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 BLAKE R. PETERSON, PH.D.
`
`MYLAN EXHIBIT - 1002
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd. - IPR2022-00722
`
`

`

`TABLE OF CONTENTS
`
` Page
`
`QUALIFICATIONS............................................................................................... 1
`I.
`SCOPE OF WORK ............................................................................................... 4
`II.
`LEGAL STANDARDS .......................................................................................... 5
`III.
`IV. OVERVIEW OF SHAILUBHAI ............................................................................... 7
`A. Claims of Shailubhai ................................................................................ 12
`B. Prosecution History of Shailubhai ............................................................ 13
`LEVEL OF ORDINARY SKILL ............................................................................ 14
`V.
`VI. CLAIM CONSTRUCTION ................................................................................... 15
`VII. THE STATE OF THE ART .................................................................................. 16
`A. Peptide Hormones in the Body and in Medicine ...................................... 16
`B. Biochemistry Foundation ......................................................................... 20
`C. Biology of Human Uroguanylin ............................................................... 23
`D. The Availability of Solid-Phase Peptide Synthesis for
`Preparation of Synthetic Analogs of Peptide Hormones .......................... 30
`E. Strategies for Engineering Peptides ......................................................... 34
`F. Assays for Measuring Therapeutic Activity for Clinical
`Constipation Were Well-Known in the Art .............................................. 39
`G. Formulating Peptides with Intestinal Targets for Oral Delivery .............. 49
`H. Treating Constipation and Inflammation ................................................. 52
`VIII. THE ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF SHAILUBHAI .............................................................. 53
`A. Currie ........................................................................................................ 53
`B. Li ............................................................................................................... 55
`C. Narayani .................................................................................................... 56
`D. Campieri ................................................................................................... 57
`E. Ekwuribe ................................................................................................... 58
`IX. GROUND 1. CLAIM 1 WAS OBVIOUS OVER CURRIE AND LI .......................... 58
`
`-i-
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`

`

`X.
`
`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 Glu3 Substitution as in Rat Uroguanylin ........... 69
`D. The Known Chemical Properties of Uroguanylins and Amino
`Acids Would Have Further Provided a Skilled Artisan with a
`Reasonable Expectation of Improving Constipation-Related
`Activity through Glu3 Substitution ........................................................... 77
`E. Routine and Conventional Testing of Synthetic Analogs ........................ 85
`F. The Known Issue of Aspartimide Formation in Solid-Phase
`Peptide Synthesis Would Have Further Supported a Glu3
`Analog of Human Uroguanylin ................................................................ 86
`G. Minimal Difference Between Currie’s Human Uroguanylin and
`the Claimed [Glu3]-Human Uroguanylin. ................................................ 87
`GROUND 2. CLAIMS 2, 4, AND 5 WERE OBVIOUS OVER CURRIE, LI,
`AND NARAYANI .............................................................................................. 88
`A. Formulating [Glu3]-Human Uroguanylin in a Unit Dose Form
`as Recited in Claim 2 Was Obvious ......................................................... 93
`B. Formulating [Glu3]-Human Uroguanylin in a Capsule as
`Recited in Claim 4 Was Obvious ............................................................. 97
`C. Formulating [Glu3]-Human Uroguanylin in a Unit Dose Form
`along with One or More Excipients as Recited in Claim 5 Was
`Obvious ..................................................................................................... 98
`XI. GROUND 3. CLAIMS 3-5 WERE OBVIOUS OVER CURRIE, LI,
`NARAYANI, AND CAMPIERI ........................................................................... 100
`A. Formulating [Glu3]-Human Uroguanylin in a Unit Dose Form
`as Recited in Claim 3 Was Obvious ....................................................... 103
`B. Formulating [Glu3]-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
`EKWURIBE .................................................................................................... 108
`XIII. SECONDARY CONSIDERATIONS ..................................................................... 116
`XIV. CONCLUDING STATEMENTS .......................................................................... 119
`
`-ii-
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`XV. APPENDIX – LIST OF EXHIBITS ..................................................................... 121
`
`-iii-
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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
`
`probes for biological systems. This research included the development of 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 cancer biology.
`
`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 Professor in 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-Leader of the
`
`Synthetic Chemical Biology Core Facility at the KU.
`
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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 member of the 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 was in bioorganic chemistry, where I used
`
`organic chemistry methods to synthesize small molecules termed “synthetic
`
`receptors,” followed by evaluation of their affinities for steroids, such as
`
`cholesterol and steroid hormones in aqueous solution.
`
`7.
`
`I was subsequently a postdoctoral fellow in Chemical Biology at
`
`Harvard University from 1995-1998. My postdoctoral research was in
`
`biochemistry, molecular biology, and chemical biology, and involved using genetic
`
`assays and biochemical systems to 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
`
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`
`

`

`transcription factors activator protein 1 (AP-1) and nuclear factor of activated T-
`
`cells (NFAT) to DNA. These proteins 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 many research grants and have been the principal
`
`investigator for multiple major research and training grants such as: “Synthetic
`
`Lethal Targeting of Growth Factor Receptors” NCI R01; “Tissue-Specific Delivery
`
`of Probes by Control of Membrane Trafficking 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” National Institutes of
`
`Health-U01. As part of the Molecular Analysis of Disease Pathways COBRE
`
`grant, I was funded to create and co-lead a new core facility at KU that offers the
`
`synthesis of molecular probes and associated fluorescent imaging services to
`
`faculty researchers at KU and beyond.
`
`10. My work has been published in numerous prestigious journals,
`
`including Journal of the American Chemical Society and Angewandte Chemie. I
`
`-3-
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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 Proceedings of the National Academy
`
`of Sciences USA, Nature Methods, and Journal of the American Chemical Society.
`
`11.
`
`For a more detailed listing of my credentials and publications, please
`
`see my curriculum vitae, EX1003.
`
`II.
`
`SCOPE OF WORK
`
`12.
`
`I understand that Mylan Pharmaceuticals Inc. (“Mylan”) is filing a
`
`petition with the United States Patent and Trademark Office for Inter Partes
`
`Review of U.S. Patent No. 7,041,786 to Shailubhai (“Shailubhai,” EX1001).
`
`Mylan retained me as a technical expert in this matter to provide my opinions
`
`regarding Shailubhai related to my experience and expertise.
`
`13. My opinions are based on my skills, 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. My opinions are based on the current record, so I reserve
`
`the ability to refine my opinions based on additional facts.
`
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`

`

`14. Mylan is compensating me at the rate of $475 per hour for services.
`
`No part of my compensation is dependent on my opinions or the outcome of this
`
`proceeding, and I have no other financial interest in the outcome of this matter.
`
`III. 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
`
`obviousness if the differences between the claimed invention and the prior art are
`
`such that the subject matter as a whole would have been obvious at the time the
`
`claimed invention was made the person of ordinary skill in the art to which the
`
`subject matter of the invention pertains.
`
`17.
`
`I 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 between the art and the claims at issue; (iii) 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.
`
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`

`

`19.
`
`I understand that in order for a claimed invention to be considered
`
`obvious, there must be some rational underpinning for combining cited references
`
`as proposed. I further understand that obviousness may also be shown by
`
`demonstrating that it would have been obvious to modify what is taught in a single
`
`piece of prior 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 element disclosed by prior art.
`
`20.
`
`I understand that the following examples are approaches and
`
`rationales that may be considered in determining whether a piece of prior art could
`
`have been combined with other prior art or with other information within a skilled
`
`artisan’s knowledge:
`
`(i)
`
`(ii)
`
`combining prior-art elements according to known methods to yield
`predictable results;
`substituting one known element for another to obtain predictable
`results;
`(iii) using a known technique to improve similar devices (methods, or
`products) in the same way;
`(iv) applying a known technique to a known device (method, or product)
`that was ready for improvement to yield predictable results;
`applying a technique or approach that would have been “obvious to
`try” (i.e., choosing something from a finite number of identified,
`predictable solutions, with a reasonable expectation of success);
`(vi) applying variations based on known work in one field of endeavor for
`
`(v)
`
`-6-
`
`

`

`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; or
`(vii) acting upon some teaching, suggestion, or motivation in the prior art to
`modify the prior-art reference or to combine prior-art reference
`teachings thereby arriving at the claimed invention.
`I have been instructed that “secondary considerations” will be
`
`21.
`
`considered when present. Counsel have informed me that such secondary
`
`considerations, where evident, may include: (i) commercial success of a product
`
`due to the merits of the claimed invention; (ii) a long-felt but unsatisfied need for
`
`the claimed invention; (iii) 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. I am informed that secondary considerations
`
`are relevant where there is a nexus between the evidence and the claimed
`
`invention.
`
`22.
`
`I am informed that the patent owner, Bausch Health Ireland Ltd.
`
`(“Bausch”), bears the burden to establish any secondary considerations indicating
`
`non-obviousness.
`
`IV. OVERVIEW OF SHAILUBHAI
`
`-7-
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`

`

`23.
`
`Shailubhai is 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 thereof for 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,” which is the sequence
`
`shown below.
`
`Asn1 Asp 2 Giu3 Cys Giu Leu' Cys 7 Val° Asn 9 Val
`10 Ala11 Cys 12 Thr" Gly' 4 Cys ts Leu16
`4
`
`5
`*
`*
`
`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. Id.
`
`24.
`
`I note that Shailubhai acknowledges that the sequence of this claimed
`
`peptide (reproduced below, top) differs only from the naturally-occurring human
`
`uroguanylin sequence (reproduced below, bottom) by one amino acid, shown in
`
`bold in the sequences below:
`
`Asn1 Asp2 Glu3 Cys4 Glu5 Leu6 Cys7 Val8 Asn9 Val10 Ala11 Cys12 Thr13 Gly14 Cys15 Leu16
`
`Asn1 Asp2 Asp3 Cys4 Glu5 Leu6 Cys7 Val8 Asn9 Val10 Ala11 Cys12 Thr13 Gly14 Cys15 Leu16
`
`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
`
`-8-
`
`

`

`aspartic acid (Asp) residue in the third position. As I discuss in more detail below,
`
`these are the only acidic amino acid 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.
`
`Upon deprotonation, glutamic and aspartic acid may also be referred 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, shown in their deprotonated state.
`
`H
`
`•N‘l
`CO2-
`
`Glu
`
`0
`4,5
`
`-
`CO2
`
`Asp
`
`26. As can be seen above, these amino acids differ structurally from one
`
`another in that the Glu residue, shown on the left, has an additional methylene unit
`
`(-CH2-) in its side chain compared to Asp, shown on the right.
`
`27. Conventional amino acid nomenclature provides one- and three-letter
`
`codes for each amino acid (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 throughout this
`
`declaration as “[Glu3]-human uroguanylin”—indicating the sequence is that of
`
`human uroguanylin where the aspartic acid (Asp) at the third position has been
`
`-9-
`
`

`

`swapped for a glutamic acid (Glu).
`
`28.
`
`I note that Shailubhai acknowledges that these types of synthetic
`
`analogs could be synthesized and purified using known, published procedures.
`
`EX1001, 15:53-55, see also id., 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 known in the art.” Id., 13:27-30 (citing
`
`Remington’s Pharmaceutical Sciences, 16th ed., A. Oslo ed., Easton PA. (1980));
`
`see also EX10101, generally. I agree that a skilled artisan would have been able to
`
`formulate the peptides described in Shailubhai into different dosage forms using
`
`methods well known in the art, and discuss such formulations in Sections VII.G
`
`and X-XII, below.
`
`29. As discussed in more detail below, a skilled artisan would have had
`
`good reason to make [Glu3]-human uroguanylin 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
`
`1 King, R. E., Chapter 89: Tablets, Capsules, and Pills, REMINGTON’S
`PHARMACEUTICAL SCIENCES, 16th ed., (ed. A. Oslo, ed., Mack Publishing Co.)
`1980 (“Remington’s,” EX1010).
`
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`

`

`uroguanylin’s activity in treating inflammatory bowel disease and related
`
`constipation, as well as to improve the 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 methods to achieve a predictable result.
`
`30.
`
`I also note that Shailubhai describes the development of [Glu3]-human
`
`uroguanylin as being the result of computational chemistry calculations. As is
`
`readily apparent from the Shailubhai disclosure, this computational work involved
`
`only known methods of 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 was applied to the design of
`
`novel guanylate cyclase receptor agonists using methods detailed 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,
`
`-11-
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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. Claims of 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 claims are
`
`dependent claims. I understand a dependent claim includes all limitations of the
`
`claim from which it depends.
`
`32.
`
`Each claim is directed to a 16-residue peptide or compositions thereof.
`
`The peptide, which I refer to as “[Glu3]-human uroguanylin,” is defined in the
`
`patent as “consisting of the amino acid sequence of SEQ ID NO: 20,” which is the
`
`sequence shown below.
`
`Asn l Asp2 Glu3 Cys 4 Glu 5 Leu6 Cys7 Val8 Asn9 Va110 Ala" Cys12 Thr13 Gly14 Cys t ' Leul6
`
`EX1001, 5:5-16, claims 1-3, 6. As the asterisk notations indicate, [Glu3]-human
`
`uroguanylin has a 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.
`
`Independent claim 1 recites:
`
`1. A peptide consisting of the amino acid sequence of SEQ ID NO:20.
`
`34.
`
`Independent claim 2 recites:
`
`2. A composition in unit dose comprising a guanylate cyclase receptor
`
`-12-
`
`

`

`agonist peptide consisting of the amino acid sequence of SEQ ID
`NO:20.
`
`35.
`
`Independent claim 3 recites:
`
`3. A composition in unit dose form comprising:
`a) a guanylate cyclase receptor agonist peptide consisting of the
`amino acid sequence of SEQ ID NO: 20; and
`b) at least one compound selected from the group consisting of:
`a cGMP-dependent phosphodiesterase inhibitor, an anti-
`inflammatory agent, an antiviral agent and an anticancer
`agent.
`
`36.
`
`Independent claim 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
`
`dose forms. Claim 5 also depends from claim 2 or 3 and further recites that the
`
`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.
`
`I have been advised that the examination process, or prosecution
`
`history of the application that led to the Shailubhai patent (EX1004) 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 was filed 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. Id., [60]; EX1054 (“the ’646
`
`provisional”). For the purposes of my opinions, I have assumed that Shailubhai is
`
`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 [Glu3]-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 known the relevant art at the time of
`
`the claimed invention. The skilled artisan is also a person of ordinary creativity. I
`
`have been advised that the skilled artisan to whom one could assign a routine task
`
`with reasonable confidence that the task would be successfully carried out.
`
`41.
`
`I have been advised that the relevant timeframe for my analysis is the
`
`time period prior to January 17, 2002—the earliest 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
`
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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 prior art
`
`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 as a skilled artisan regarding the understanding of a skilled
`
`artisan at the relevant time, as I am and was by 2002 a person of ordinary skill in
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`the art.
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`VI. CLAIM CONSTRUCTION
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`44.
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`I have been advised that the claim terms of Shailubhai are to be given
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`their plain and ordinary meaning, i.e., the meaning that the terms would have had
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`to a skilled artisan at the time of the claimed invention.
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`45.
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`I understand that this analysis focuses on intrinsic evidence, including
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`how the patentee used the claim term in the claims, specification, and prosecution
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`history. I also understand that dictionaries or other extrinsic sources may assist in
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`determining the plain and ordinary meaning but cannot override a meaning that is
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`unambiguous from the intrinsic evidence. I have followed these principles in my
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`analysis throughout this declaration.
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`VII. THE STATE OF THE ART
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`A. Peptide Hormones in the Body and in Medicine
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`46.
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`Peptides are short chains of amino acids linked together covalently
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`through peptide bonds. See, e.g., EX1011, 1088 (describing, e.g., “peptides of
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`some 20-30 amino acid residues”).2 Peptide chains fold into three dimensional
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`structures that are commonly called proteins. Peptide function involves the
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`reversible and specific binding of peptide ligands to the binding site of a receptor.
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`EX1012, 203.3 A peptide ligand “discriminate[s] among the thousands of different
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`molecules in its environment and selectively bind[s] only one or a few” based on
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`the physical and chemical properties of the receptor and the ligand. Id.
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`47.
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`Peptides that function as chemical messengers are called peptide
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`2 Rehfeld, J. F., The New Biology of Gastrointestinal Hormones, PHYSIOL. REV.,
`78(4), 1998, 1087-1108 (“Rehfeld”, EX1011).
`3 Nelson, D. L., et al., Chapters 4-5, 7, LEHNINGER PRINCIPLES OF
`BIOCHEMISTRY, 3rd ed. (eds. Ryan, M., et al., Worth Publishers) 2000 (“Nelson,”
`EX1012).
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`hormones. See generally EX1013.4 In the paragraphs that follow, I will explain this
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`process in greater detail. For summary purposes, however, it is helpful to
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`understand that a particular peptide hormone may bind with the extracellular
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`portion of a protein structure that extends through a membrane (membrane-bound
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`protein). This binding interaction may change the shape (conformation) of the
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`membrane-bound protein, thus changing the way the intracellular portion of the
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`membrane-bound protein interacts with other proteins within the cell, for example.
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`In this way, the body uses peptides to generate signaling cascades to activate
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`(agonist hormones) or deactivate (antagonist hormones) functions within the body.
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`48. Well before 2002, skilled artisans knew many examples of naturally-
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`occurring peptide hormones. Insulin is an example discovered more than 100 years
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`ago. Rehfeld confirms that skilled artisans were aware of many peptide hormones,
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`including peptide hormones that act on receptors located in the gut. EX1011, 1087.
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`According to Rehfeld, “more than 30 peptide hormone genes are known to be
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`expressed throughout the digestive tract, which makes the gut the largest endocrine
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`organ in the body.” EX1011, 1087. Rehfeld also reports that skilled artisans had
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`identified “many more gut hormones, and each has its own or even more receptors,
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`4 Segaloff, D. L., et al., Chapter 9: Internalization of Peptide Hormones and
`Hormone Receptors, HORMONES AND THEIR ACTIONS, PART I, (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
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`peptides may act on the same receptor.” EX1011, 1088.
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`49. By 2002, skilled artisans understood that peptide hormones, including
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`those regulating the gut, transmit signals by binding to their receptors expressed on
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`the surface of certain cells. Segaloff confirms that the “ability of a particular
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`peptide hormone to elicit an effect in the appropriate target cell is dictated by the
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`presence of receptors on the surface of the target cell which specifically bind that
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`hormone.” EX1013, 133. It also was known that the sensitivity of any given cell to
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`a particular hormone depends on the number of receptors that cell expressed for the
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`particular hormone. Segaloff states, for example, that “the amount of hormone that
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`is processed in this case is dictated by the number of hormone receptors.” EX1013,
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`139.
`
`50.
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`It was well known before 2002 that hormone-receptor binding is
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`driven both by the physical shape of the binding sites of the hormone and the
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`receptor as well as by their chemical properties. For example, it was known that
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`complementary electrostatic interactions between the hormone and receptor, across
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`their interface, promote the binding relationship of ligand to receptor, thereby
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`promoting their signaling activity. In addition to other physical and chemical
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`forces, the binding interaction may be promoted when water is excluded from the
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`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
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`between the molecules and a thermodynamically driven desolvation (water
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`removal) at the hormone-receptor interface. EX1014, 100.5 As Chipens published
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`in 1978, skilled artisans long understood the power of properly designed
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`counterion interactions between hormone and receptor.
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`51. Unson similarly explains that it was known that charged residues
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`could “contribute strongly to the stabilization of the binding interaction with the
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`[peptide] receptor that leads to maximum biological potency.” EX1015, 10308.6 As
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`I will discuss below, certain amino acids, such as aspartate and glutamate, have
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`charged side groups that can contribute to hormone-receptor