UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`MYLAN PHARMACEUTICALS INC.,
`MSN LABORATORIES PRIVATE LTD.,
`and MSN PHARMACEUTICALS INC.
`Petitioners,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`_____________________________
`
`Case IPR2022-007221
`Patent 7,041,786
`_____________________________
`
`SECOND DECLARATION OF BLAKE R. PETERSON, PH.D.
`
`1 IPR2023-00016 has been joined with this proceeding.
`
`MYLAN EXHIBIT - 1063
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd.
`IPR2022-00722
`
`REDACTED PUBLIC VERSION
`
`

`

`TABLE OF CONTENTS
`
` Page
`
`INTRODUCTION ................................................................................................. 1
`I.
`LEVEL OF ORDINARY SKILL .............................................................................. 3
`II.
`III. A PERSON OF ORDINARY SKILL IN THE ART WOULD HAVE
`SELECTED HUMAN UROGUANYLIN FOR MODIFICATION ................................... 4
`A. Enterotoxin Activity Would Not Dissuade a Person of Ordinary
`Skill in the Art From Modifying Human Uroguanylin .............................. 9
`B. Bausch Fails to Establish Topoisomerism Would Have
`Dissuaded a Person of Ordinary Skill in the Art From
`Modifying Uroguanylin. ........................................................................... 15
`IV. A PERSON OF ORDINARY SKILL IN THE ART WOULD HAVE
`SUBSTITUTED ASP3 WITH GLU3 IN HUMAN UROGUANYLIN. ............................ 35
`A. Potential Uroguanylin Interconversion as a Motivation to
`Modify ...................................................................................................... 36
`B. The Conservative, Evolutionary Conserved [Glu3]-Substitution
`Supports the Modification ........................................................................ 43
`C. The Prior Art Does Not Indicate That Asp3 Was Required to
`Maintain Activity ...................................................................................... 51
`D. [Glu3]-Substitution Would Have Been Expected to Modulate
`Protonation Favorably as a Matter of Routine Optimization ................... 65
`E. Aspartimide Formation Provides Additional Motivation for
`Making [Glu3]-Human Uroguanylin ........................................................ 74
`REASONABLE EXPECTATION OF SUCCESS ....................................................... 76
`V.
`VI. BAUSCH’S EXPERIMENTAL RESULTS DO NOT DEMONSTRATE
`UNEXPECTED SUPERIORITY FOR WHAT IS CLAIMED AS COMPARED
`TO THE CLOSEST PRIOR ART ........................................................................... 79
`A. Summary of Bausch’s Experiments ......................................................... 79
`A. Bausch’s Experimental Results Are Not Commensurate with
`the Scope of the Claims .......................................................................... 101
`B. Bausch’s Experimental Results Do Not Compare to the Closest
`Prior Art .................................................................................................. 104
`
`-i-
`
`REDACTED PUBLIC VERSION
`
`

`

`C. Bausch’s cGMP and Affinity Results Do Not Show An
`Unexpected Improvement Nor Any Difference in Kind ........................ 116
`D. Bausch’s Heat Stability Results Show Neither an Unexpected
`Improvement Nor Any Difference in Kind ............................................ 120
`E. Bausch’s Topoisomerism Experiment Shows Neither an
`Unexpected Improvement Nor Any Difference in Kind ........................ 121
`VII. CONCLUDING STATEMENTS .......................................................................... 122
`VIII. APPENDIX – LIST OF EXHIBITS ..................................................................... 124
`
`-ii-
`
`REDACTED PUBLIC VERSION
`
`

`

`I, Blake R. Peterson, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am the same Blake R. Peterson who previously filed a declaration
`
`(EX1002) in this proceeding. EX1002 contains the legal standards I was given to
`
`apply to this case, as well as my opinions regarding the level of skill of a person of
`
`ordinary skill in the art (POSA) and the obviousness of claims 1-6 of the ’786
`
`patent (7,041,786, EX1001) in view of the prior art. My qualifications are
`
`discussed in EX1002 as well as in my CV (EX1003). I also was deposed by
`
`attorneys for the Patent Owner (Bausch). EX2026.
`
`2.
`
`I have been asked to review the declarations of Dr. Shailubhai
`
`(EX2023), Dr. Davies (EX2024), and Dr. Waldman (EX2025), and the materials
`
`they discussed. I have been asked to provide my opinions regarding those
`
`declarations and the materials they discussed from the perspective of a person of
`
`ordinary skill in the art. For purposes of my evaluation, I understand that the
`
`critical date for this patent is January 17, 2002. EX2024, ¶4. My opinions are based
`
`on my skills, knowledge, training, education, and experience, and my examination
`
`of the materials used in preparing this testimony, including the declarations and
`
`cited materials discussed above. I also have reviewed the transcripts of the
`
`depositions of Drs. Davies (EX1060), Shailubhai (EX1061), and Waldman
`
`(EX1062). My opinions are based on the current record, so I reserve the ability to
`
`-1-
`
`REDACTED PUBLIC VERSION
`
`

`

`refine my opinions based on additional facts.
`
`3.
`
`In summary, it is my opinion that a person of ordinary skill in the art
`
`at the critical date would have recognized that human uroguanylin was a most
`
`promising peptide for modification, and that a person of ordinary skill in the art
`
`would not have been dissuaded from selecting human uroguanylin for modification
`
`by the potency of ST enterotoxins or by topoisomeric conversion properties.
`
`4.
`
`It is also my opinion that a person of ordinary skill in the art at the
`
`critical date would have been motivated to make [Glu3]-human uroguanylin for
`
`several reasons, discussed at length in my first declaration (EX1002). It is further
`
`my opinion that a person of ordinary skill in the art would not have been dissuaded
`
`from doing so in favor of making the peptide more like the ST enterotoxins, and
`
`none of the arguments presented by Drs. Davies or Waldman undermine the
`
`motivations for the modification discussed in my first declaration.
`
`5.
`
`Furthermore, it is my opinion that the experimental data for human
`
`uroguanylin and [Glu3]-human uroguanylin discussed by Drs. Shailubhai, Davies,
`
`and Waldman do not demonstrate any unexpected, significant, and material
`
`improvement between the two compounds. They certainly do not demonstrate a
`
`difference in kind between the two compounds. Moreover, the data relate to only a
`
`portion of what is encompassed by the claims of the ’786 patent and do not provide
`
`an apples-to-apples comparison of [Glu3]-human uroguanylin to the most similar
`
`-2-
`
`REDACTED PUBLIC VERSION
`
`

`

`prior art.
`
`6.
`
`Mylan is compensating me at the rate of $475 per hour for my time.
`
`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.
`
`7.
`
`For reference, and as a reminder, I have provided (below) the primary
`
`structure of human uroguanylin and [Glu3]-human uroguanylin. After those amino
`
`acid sequences, I have provided the chemical structures of the Glu and Asp
`
`residues, shown in their deprotonated state, which constitutes the only difference in
`
`sequence between the two peptides.
`
`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
`
`0
`
`CO2
`
`CO2"
`
`Glu
`
`Asp
`
`II.
`
`LEVEL OF ORDINARY SKILL
`
`8.
`
`Dr. Davies states a person of ordinary skill in the art would include
`
`someone with a Ph.D. in chemistry with experience with drug development
`
`involving peptide chemistry and/or peptide engineering but could also include
`
`someone with a master’s degree, or even a bachelor’s degree in chemistry or a
`
`-3-
`
`REDACTED PUBLIC VERSION
`
`

`

`related field with 2-5 years of experience in drug development with peptide
`
`chemistry and/or peptide engineering. EX2024, ¶¶31-32; see also EX2025, ¶¶16-
`
`18. Dr. Davies states that his analysis and conclusions would be the same if my
`
`description of the level of ordinary skill in the art is applied. EX2024, ¶32. Dr.
`
`Davies provides no reason why a person of ordinary skill in the art would lack an
`
`advanced degree or experience in peptide chemistry and/or peptide engineering. In
`
`fact, Dr. Davies appears to agree that a person of ordinary skill in the art would
`
`include someone experienced in peptide chemistry and/or peptide engineering,
`
`including someone with a Ph.D. Accordingly, Dr. Davies’s definition of the level
`
`of skill in the art does not alter any of my opinions. To the extent our definitions
`
`differ, my definition including advanced degrees better reflects the typical
`
`education and experience that I have seen throughout my career.
`
`III. A PERSON OF ORDINARY SKILL IN THE ART WOULD HAVE SELECTED
`HUMAN UROGUANYLIN FOR MODIFICATION
`
`9.
`
`I explained in my first declaration that human uroguanylin was known
`
`in the prior art to be a most promising natural GC-C ligand to modify to make a
`
`synthetic analog. Indeed, the prior art discussed the properties of human
`
`uroguanylin and illustrated why those properties motivated the creation of
`
`synthetic analogs. For example, the prior art identified uroguanylin as a natural
`
`ligand produced by the body to enhance water content in the intestinal lumen by
`
`increasing cyclic Guanosine Monophosphate (“cGMP”) levels through activation
`
`-4-
`
`REDACTED PUBLIC VERSION
`
`

`

`of the intestinal guanylate cyclase (“GC-C”) receptor. EX1002, ¶¶58-59; EX1016,
`
`E957, E962; EX1020, 222 & Fig. 2; EX1018, G635-36, G639-41; EX1019, G708;
`
`EX1017, 807. The prior art explained that GC-C is expressed throughout the entire
`
`length of the small and large intestines but with higher density in the small
`
`intestines. Id.; see also EX2021, 3:1-2 (uroguanylin and guanylin are produced
`
`throughout the intestinal mucosa); see also EX1062 (Waldman), 57:3-11, 65:12-
`
`67:6 (the body uses uroguanylin naturally to introduce fluid into the intestinal
`
`lumen, primarily introduces fluid at the small intestines, and primarily removes
`
`fluid at the large intestines). The fact that uroguanylin was known to be the body’s
`
`natural ligand for increasing water content in the intestinal lumen with the highest
`
`receptor density provided a strong indication that it was both safe and effective,
`
`and also was well-calibrated to work for this purpose without causing adverse
`
`effects. EX1002, ¶¶59-60 (discussing uroguanylin’s “more controlled” version of
`
`activating the cGMP pathway).
`
`10. Not only was endogenous uroguanylin known to work naturally in the
`
`body, but oral administration of uroguanylin already had been shown to stimulate
`
`intestinal fluid secretion markedly. EX1018, G641-G642; EX1002, ¶¶59
`
`(uroguanylin signaling suggested it as a treatment for constipation), 99 (oral
`
`uroguanylin stimulates intestinal fluid secretion). The prior art, including the
`
`Currie reference (EX1005), thus identified human uroguanylin as a good candidate
`
`-5-
`
`REDACTED PUBLIC VERSION
`
`

`

`for oral administration for delivery to the intestines to treat constipation. EX1005,
`
`1:34-44, 1:50-55, 2:6-24, 2:53-65, 6:11-22; EX1002, ¶¶85-86 & 107. Indeed,
`
`Currie was certainly aware of and even discussed human uroguanylin’s amino acid
`
`sequence, including the location and implications of its disulfide bridges, and still
`
`concluded that its “physiological characteristics” suggest that it “is important to
`
`medical science in the study of regulators of guanylate cyclase.” EX1005, 1:47-63,
`
`2:3-7.
`
`11. A person of ordinary skill in the art would have understood Currie to
`
`suggest making a synthetic analog of human uroguanylin to understand the
`
`regulation of intestinal guanylate cyclase, including for purposes of making a
`
`synthetic therapeutic for treating constipation or, alternatively, for treating toxic
`
`ST-induced activation of GC-C. Currie explained that uroguanylin stimulates
`
`“increases in cyclic GMP levels in a manner similar to guanylin and the STs” (heat
`
`stable enterotoxins) but is instead “an endogenous stimulator of intestinal
`
`guanylate cyclase,” that it is “useful for the control of intestinal absorption,” that it
`
`has been found to displace ST binding to cultured T84 human colon carcinoma
`
`cells, and that it may “act as a laxative and be useful in patients suffering from
`
`constipation[.]” EX1005, 2:6-24; see also EX1002, ¶¶97-98; EX1046, 28. Dr.
`
`Waldman testified during his deposition that a variety of medications used to treat
`
`constipation before the critical date did so by increasing water content of the
`
`-6-
`
`REDACTED PUBLIC VERSION
`
`

`

`intestinal lumen including at the small intestines. EX1062 (Waldman), 52:12-
`
`53:14.
`
`12. Currie explained that the STs are a class of acidic peptides obtained
`
`from “[p]athogenic strains of E. coli,” that they require three disulfide bridges “for
`
`full expression of bioactivity,” and that “[t]he increase of intestinal epithelial cyclic
`
`GMP elicited by STs is thought to cause…secretory diarrhea” leading potentially
`
`to death, “particularly in the infant population,” and was the leading cause of
`
`morbidity in domestic animals.” EX1005, 1:21-23, 1:31-44. The Currie reference
`
`thus suggests exploiting uroguanylin’s natural laxative effects for treating
`
`constipation and discloses that uroguanylin’s activity was desirable because it was
`
`naturally effective but not so strong as enterotoxins’ toxic activity. EX1005, 6:11-
`
`15, Fig. 3A; EX1002, ¶¶88-90. Based on uroguanylin’s useful properties, and
`
`accounting for the higher potency (and its resultant toxicity) of ST enterotoxins,
`
`the prior art thus identified human uroguanylin as a natural GC-C ligand for further
`
`modification. EX1005, 1:21-23, 1:31-44, 2:6-24, 2:53-65, 6:11-22, Fig. 3A;
`
`EX1006, 45. I agree with the teachings of the Currie reference that the natural
`
`approach of uroguanylin was a more promising pathway for treating constipation
`
`than the pathogenic toxicity of enterotoxins. As Dr. Waldman explained during his
`
`deposition, STs are not endogenous ligands created by the body’s cells to naturally
`
`increase fluid content in the intestinal lumen, but are instead molecular mimics
`
`-7-
`
`REDACTED PUBLIC VERSION
`
`

`

`designed to cause massive fluid increases to force the host to expel the fluid and
`
`thereby propagate the pathogen to new hosts. EX1062 (Waldman), 78:22-79:5; see
`
`also EX1064 (Epstein), ¶43. Millions of years of evolution tailored each of
`
`uroguanylin and STs to a different purpose, and the purpose of the former was
`
`more suited to treating constipation while the latter was more suited to causing
`
`illness to better spread pathogens.
`
`13. Another reason I previously explained that a person of ordinary skill
`
`in the art would have selected human uroguanylin for further modification was
`
`because the prior art recognized that uroguanylin had markedly enhanced activity
`
`at a pH similar to that within the fluid microclimate domain at the mucosal surface
`
`of the intestine. EX1002, ¶¶61-65, 91; EX1021, 2705, 2709. This pronounced pH
`
`effect was believed to correlate with the presence of acidic aspartate or glutamate
`
`amino acid residues at positions 2 and 3 of the peptide. Id. Accordingly, the art
`
`recognized that this markedly enhanced activity at relevant pH could be preserved
`
`and optimized through routine replacement of the aspartate with a glutamate.
`
`14. Another reason I previously explained that a person of ordinary skill
`
`in the art would have selected human uroguanylin for further modification was
`
`because synthesis of analogs to the natural ligand was straightforward, was
`
`desirable for studying the ligand-receptor structure-activity relationship, and
`
`provided a foundation to develop drugs to intervene in the natural peptide’s
`
`-8-
`
`REDACTED PUBLIC VERSION
`
`

`

`signaling pathway. EX1002, ¶¶66-67, 71, 80-81, 136 (discussing EX1025,
`
`EX1028- EX1030). A person of ordinary skill in the art routinely made synthetic
`
`analogs of naturally occurring peptide hormones, including to make more potent,
`
`longer acting, or higher-stability analogs, to gain mechanistic insight into peptide
`
`binding, to modulate charge, or to routinely characterize their properties. Id. Such
`
`synthesis was routine, and Currie taught that synthesis of uroguanylin using known
`
`methods was straightforward. EX1002, ¶¶66-67 (synthesis was routine), 106, 130-
`
`31; EX1005, 3:8-45. The properties of human uroguanylin thus made it a most
`
`promising starting point for making a synthetic GC-C ligand.
`
`15. Dr. Davies makes various arguments as to why he concludes that a
`
`person of ordinary skill in the art would avoid making any synthetic analog of
`
`human uroguanylin peptide. EX2024, ¶¶123-141. I disagree with Dr. Davies and
`
`address his arguments below.
`
`A. Enterotoxin Activity Would Not Dissuade a Person of
`Ordinary Skill in the Art From Modifying Human
`Uroguanylin
`
`16. Dr. Davies argues that a person of ordinary skill in the art would have
`
`been led away from modifying human uroguanylin because, he argues, ST
`
`enterotoxins had “higher binding affinity,” stability, and pH-independence
`
`reflected in “superior” potency, especially in the colon. See, e.g., EX2024, ¶¶35,
`
`45, 88, 91, 93-95, 124, 135-137; see also EX2025, ¶¶58, 63-69, 74-82 (Dr.
`
`-9-
`
`REDACTED PUBLIC VERSION
`
`

`

`Waldman discussing activities). For example, Dr. Davies relies on Currie
`
`(EX1005) Fig. 3A to argue that human uroguanylin had “intermediate potency” for
`
`cGMP production that was 10-fold higher than guanylin’s but lower than STa’s.2
`
`EX2024, ¶¶93, 95. Dr. Davies relies on Currie Fig. 3B to argue that uroguanylin’s
`
`affinity for the GC-C receptor was likewise somewhere in between that of STa and
`
`guanylin. EX2024, ¶94. Dr. Davies argues that STs “were touted in the art” as
`
`having “extraordinary high affinities” and “remarkable potency.” EX2024, ¶¶97-
`
`98; EX1021, 2710). Dr. Waldman argues that enterotoxins were known as “long-
`
`lived super agonists” due to their resistance to degradation, and Dr. Davies
`
`suggests that enzymatic degradation can unpredictably impact some peptides
`
`(though he never asserts this was an expected issue for human uroguanylin—it was
`
`not). EX2025, ¶64; EX2024, ¶¶41, 60, 73, 100, 134. Dr. Davies then argues,
`
`without citation to any supporting evidence, that a person of ordinary skill in the
`
`art generally would select the most potent compound and then seek to address any
`
`unwanted side effects or other toxicity issues. EX2024, ¶141. Dr. Davies also
`
`argues that a person of ordinary skill in the art would have focused on a compound
`
`2 Currie’s assay reported much closer activity results at the micromolar
`
`concentration. EX1005, Fig. 3A (10,000 pmol/well cGMP for human uroguanylin).
`
`-10-
`
`REDACTED PUBLIC VERSION
`
`

`

`whose activity was “independent of pH” to act “in the colon rather than the small
`
`intestine.” EX2024, ¶¶45, 96-97, 141, 188. I disagree.
`
`17. As I explained above, where “full expression of bioactivity” was
`
`understood to “cause…secretory diarrhea” leading potentially to death,
`
`“particularly in the infant population” and “in domestic animals,” (EX1005, 1:21-
`
`23, 1:31-44), that level of potency would not be so desirable that a person of
`
`ordinary skill in the art would be dissuaded from modifying human uroguanylin.
`
`Indeed, as explained above, the Currie reference taught that human uroguanylin’s
`
`potency was desirable because it achieved the intended physiological effect (e.g.,
`
`stimulates intestinal fluid accumulation) in a natural way but without the toxicity
`
`associated with diarrhea. A person of ordinary skill in the art would have
`
`understood that increasing the potency too high (e.g., close to enterotoxin) or
`
`making it independent of pH (e.g., like enterotoxin) would increase the risk of
`
`severe diarrhea, with the potential for an undesirable black box warning. EX1062
`
`(Waldman), 77:1-7, 79:13-20 (black box warning is not desirable); EX1064
`
`(Epstein), ¶45. Accordingly, I cannot agree with Dr. Davies that a desire to
`
`maximize potency would have led a person of ordinary skill in the art away from
`
`human uroguanylin.
`
`18. Dr. Davies and Dr. Waldman argue that enterotoxin can be purified
`
`and administered in smaller doses to reduce the risk of causing severe diarrhea, or
`
`-11-
`
`REDACTED PUBLIC VERSION
`
`

`

`that an enterotoxin might have been modified to “avoid this known side effect.”
`
`EX2024, ¶¶138-39; EX2025, ¶¶70-73; EX1060 (Davies), 98:9-22 (Dr. Davies
`
`admitting that heat-stable enterotoxins (STs) are not secreted by human cells but
`
`instead “come from bacteria.”). As this “side effect” is actually the “potency” of
`
`this class of peptide toxins, Drs. Davies and Waldman appear to be arguing that an
`
`enterotoxin must be selected for modification because of its potent toxicity but
`
`then modified to reduce that toxicity. EX1062 (Waldman), 72:3-74:14 (Dr.
`
`Waldman proposed to modify STs to reduce their activity by reducing their
`
`residence time in the body). I agree that the toxicity of enterotoxin would have
`
`been a concern, but I disagree that a person of ordinary skill in the art would have
`
`been dissuaded from making a synthetic analog of uroguanylin because of the
`
`potent toxicity of enterotoxins.
`
`19.
`
` Moreover, pharmaceutical purification and dosage control would not
`
`completely eliminate the concern of a person of ordinary skill in the art regarding
`
`toxicity of enterotoxins. Even a purified and pharmaceutically-controlled dosage
`
`can still be too potent. Indeed, what makes a toxin dangerous often is its potency at
`
`low concentrations. Genetically diverse human populations with variable responses
`
`or children, animals, or small adults may be detrimentally affected by the
`
`exceptionally high potency of a toxin, leading to disastrous results. Moreover, a
`
`person of ordinary skill in the art would have recognized that focusing that potency
`
`-12-
`
`REDACTED PUBLIC VERSION
`
`

`

`on the colon as Dr. Davies contemplates may raise the likelihood of causing severe
`
`diarrhea. See EX2025 (Waldman), ¶110 (targeting the more alkaline pH of the
`
`colon would increase the likelihood of diarrhea). A person of ordinary skill would
`
`have understood that replicating the potency, pH-independence, and “stability” of
`
`enterotoxins could increase the risk of causing severe diarrhea, which can result in
`
`death, especially in children, domestic animals, or adults of small stature. Given
`
`the excellent known potency of uroguanylin, and its natural ability to increase
`
`water accumulation in the intestinal lumen, attaining pH-independent and toxic
`
`levels of potency associated with enterotoxin would not be a clear favorite of
`
`person of ordinary skill in the art, and certainly would not dissuade them from
`
`modifying uroguanylin.
`
`20.
`
`I disagree with Dr. Davies’s assertion that a POSA always must
`
`choose the most potent compound for further modification. Just as Currie taught,
`
`there are important tradeoffs achieved by ceding unneeded potency in favor of
`
`other desired physicochemical properties. Dr. Davies ignores the routine balancing
`
`and optimization that POSAs had long undertaken, and which is exemplified in
`
`Currie. Dr. Davies’ categorical assertion that potency always must be maximized
`
`also ignores that fact that increased potency often corresponds with properties that
`
`a POSA does not wish to maximize. For example, more lipophilic compounds
`
`generally have greater potency than their less lipophilic counterparts but exhibit
`
`-13-
`
`REDACTED PUBLIC VERSION
`
`

`

`less beneficial pharmacokinetic properties. Hence, the most potent compound is
`
`often not the most desirable preclinical or clinical candidate.
`
`21. Dr. Davies also argues that a person of ordinary skill in the art would
`
`have “selected a heat-stable enterotoxin (ST) as a lead compound for further
`
`development and modified it to invent linaclotide consistent with Dr. Currie’s
`
`course of development. EX2024, ¶¶99, 140-141, 92-93; see also EX2025, ¶¶68-69.
`
`I have not been asked to form an opinion whether it was or was not obvious to
`
`make linaclotide. But I disagree with Dr. Davies that a person of ordinary skill in
`
`the art was faced with a choice of either synthesizing a synthetic analogue of
`
`human uroguanylin or of ST enterotoxin. In my opinion, Drs. Davies and Waldman
`
`present a false dichotomy. A person of ordinary skill in the art was not less likely
`
`to make synthetic analogs of human uroguanylin simply because ST enterotoxins
`
`also could have been modified and studied for further development. Indeed, if it
`
`had been known that Dr. Currie was making synthetic analogs of enterotoxins, this
`
`knowledge would have motivated a person of ordinary skill in the art to make a
`
`synthetic analog of human uroguanylin as an alternative to Dr. Currie’s
`
`enterotoxin-derived peptide. If a person of ordinary skill in the art did not know
`
`Dr. Currie was making synthetic analogs of enterotoxins, Dr. Currie’s unknown
`
`work on enterotoxins certainly would not have dissuaded a person of ordinary skill
`
`in the art from uroguanylin.
`
`-14-
`
`REDACTED PUBLIC VERSION
`
`

`

`22. Having considered all of the arguments by Drs. Davies and Waldman
`
`that enterotoxic potency would have led a person of ordinary skill in the art away
`
`from human uroguanylin, based on my experience, none of these arguments would
`
`have discouraged a chemist from making a synthetic uroguanylin analog.
`
`B. Bausch Fails to Establish Topoisomerism Would Have
`Dissuaded a Person of Ordinary Skill in the Art From
`Modifying Uroguanylin.
`
`23. Dr. Davies argues “topoisomerism” would have dissuaded a person of
`
`ordinary skill in the art from making a synthetic analog of uroguanylin. See, e.g.,
`
`EX2024, ¶¶35, 50-60, 64-73, 91, 123-134; see also EX2025, ¶¶46-53 (Dr.
`
`Waldman). Dr. Davies indulges in some hyperbole in this regard, stating that
`
`uroguanylin and guanylin were “beset by a topoisomerism problem,” but that
`
`enterotoxins “were not so afflicted.” EX2024, ¶¶49. Dr. Davies even goes so far as
`
`to repeatedly characterize topoisomerism as a “plague.” EX2024, ¶¶52, 73, 99,
`
`135. I disagree with Dr. Davies that “topoisomerism” is a “plague,” that it would
`
`have dissuaded a person of ordinary skill in the art from making a synthetic analog
`
`of human uroguanylin, or that [Glu3]-human uroguanylin is immune from all the
`
`topoisomerism concerns Drs. Davies and Waldman raise.
`
`24. As a threshold matter, I disagree with Dr. Davies that a person of
`
`ordinary skill in the art before the critical date would have viewed topoisomerism,
`
`including topoisomeric interconversion, as a plague, an affliction, or a reason to
`
`-15-
`
`REDACTED PUBLIC VERSION
`
`

`

`avoid synthetic analogs of uroguanylin. Dr. Davies speculates that human
`
`uroguanylin might interconvert between active and inactive topoisomers naturally
`
`in the body under biological conditions. EX2024, ¶¶50, 52, 60, 131-134. Dr.
`
`Davies bases this hypothesis on the disclosure of Marx 1998 that 25% of human
`
`uroguanylin interconverted in one solution after 24 hours when kept at body
`
`temperature. EX2024, ¶¶70, 131; see also EX2025, ¶52. Dr. Waldman argues that
`
`human uroguanylin’s isomers are “freely convertible” at acidic pH. EX2025, ¶51.
`
`25. But the 25% interconversion Drs. Davies and Waldman rely upon was
`
`observed after storage in solution for 24 hours at a pH of 4.5. EX2010, 236 (left
`
`column). Drs. Davies and Waldman concede that this degree of acidic pH is not
`
`generally observed in the small or large intestines (pH 5.5-8.0), most commonly
`
`being relegated to the stomach during a fasting state (pH 1.4-2.1) or perhaps in the
`
`stomach with food (pH 4.3-5.4). EX2024, ¶¶43-44; see also EX2025, ¶¶20-22. As
`
`Dr. Epstein explains, a clinician would have understood that uroguanylin would
`
`clear the stomach within about 30 minutes in a fasting state and within about 60
`
`minutes when taken with food. EX1064, ¶¶25-31. Any topoisomerism
`
`interconversion experiment performed at a pH of 4.5 or lower for longer than one
`
`hour is not representative of biological conditions for oral administration of
`
`uroguanylin. The topoisomeric interconversion rate Drs. Davies and Waldman cite
`
`-16-
`
`REDACTED PUBLIC VERSION
`
`

`

`would not dissuade a person of ordinary skill in the art from making a synthetic
`
`analog of human uroguanylin.
`
`26.
`
`Indeed, Figure 6C of Marx 1998, the same data (below, right) that
`
`indicate a 25% interconversion after 24 hours at pH 4.5, indicates at most 1%
`
`interconversion of topoisomer A to topoisomer B after one hour. I added a vertical
`
`red dotted line to represent the 1-hour mark (below right). Figure 6C of Marx 1998
`
`further indicates that in a slightly alkaline pH more relevant to the intestines
`
`(below, left), it took approximately 70 hours to see 5% interconversion of
`
`topoisomer A to topoisomer B. I added a horizontal red dotted line to represent the
`
`(70 hrs for 5% A —> 8)
`
`95%
`
`100
`
`E 80
`o
`
`V. 60
`
`(≤1% A —0-8)
`
`95% mark.
`
`100
`
`g°
`
`•-• 60
`
`5-,
` 40
`_0
`p3O
`§ 20
`
`27.
`
`g 40 -
`go
`-
`§ 20 -
`e
`
`0 _
`
`80
`
`100
`50
`20
`40
`Time (h)
`Time (h)
`Even assuming human uroguanylin would have been exposed to the
`
`0
`
`lir
`
`150
`
`200
`
`acidic environment of the stomach (as opposed to being administered in a
`
`conventional dosage form designed to time its release specifically for the
`
`intestines, EX1002, ¶¶97-98, 112, 189, 193; EX1007, 39-40, 47; EX1046, 28-29;
`
`-17-
`
`REDACTED PUBLIC VERSION
`
`

`

`EX1047, 3708), a person of ordinary skill in the art would not have been dissuaded
`
`from modifying human uroguanylin based on the minor degree of potential
`
`topoisomeric interconversion discussed in Marx 1998 for the time uroguanylin
`
`would spend in the stomach. Indeed, prior art references already reported that
`
`uroguanylin was active after emerging through the stomach after oral
`
`administration, and that it increased water flow in the intestinal lumen. See, e.g.,
`
`EX1018, G641-G642; EX1002, ¶99 (oral uroguanylin stimulates intestinal fluid
`
`secretion). Additionally, the prior art Shailubhai ’266 patent publication teaches
`
`that “[u]roguanylin is an acid-stable and proteolysis resistant peptide, which will
`
`remain intact to act on the intestinal lumen directly rather than being absorbed
`
`systemically.” EX2021, 2:28-3:1. Accordingly, the pH 4.5 study from Marx that
`
`Drs. Davies and Waldman cite would not dissuade a person of ordinary skill in the
`
`art from human uroguanylin.
`
`28. A person of ordinary skill in the art also would not have been
`
`dissuaded from human uroguanylin based on potential in vivo topoisomeric
`
`conversion in the stomach because this would have been easily avoided by
`
`administering it in a dosage form designed to time its release specifically for the
`
`intestines rather than the stomach. EX1002, ¶¶97-98, 112, 189, 193; EX1007, 39-
`
`40, 47; EX1046, 28-29; EX1047, 3708.
`
`-18-
`
`REDACTED PUBLIC VERSION
`
`

`

`29. At the rate of interconversion reported in Marx for pH relevant to the
`
`small intestines, interconversion was much too slow to present any material
`
`concern of any kind (e.g., ~95% purity for 70 hours). Consistent with my analysis,
`
`Marx 1998 teaches that even “a slight alkaline pH drastically reduced the rate of
`
`interconversion” as compared to pH 4.5. EX2010, 236. Marx 1998 then teaches
`
`that “it is possible that, under conditions reflecting the pH of blood and within the
`
`wide range of mucosal acidity ([Hamra 1997]), both uroguanylin isomers may
`
`exist without generating a significant amount of their corresponding stereoisomer.”
`
`EX2010, 236 (emphases added). Marx 1998 similarly teaches that, due to the
`
`“significantly slower kinetics” of the topoisomeric interconversion of uroguanylin
`
`as compared to guanylin, “the two isomers of human uroguanylin may exist
`
`physiologically in a nonequimolar ratio.” EX2010, 239. A person of ordinary skill
`
`in the art would understand these quotes from Marx 1998 to teach that human
`
`uroguanylins do not necessarily undergo significant topoisomeric interconversion
`
`in vivo.
`
`30. Klodt 1997 and Marx 1998 also indicate that topoisomeric
`
`interconversion is not inherent to all uroguanylins and suggest that topoisomeric
`
`interconversion can be modul