claims of Shatlubhat ..0....0....0.ccceccceeccecceeeceecceeceeeseeeseecseecseeeeeenseeeeenseenes 12
`
`B. Prosecution History of Shailubhat...........00000000ccccecceecsscceeseceeeesseceeeseeees 13
`
`
`
`V.—-LEVEL OF ORDINARYSKILL............scc--ccecccecceesceeeceeeeeeeececeeceneeceeesceecneeeeesseeeess 14
`
`VI.
`
`CLAIM CONSTRUCTION...........2:ccecscceececeeeceeeceeeeceeeeceeesccecencesseaeceaeeeeseessaaeennees 15
`
`VIL,
`
`THE STATE OP THE. ARTwccssescsccosscuic........ccecccceesecsensesececeescensoeeccnsesseneeseeeesesess 16
`
`A. Peptide Hormonesin the Body and in Medicine............0..cece 16
`
`B. Biochemistry Foundation .0.......000.0.ccccccecccccccsccecssceeeeesceceesecesesseeeeesseeeeees 20
`
`C. Biology of Human Uroguanylin.......... cece cccceccececeeseecececeenseceeseessseese 23
`
`D. The Availability of Solid-Phase Peptide Synthesis for
`Preparation of Synthetic Analogs of Peptide Hormones.......................... 30
`
`E. Strategies for Engineering Peptides .......0.....000.cccecccceececeeeeseeceessceeeeneeeeees 34
`
`F. Assays for Measuring Therapeutic Activity for Clinical
`Constipation Were Well-Knownin the Art.........0.00cecceecceeeeeeeseeeeeeeeseeee 39
`
`G. Formulating Peptides with Intestinal Targets for Oral Delivery.............. 49
`
`H. Treating Constipation and Inflammation ........00..000cceececceeeeeeeteeeeeeeens 52
`
`VIII. THE ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF SHAILUBHAL...........0.00cccccccccccececssesececcceccecesssseseeecesees 53
`
`AL CUITIC ooo. eee ec cece cece ccececcesesseseeseaecesseececsseeccesseseeesseeceaseceessseseeseeeeetseseeesseeess 53
`
`Bl Li eoceecccccccccccccsccessccessecessceseseessscessesessecessscessescessecessesessesessscesseceesssesseeesees 55
`
`Ge NABAVOM ce ssscseesssrencoes nets teceme iL... uke ceuveccecensceececceceussesecsnsuceuscccecsrseccecscees 56
`
`DININGN cess cscncscsccmumseunrancasmaetpiigig....00+--000-cssancceseorcersenecesseanerenenescnsnacceseeneees 57
`
`E. EKWurtbe oo... cece ccc cececceeseesecesesseecessececscseceeseeeceesseecesseeesessseseesseeenses 58
`
`IX.
`
`GROUND 1. CLAIM 1 WAS OBVIOUS OVER CURRIE AND LI....0.....ceeeeeseeeeees 58
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`A. Currie Suggests Uroguanylins For Treating Constipation....................... 63
`
`B. Reason to Look to Synthetic Analogs of Human Uroguanylin................. 66
`C. Currie and Li Suggest a Glu’ Substitution as in Rat Uroguanylin............ 69
`
`D . The Known ChemicalProperties of Uroguanylins and Amino
`Acids Would Have Further Provided a Skilled Artisan with a
`Reasonable Expectation of Improving Constipation-Related
`Woclivily Cwousls Golet” SuabyetBatcress sre specs eeaneeecrneeasees Tt
`
`mH . Routine and Conventional Testing of Synthetic Analogs.............ccee 85
`
`F. The KnownIssue of Aspartimide Formation in Solid-Phase
`Peptide Synthesis Would Have Further Supported a Glu*
`Asalee ef Hiiiai UrORNGININ esi cccceonan aamunasaest 86
`
`G. Minimal Difference Between Currie’s Human Uroguanylin and
`the Claimed [Glu*]-Human Uroguanylin.....0..0.0.cccceeeceecesceceeceseseeeeseeeeees 87
`
`X.
`
`GROUND 2. CLAIMS 2, 4, AND 5 WERE OBVIOUS OVER CURRIE,LI,
`AND NARAYAN ........cccceceeescesssesseeeseeeseececeesneceseesaeeescesceeeaeceaeesteneeesaeeereeseeeens 88
`
`A. Formulating [Glu*]-Human Uroguanylin in a Unit Dose Form
`as Recited in Claim 2 Was ODVIOUS...........0.......ccccccccseseesceceeeeeessceeceseeseese 93
`
`B. Formulating [Glu*]-Human Uroguanylin in a Capsule as
`Recited in Claim 4 Was ODVIOUS..0........0.0..ccccccceecccceeescceeeeseecesssceeesseeeenes 97
`
`C. Formulating [Glu*]-Human Uroguanylin in a Unit Dose Form
`along with One or More Excipients as Recited in Claim 5 Was
`CNSUIS se scses ye ccsevecweaesesvea ei See sae SES UNG PURIS CSRS GORE UEAISE 98
`
`XI.
`
`GROUND 3. CLAIMS 3-5 WERE OBVIOUS OVER CURRIE, LI,
`NARAYANI, AND CAMPIERI............0c000sseseessssesssssssesessesssssssssssssssssessssssssseessees 100
`A. Formulating [Glu*]-Human Uroguanylin in a Unit Dose Form
`as Recited in Claim 3 Was ODVIOUS................cccccceescceeseceeeeeeesceeeeeeeeseeees 103
`
`B. Formulating [Glu*]-Human Uroguanylin with an Anti-
`Inflammatory Agent in a Capsule with One or More Excipients
`as Recited in Claims 4 and 5 Would Have Been Obvious..................... 107
`
`XII. GROUND 4. CLAIM 6 WAS OBVIOUS OVER CURRIE, LI, AND
`ERWORIBE sicsscsswrcacisesavsavvceseerassieveets......00cccccccccesencccenecccesanceesessncssaneccnesensenens 108
`
`XIII. SECONDARY CONSIDERATIONS ......ccc0c0cccccccecceceesssesceeeceecesessesersseeeeeeeeeeeeeeees 116
`
`XIV. CONCLUDING STATEMENTS..........::0:cccccccccceececssceceecesseceeeeeessesseeeeessesseeeeeenaaes 119
`
`MSN Exhibit 1002 - Page 3 of 129
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`-ll-
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`XV. APPENDIX — LIST OF EXHIBITS...0.....0.00cccccccccccccssssseceececeecessesesesseeeeceeeeeeeeeeenes 121
`
`MSNExhibit 1002 - Page 4 of 129
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`-iii-
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`

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`I, Blake R. Peterson, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1,
`
`I am the John W. Wolfe Chair in Cancer Research with a focus on
`
`Medicinal Chemistry and Chemical Biology at The Ohio State University (OSU). I
`
`have held faculty appointments from 1998 to the present. My research for over two
`
`decades has been directed toward understanding and developing small molecule
`
`probesfor biological systems. This research included the developmentof small
`
`molecules and peptides that promote cellular uptake of proteins, the synthesis and
`
`evaluation of antiviral agents and anticancer agents, the identification of biological
`
`targets of small molecules, and the construction of new types of fluorescent probes
`
`for immunology and cancerbiology.
`
`2.
`
`I also currently serve as a Professor of Medicinal Chemistry and
`
`Pharmacognosy at OSU, as well as Chair of the Division of Medicinal Chemistry
`
`and Pharmacognosy at OSU. I also serve as Co-Leader of the Translational
`
`Therapeutics Program of the OSU Comprehensive Cancer Center (CCC) and as
`
`Co-Director of the Medicinal Chemistry Shared Resource of the OSU CCC.
`
`3.
`
`I previously served as a Regents Distinguished Professorin the
`
`Department of Medicinal Chemistry at the University of Kansas (KU) School of
`
`Pharmacy from 2008-2019. I also served for seven years as Co-Leaderof the
`
`Synthetic Chemical Biology Core Facility at the KU.
`
`MSN Exhibit 1002 - Page 5 of 129
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`

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`4.
`
`Prior to joining the faculty at the KU,I served as an Assistant
`
`Professor (1998-2004) and Associate Professor with tenure (2004-2007) in the
`
`Department of Chemistry at The Pennsylvania State University (PSU). While at
`
`PSU, I was a memberofthe Life Sciences Consortium, of the Center for
`
`Biomolecular Structure and Function, of the Cancer Center, and of the
`
`Experimental Therapeutics Program of the PSU Hershey Medical School.
`
`5.
`
`Thus, my faculty appointments encompass 23 years of experience
`
`with teaching and research in organic chemistry, medicinal chemistry, and
`
`chemical biology.
`
`6.
`
`I earned my Ph.D. in Chemistry from the University of California, Los
`
`Angeles in 1994. My Ph.D. research wasin bioorganic chemistry, where I used
`
`organic chemistry methods to synthesize small molecules termed “synthetic
`
`receptors,” followed by evaluation oftheir affinities for steroids, such as
`
`cholesterol and steroid hormonesin aqueoussolution.
`
`T.
`
`I was subsequently a postdoctoral fellow in Chemical Biologyat
`
`Harvard University from 1995-1998. My postdoctoral research was in
`
`biochemistry, molecular biology, and chemical biology, and involved using genetic
`
`assays and biochemical systemsto investigate the molecular basis of interactions
`
`of transcription factor proteins that control activation of T-cells. This research
`
`identified specific amino acids that mediate cooperative binding of the
`
`MSN Exhibit 1002 - Page 6 of 129
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`

`

`transcription factors activator protein 1 (AP-1) and nuclear factor of activated T-
`
`cells (NFAT) to DNA. Theseproteins are involved in regulating expression of the
`
`cytokine IL-2, which plays a central role in the T-cell-mediated inflammatory
`
`response.
`
`8.
`
`I have received manyresearch grants and have beenthe principal
`
`investigator for multiple major research andtraining grants such as: “Synthetic
`
`Lethal Targeting of Growth Factor Receptors” NCI RO1; “Tissue-Specific Delivery
`
`of Probes by Control of MembraneTrafficking of Endoprotease Substrates” NIH
`
`RC1; and “A New Approach for Systemic Delivery of siRNA: Cholesterylamine
`
`Conjugates that Target and Selectively Disrupt Early / Recycling Endosomes”
`
`Novartis Institutes for Biomedical Research.
`
`9.
`
`Additionally, over the past ten years, I served as a co-investigator on
`
`five grants, including: “Molecular Analysis of Disease Pathways” NIH COBRE
`
`and “Development of Antiviral Therapeutics for Dengue” NationalInstitutes of
`
`Health-U01. As part of the Molecular Analysis of Disease Pathways COBRE
`
`grant, | was funded to create and co-lead a new corefacility at KU that offers the
`
`synthesis of molecular probes andassociated fluorescent imaging services to
`
`faculty researchers at KU and beyond.
`
`10. My workhasbeen published in numerousprestigious journals,
`
`including Journal of the American Chemical Society and Angewandte Chemie.|
`
`3
`
`MSNExhibit 1002 - Page 7 of 129
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`have over 80 peer reviewed publications, as well as over 10 non-peer reviewed
`
`publications and abstracts. I have also authored or co-authored two book chapters.
`
`I have additionally provided manuscript reviews for over 200 publications in
`
`upwards of 60 scientific journals, including Proceedingsof the National Academy
`
`ofSciences USA, Nature Methods, and Journal of the American Chemical Society.
`
`11.
`
`Fora more detailed listing of my credentials and publications, please
`
`see my curriculum vitae, EX 1003.
`
`IL.
`
`SCOPE OF WORK
`
`12.
`
`IT understand that Mylan Pharmaceuticals Inc. (“Mylan”) is filing a
`
`petition with the United States Patent and Trademark Office for /nier Partes
`
`Review of U.S. Patent No. 7,041,786 to Shailubhai (“Shailubhai,” EX1001).
`
`Mylan retained meas a technical expert in this matter to provide my opinions
`
`regarding Shailubhai related to my experience and expertise.
`
`13. My opinionsare based on myskills, knowledge, training, education,
`
`and experience in matters of this nature, and my examination of the materials used
`
`in preparing this testimony. In addition to Shailubhai, I have also reviewed and
`
`considered various other documents in arriving at my opinions and cite them in this
`
`declaration. For convenience, documents cited in this declaration are listed in the
`
`Appendix in Section XV. Myopinionsare based on the current record, so I reserve
`
`the ability to refine my opinions based on additional facts.
`
`Ae
`
`MSNExhibit 1002 - Page 8 of 129
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`14. Mylan is compensating meat the rate of $475 per hourfor services.
`
`No part of my compensation is dependent on my opinionsor the outcomeofthis
`
`proceeding, and I have no otherfinancial interest in the outcomeofthis matter.
`
`Ill.
`
`LEGAL STANDARDS
`
`15.
`
`I have been advised that the burden in this proceeding is on Mylan to
`
`demonstrate the unpatentability of the challenged claims.
`
`16._I have been advised that a claimed invention is not patentable for
`
`obviousnessif the differences between the claimed invention and the priorart are
`
`such that the subject matter as a whole would have been obviousat the time the
`
`claimed invention was madethe person of ordinary skill in the art to which the
`
`subject matter of the invention pertains.
`
`17.
`
`understand that a determination of obviousness requires inquiries
`
`into: (i) the scope and content of the art when the claimed invention was made;
`
`(ii) the differences betweenthe art and the claimsat issue; (ii/) the level of ordinary
`
`skill in the pertinent art when the claimed invention was made;and,to the extent
`
`any exist, (iv) secondary considerations indicating non-obviousness.
`
`18.
`
`I understand that hindsight must not be used when comparing the
`
`prior art to the claimed invention for obviousness. Thus, a conclusion of
`
`obviousness must be firmly based on the knowledge and skill of the artisan at the
`
`time the claimed invention was made, without the use of post-filing knowledge.
`
`MSNExhibit 1002 - Page 9 of 129
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`5.
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`

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`19.
`
`J understand that in order for a claimed invention to be considered
`
`obvious, there must be somerational underpinning for combining cited references
`
`as proposed. I further understand that obviousness mayalso be shown by
`
`demonstrating that it would have been obvious to modify what is taught in a single
`
`piece ofprior art to create the claimed invention. Obviousness may be shown by
`
`demonstrating that the skilled artisan would have found it obvious to combine the
`
`teachings of more than one elementdisclosed by priorart.
`
`20.
`
` Iunderstand that the following examples are approaches and
`
`rationales that may be considered in determining whethera piece ofprior art could
`
`have been combined with otherprior art or with other information within a skilled
`
`artisan’s knowledge:
`
`(i)
`
`combining prior-art elements according to known methodsto yield
`
`predictable results;
`
`(ii)
`
`substituting one known element for another to obtain predictable
`
`results;
`
`(111) using a knowntechnique to improvesimilar devices (methods, or
`
`products) in the same way;
`
`(iv)
`
`applying a knowntechnique to a known device (method,or product)
`
`that was ready for improvementto yield predictable results;
`
`(v)
`
`applying a technique or approach that would have been “obvious to
`
`try” (7.e., choosing something from a finite numberofidentified,
`
`predictable solutions, with a reasonable expectation of success);
`
`(vi)
`
`applying variations based on known workin onefield of endeavor for
`
`MSNExhibit 1002 - Page 10 of 129
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`6
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`use in either the samefield 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; or
`
`(vil) acting upon someteaching, suggestion, or motivation in the prior art to
`
`modify the prior-art reference or to combineprior-art reference
`
`teachings thereby arriving at the claimed invention.
`
`21.
`
`I have been instructed that “secondary considerations” will be
`
`considered whenpresent. Counsel have informed methat such secondary
`
`considerations, where evident, may include: (/) commercial success of a product
`
`due to the merits of the claimed invention; (i/) a long-felt but unsatisfied need for
`
`the claimed invention; (ii/) failure of others to find the solution provided by the
`
`claimed invention; (iv) deliberate copying of the claimed invention by others; (v)
`
`unexpected results achieved by the claimed invention; (vi) praise of the claimed
`
`invention by others skilled in the art; (vii) lack of independent, simultaneous
`
`invention within a comparatively short span of time; and (viii) teaching away from
`
`the claimed invention in the prior art. | am informed that secondary considerations
`
`are relevant wherethere is a nexus between the evidence and the claimed
`
`invention.
`
`22.
`
`Jam informedthat the patent owner, Bausch Health Ireland Ltd.
`
`(“Bausch”), bears the burden to establish any secondary considerations indicating
`
`non-obviousness.
`
`
`
`TV.OVERVIEWSHAILUBHAIOF MSNExhibit 1002 - Page 11 of 129
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`MSNv. Bausch - IPR2023-00016
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`23.
`
`Shailubhaiis entitled “Guanylate Cyclase Receptor Agonists for the
`
`Treatment of Tissue Inflammation and Carcinogenesis.” EX1001, [54]. Shailubhai
`
`is generally directed to a 16-residue peptide and compositions thereoffor treating
`
`cancer. EX1001, [57], 2:1-61, 3:61-4:42. The peptide is defined in the patent as
`
`“consisting of the amino acid sequence of SEQ ID NO: 20,” whichis the sequence
`
`shown below.
`
`Asn’ Asp” Glu’ Cys* Glu® Leu® Cys’ Val® Asn® Val?® Ala’? Cys’? Thr’? Gly*’ cys’® Leu’®
`*
`ee
`*
`ee
`
`EX1001, 5:5-16, claims 1-3, 6. As the asterisk notations indicate, a first disulfide
`
`linkage exists between the cysteines at positions 4 and 12 in the sequence, and a
`
`second disulfide linkage exists between the cysteines at positions 7 and 15. Jd.
`
`24.
`
` Inote that Shailubhai acknowledges that the sequence ofthis claimed
`
`peptide (reproduced below, top) differs only from the naturally-occurring human
`
`uroguanylin sequence (reproduced below, bottom) by one amino acid, shownin
`
`bold in the sequences below:
`
`Asn! Asp? Glu? Cys* Glu’ Leu® Cys’ Val® Asn? Val!® Ala!! Cys!* Thr!? Gly'* Cys! Leu!®
`
`Asn! Asp* Asp? Cys* Glu? Leu® Cys’ Val® Asn? Val!° Ala!! Cys! ThrGly'# CysLeu!®
`
`Id., 7:55-58.
`
`25.
`
`Thus, the claimed peptide differs from the native human uroguanylin
`
`sequence only in that a glutamic acid (Glu) residue has been swapped in for the
`
`MSNExhibit 1002 - Page 12 of 129
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`-8-
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`aspartic acid (Asp) residuein the third position. As I discuss in more detail below,
`
`these are the only acidic aminoacid residues with negatively-charged side chains
`
`at physiologically-relevant pH values. That is, both of these amino acids possess
`
`carboxylic acid groups that become deprotonated under physiological conditions.
`
`Upondeprotonation, glutamic and aspartic acid mayalso bereferred to as
`
`glutamate and aspartate. I use both of these terms throughout this declaration. For
`
`convenience, and to assist in visualizing these amino acids, I provide the chemical
`
`structures of these residues below, shownin their deprotonatedstate.
`
`O
`Hy
`9
`Hy
`NL NL
`
`C0,"
`
`Coz
`
`Glu
`
`Asp
`
`26. Ascan be seen above,these aminoacidsdiffer structurally from one
`
`anotherin that the Glu residue, shown onthe left, has an additional methylene unit
`
`(-CH2-) in its side chain compared to Asp, shown on theright.
`
`27.
`
`Conventional amino acid nomenclature provides one- and three-letter
`
`codes for each aminoacid (e.g., E or Glu for glutamic acid). I refer to the claimed
`
`peptide consisting of the amino acid sequence of SEQ ID NO:20 throughoutthis
`
`_
`
`declaration as “[Glu*]-human uroguanylin’—indicating the sequenceis that of
`
`human uroguanylin wherethe aspartic acid (Asp)at the third position has been
`
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`swapped for a glutamic acid (Glu).
`
`28.
`
`I note that Shailubhai acknowledgesthat these types of synthetic
`
`analogs could be synthesized and purified using known,published procedures.
`
`EX1001, 15:53-55, see alsoid., 16:1-19, Table 4, 18:32. Shailubhai further
`
`acknowledges that the resulting peptides could be formulated and made into
`
`different dosage forms “using methods well knownin theart.” /d., 13:27-30 (citing
`
`Remington’s Pharmaceutical Sciences, 16" ed., A. Oslo ed., Easton PA. (1980));
`
`see also EX1010', generally. | agree that a skilled artisan would have beenable to
`
`formulate the peptides described in Shailubhai into different dosage forms using
`
`methods well knownin the art, and discuss such formulations in Sections VII.G
`
`and X-XII, below.
`
`29.
`
`Asdiscussed in more detail below, a skilled artisan would have had
`
`good reason to make [Glu*]-humanuroguanylin by replacing the aspartic acid at
`
`human uroguanylin’s third position with a glutamic acid, and further to formulate
`
`the resulting peptide using known, routine, and conventional methods to yield a
`
`composition for potential medical applications. In particular, a skilled artisan
`
`would have reasonably expected such a substitution to maintain or improve human
`
`' King, R. E., Chapter 89: Tablets, Capsules, and Pills, REMINGTON’S
`PHARMACEUTICALSCIENCES,16” ed., (ed. A. Oslo, ed., Mack Publishing Co.)
`1980 (“Remington’s,” EX1010).
`
`MSN Exhibit 1002 - Page 14 of 129
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`uroguanylin’s activity in treating inflammatory boweldisease and related
`
`constipation, as well as to improvethe stability of uroguanylin during synthesis.
`
`See my discussion in Sections VII-XII. A skilled artisan would have seen the
`
`claimed invention as simply an obvious combination of familiar elements using
`
`known methodsto achieve a predictable result.
`
`30.
`
`ILalso note that Shailubhai describes the development of [Glu*]-human
`
`uroguanylin as being the result of computational chemistry calculations. Asis
`
`readily apparent from the Shailubhai disclosure, this computational work involved
`
`only known methodsof performing computational analyses to identify
`
`energetically interesting analogs of human uroguanylin. See, e.g., EX1001, 7:52-
`
`12:45; see also id., 7:52-55 (“Molecular modeling wasapplied to the design of
`
`novel guanylate cyclase receptor agonists using methodsdetailed in (30).”), 8:9-12
`
`(“Energy calculations were performed by use of build-up procedures(30). The
`
`ECEPP/2 potential field (31,32) was used...”), 8:22-28 (“At this step, all possible
`
`combinations...were considered. ..according to the notation in (33).”), 8:50-58
`
`(“[M]issing side chains in the model fragments were restored, and energy
`
`calculations were performed again...employing an algorithm previously described
`
`(34).”), 9:2-5 (“The best fit in the superposition...was assessed...according to
`
`(35).”), 18:20-29 (providing citations for these known computational methods).
`
`Thus, rather than creating any novel analysis or method for analog exploration,
`
`She
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`MSN Exhibit 1002 - Page 15 of 129
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`Shailubhai merely performed conventional calculations in a routine way to confirm
`
`the potential utility of an already obvious structural analog.
`
`A. Claimsof Shailubhai
`
`31.
`
`I understand that Shailubhai includes 6 claims. Four of those claims—
`
`claims 1, 2, 3, and 6—are independent, while the remaining two claimsare
`
`dependentclaims. I understand a dependentclaim includesall limitations of the
`
`claim from whichit depends.
`
`32.
`
`Each claim is directed to a 16-residue peptide or compositionsthereof.
`
`The peptide, which I refer to as “[Glu*]-human uroguanylin,” is defined in the
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`patent as “consisting of the amino acid sequence of SEQ ID NO: 20,” whichis the
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`sequence shown below.
`
`Asn’ Asp? Glu? Cys* Glu® Leu® Cys’ Val® Asn® Val’® Ala’? cys’? Thr’? Gly** cys** Leu’®
`*
`kk
`*
`**
`
`EX1001, 5:5-16, claims 1-3, 6. As the asterisk notations indicate, [Glu*]-human
`
`uroguanylin hasa first disulfide linkage between the cysteines at positions 4 and 12
`
`in the sequence, and a second disulfide linkage between the cysteines at positions 7
`
`and 15. Id.
`
`33.
`
`Independentclaim | recites:
`
`1. A peptide consisting ofthe amino acid sequence ofSEQ ID NO:20.
`
`34.
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`Independentclaim 2 recites:
`
`2. A composition in unit dose comprising a guanylate cyclase receptor
`
`-13
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`agonist peptide consisting of the amino acid sequence of SEQ ID
`
`NO:20.
`
`35.
`
`Independent claim 3 recites:
`
`3. A composition in unit doseform comprising:
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`a) a guanylate cyclase receptor agonist peptide consisting ofthe
`
`amino acid sequence ofSEQ ID NO:20; and
`
`b) at least one compoundselectedfrom the group consisting of:
`
`a cGMP-dependent phosphodiesterase inhibitor, an anti-
`
`inflammatory agent, an antiviral agent and an anticancer
`
`agent.
`
`36.
`
`Independentclaim 6 recites:
`
`6. A peptide conjugate comprising polyethylene glycol
`
`(PEG)
`
`attached to a peptide consisting of the amino acid sequence SEQ ID
`
`NO:20.
`
`37.
`
`Claim 4 depends from claim 2 or 3 and further recites known unit
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`dose forms. Claim 5 also depends from claim 2 or 3 and further recites that the
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`composition further comprises “one or more excipients.” I discuss these limitations
`
`in more detail in my detailed claim analysis below.
`
`B. Prosecution History of Shailubhai
`
`38.
`
`[have been advised that the examination process, or prosecution
`
`history of the application that led to the Shailubhai patent (EX 1004) may be
`
`relevant to my analysis of the patentability of the claims. I understand that the
`
`“13
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`application that led to Shailubhai wasfiled on March 28, 2002. EX1001, [22]. I
`
`understand that Shailubhai purports to claim priority to U.S. Provisional Patent
`
`Application No. 60/348,646, filed January 17, 2002. /d., [60]; EX1054 (“the 646
`
`provisional”). For the purposes of my opinions, I have assumed that Shailubhaiis
`
`entitled to claim priority to the ’646 provisional.
`
`39. However, I have reviewed the ’646 provisional and note that it does
`
`not mention treating constipation or the use of [Glu*]-human uroguanylin as a
`
`therapeutic for treating constipation. See EX1054.
`
`V.
`
`LEVEL OF ORDINARY SKILL
`
`40.
`
`I have been advised that the person of ordinary skill in the art is a
`
`hypothetical person who is presumed to have knownthe relevantart at the time of
`
`the claimed invention. The skilled artisan is also a person of ordinary creativity. I
`
`have been advisedthat the skilled artisan to whom one could assign a routine task
`
`with reasonable confidencethat the task would be successfully carried out.
`
`41.
`
`Ihave been advisedthat the relevant timeframe for my analysis is the
`
`time period prior to January 17, 2002—theearliest claimed priority date for
`
`Shailubhai. See Section IV.B, above. Unless otherwise specifically noted, all of my
`
`opinions expressed here regarding the skilled artisan apply to the skilled artisan as
`
`of January 17, 2002.
`
`42.
`
`By virtue of my education, experience, and training, I am familiar
`
`id
`
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`with the level of ordinary skill in the art of Shailubhai. A skilled artisan as of
`
`January 17, 2002 would typically have a Ph.D. in chemistry or protein engineering
`
`or a related field. Skilled artisans could also include individuals with a master’s
`
`degree in one of these fields plus two-to-five years of experience in drug
`
`development. This individual would have worked in consultation with a team
`
`including, e.g., a pharmaceutical chemist or a pharmacist familiar with formulating
`
`peptides for administration. This level of skill is consistent with that presumed by
`
`Shailubhai itself. See Section IV.
`
`43.
`
`Furthermore, skilled artisans would be familiar with priorart
`
`pertaining to signaling peptides and their biochemistry, including the patents and
`
`publications discussed in this declaration. My education, experience, and training
`
`qualify me to opine asa skilled artisan regarding the understanding ofa skilled
`
`artisan at the relevant time, as I am and was by 2002 a person of ordinary skill in
`
`theart.
`
`VI.
`
`CLAIM CONSTRUCTION
`
`44.
`
`| have been advised that the claim terms of Shailubhai are to be given
`
`their plain and ordinary meaning,i.e., the meaning that the terms would have had
`
`to a skilled artisan at the time of the claimed invention.
`
`45.
`
`[understand that this analysis focuses on intrinsic evidence, including
`
`how the patentee used the claim term in the claims, specification, and prosecution
`
`15
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`history. I also understand that dictionaries or other extrinsic sources mayassist in
`
`determining the plain and ordinary meaning but cannot override a meaningthatis
`
`unambiguous from the intrinsic evidence. I have followed these principles in my
`
`analysis throughoutthis declaration.
`
`VII. THE STATE OF THE ART
`
`A. Peptide Hormonesin the Body and in Medicine
`
`46.
`
`Peptides are short chains of amino acids linked together covalently
`
`through peptide bonds. See, e.g., EX1011, 1088 (describing, e.g., “peptides of
`
`some 20-30 aminoacid residues”).* Peptide chains fold into three dimensional
`
`structures that are commonly called proteins. Peptide function involves the
`
`reversible and specific binding of peptide ligandsto the bindingsite of a receptor.
`
`EX1012, 203.° A peptide ligand “discriminate[s] among the thousandsof different
`
`molecules in its environment andselectively bind[s] only one or a few” based on
`
`the physical and chemical properties of the receptor and the ligand. Jd.
`
`47.
`
`Peptides that function as chemical messengersare called peptide
`
` Rehfeld, J. F., Zhe New Biology ofGastrointestinal Hormones, PHYSIOL. REV.,
`78(4), 1998, 1087-1108 (“Rehfeld”, EX1011).
`> Nelson, D. L., et al., Chapters 4-5, 7, LEHNINGER PRINCIPLES OF
`BIOCHEMISTRY,3rd ed. (eds. Ryan, M., ef a/., Worth Publishers) 2000 (“Nelson,”
`EX1012).
`
`16
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`hormones. See generally EX1013.4 In the paragraphsthat follow, I will explain this
`
`process in greater detail. For summary purposes, however, it is helpful to
`
`understand that a particular peptide hormone maybind with the extracellular
`
`portion of a protein structure that extends through a membrane (membrane-bound
`
`protein). This binding interaction may change the shape (conformation) of the
`
`membrane-boundprotein, thus changing the way the intracellular portion of the
`
`membrane-boundprotein interacts with other proteins within the cell, for example.
`
`In this way, the body uses peptides to generate signaling cascadesto activate
`
`(agonist hormones)or deactivate (antagonist hormones) functions within the body.
`
`48. Well before 2002, skilled artisans knew many examplesofnaturally-
`
`occurring peptide hormones. Insulin is an example discovered more than 100 years
`
`ago. Rehfeld confirmsthat skilled artisans were aware of many peptide hormones,
`
`including peptide hormonesthat act on receptors located in the gut. EX1011, 1087.
`
`According to Rehfeld, “more than 30 peptide hormone genes are knownto be
`
`expressed throughout the digestive tract, which makes the gut the largest endocrine
`
`organ in the body.” EX1011, 1087. Rehfeld also reports that skilled artisans had
`
`identified “many more gut hormones, and each has its own or even more receptors,
`
`4 Segaloff, D. L., et al., Chapter 9: Internalization ofPeptide Hormones and
`Hormone Receptors, HORMONES AND THEIR ACTIONS,PARTI, (eds. Cooke, B. A.,
`et al., Elsevier) 1988, 133-149 (“Segaloff,” EX1013).
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`although, vice versa, there are also examples showing that different gastrointestinal
`
`peptides may act on the same receptor.” EX1011, 1088.
`
`49.
`
`By 2002, skilled artisans understood that peptide hormones, including
`
`those regulating the gut, transmit signals by binding to their receptors expressed on
`
`the surface of certain cells. Segaloff confirmsthat the “ability of a particular
`
`peptide hormoneto elicit an effect in the appropriate target cell is dictated by the
`
`presence of receptors on the surface of the target cell which specifically bind that
`
`hormone.” EX1013, 133. It also was knownthat the sensitivity of any given cell to
`
`a particular hormone depends on the numberof receptors that cell expressed for the
`
`particular hormone. Segaloff states, for example, that “the amount of hormonethat
`
`is processed in this case is dictated by the number of hormonereceptors.” EX1013,
`
`139.
`
`50.
`
`It was well known before 2002 that hormone-receptor bindingis
`
`driven both by the physical shape of the binding sites of the hormone and the
`
`receptor as well as by their chemical properties. For example, it was knownthat
`
`complementary electrostatic interactions between the hormone and receptor, across
`
`their interface, promote the bindingrelationship of ligand to receptor, thereby
`
`promoting their signaling activity. In addition to other physical and chemical
`
`forces, the binding interaction may be promoted when wateris excluded from the
`
`binding region as the hormone locks together with the receptor. Chipens, for
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`example, describes hormone-receptor binding as both a mutual recognition
`
`between the molecules and a thermodynamically driven desolvation (water
`
`removal) at the hormone-receptor interface. EX1014, 100.° As Chipens published
`
`in 1978, skilled artisans long understood the powerof properly designed
`
`counterion interactions between hormon