UNITED STATES PATENT AND TRADEMARK OFFICE
`
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`————————————————
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`————————————————
`Case IPR2022-00722
`Patent US 7,041,786 B2
`————————————————
`
`PETITION FOR INTER PARTES REVIEW
`
`

`

`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
`I.
`II. MANDATORY NOTICES ............................................................................. 2
`A.
`Real Parties-In-Interest .......................................................................... 2
`B.
`Related Matters ...................................................................................... 2
`C.
`Identification of Counsel and Service Information ............................... 3
`STANDING CERTIFICATIONS ................................................................... 3
`III.
`IV. CHALLENGES AND PRECISE RELIEF REQUESTED ............................. 3
`V.
`SHAILUBHAI PATENT ................................................................................ 5
`A.
`Specification .......................................................................................... 5
`B.
`Challenged Claims .............................................................................. 11
`C.
`Prosecution History ............................................................................. 12
`LEVEL OF ORDINARY SKILL .................................................................. 13
`VI.
`VII. CLAIM CONSTRUCTION .......................................................................... 14
`VIII. PRIOR ART ................................................................................................... 15
`A.
`Background ......................................................................................... 15
`B.
`Currie ................................................................................................... 22
`C.
`Li .......................................................................................................... 24
`D.
`Narayani .............................................................................................. 26
`E.
`Campieri .............................................................................................. 27
`F.
`Ekwuribe ............................................................................................. 28
`LEGAL STANDARDS ................................................................................. 31
`GROUND 1: CLAIM 1 WAS OBVIOUS OVER CURRIE AND LI .......... 32
`A.
`Claim 1 ................................................................................................ 32
`B.
`Reason to Modify ................................................................................ 34
`XI. GROUND 2: CLAIMS 2, 4, AND 5 WERE OBVIOUS OVER
`CURRIE, LI, AND NARAYANI .................................................................. 40
`A.
`Claim 2 ................................................................................................ 40
`
`IX.
`X.
`
`-ii-
`
`

`

`Claims 4-5 ........................................................................................... 42
`B.
`XII. GROUND 3: CLAIMS 3-5 WERE OBVIOUS OVER CURRIE, LI,
`NARAYANI, AND CAMPIERI ................................................................... 45
`XIII. GROUND 4: CLAIM 6 WAS OBVIOUS OVER CURRIE, LI,
`AND EKWURIBE......................................................................................... 50
`XIV. SECONDARY CONSIDERATIONS ........................................................... 54
`XV. DISCRETIONARY DENIAL IS UNWARRANTED .................................. 54
`A.
`Co-Pending Litigation ......................................................................... 54
`B.
`Prior Office Consideration .................................................................... 56
`XVI. CONCLUSION .............................................................................................. 57
`LIST OF EXHIBITS ................................................................................................ 60
`
`-iii-
`
`

`

`TABLE OF AUTHORITIES
`
`Cases
`
`Apple Inc. v. Fintiv, Inc., IPR2020-00019, Paper 11 (2020)
`(precedential)................................................................................................ 54, 55
`
`Bayer Pharma AG v. Watson Labs., Inc., 874 F.3d 1316 (Fed. Cir.
`2017) ...................................................................................................................39
`
`British Telecomms. v. IAC/Interactivecorp., No. 18-366-WCB,
`2020 WL 5517283 (D. Del. Sep. 11, 2020) ........................................................55
`
`CRFD Research, Inc. v. Matal, 876 F.3d 1330, 1347 (Fed. Cir. 2017) ..................39
`
`Google LLC v. Koninklijke Philips N.V., 795 Fed. Appx. 840 (Fed.
`Cir. 2020) ............................................................................................................39
`
`In re Diamond, 360 F.2d 214 (CCPA 1966) ............................................................50
`
`In re Dillon, 919 F.2d 688 (Fed. Cir. 1990) (en banc) ..................................... 31, 54
`
`In re Fout, 675 F.2d 297 (Fed. Cir. 1982) ...............................................................39
`
`In re Fulton, 391 F.3d 1195 (Fed. Cir. 2004) ..........................................................39
`
`In re Harris, 409 F.3d 1339 (Fed. Cir. 2005) ..........................................................31
`
`In re Mouttet, 686 F.3d 1322 (Fed. Cir. 2012) ........................................................39
`
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ......................................... 31, 38
`
`Par Pharm. v. TWI Pharm., 773 F.3d 1186 (Fed. Cir. 2014) .................................39
`
`Spectrum Pharm. v. Sandoz Inc., 802 F.3d 1326 (Fed. Cir. 2015) ..........................39
`
`Tyco Healthcare Group v. Ethicon Endo-Surgery, 774 F.3d 968 (Fed.
`Cir. 2014) ............................................................................................................39
`
`Uber Tech., Inc. v. X One, Inc., 957 F.3d 1334 (Fed. Cir. 2020) ............................44
`
`-iv-
`
`

`

`Statutes
`
`18 U.S.C. §1001 .......................................................................................................64
`
`35 U.S.C. §102(b) (pre-AIA) ........................................................................... passim
`
`35 U.S.C. §103 (pre-AIA) ....................................................................................4, 38
`
`35 U.S.C. §112 .........................................................................................................12
`
`35 U.S.C. §316(b) .....................................................................................................55
`
`-v-
`
`

`

`I.
`
`INTRODUCTION
`Petitioner Mylan Pharmaceuticals Inc. (“Mylan”) requests inter partes
`
`review (“IPR”) to cancel claims 1-6 of U.S. Patent No. 7,041,786 (“Shailubhai,”
`
`EX1001). As this petition shows, these claims are unpatentable.
`
`Patentee (“Bausch”) claims a peptide, and compositions or conjugates
`
`comprising this peptide. The claimed peptide is an analog of the known, 16-amino
`
`acid long, human uroguanylin peptide. By the patent’s earliest claimed filing date
`
`(in 2002), human uroguanylin and at least its natural utility as a laxative—that is,
`
`as an activator of a particular receptor on the endothelium of the intestines to draw
`
`water into the intestinal lumen—were known.
`
`The only difference between the claimed peptide and the naturally-occurring
`
`prior art peptide is a single, conservative replacement of aspartic acid (aspartate,
`
`“D”) with glutamic acid (glutamate, “E”) at the peptide’s third residue (“[Glu3]”).
`
`Replacing aspartate with glutamate is a conservative substitution (i.e., substituting
`
`one amino-acid residue for another similar amino-acid residue). These two amino
`
`acids are very close structural analogs with similar and predictable properties,
`
`differing only by one additional methylene (-CH2-) link in glutamate’s side chain.
`
`Indeed, glutamate at the peptide’s third residue was already found in nature,
`
`specifically in uroguanylin found in mammals closely related to humans (e.g.,
`
`rats). Moreover, rat and human uroguanylin were known to be so functionally
`
`-1-
`
`

`

`interchangeable that the prior art actually discloses reliable potency studies
`
`performed using the peptide from one species on the receptors for the other
`
`species. In view of the evidence presented here, a person having ordinary skill in
`
`the art (“skilled artisan”) thus would have considered this conservative and natural
`
`substitution sufficient reason to make the claimed [Glu3]-human uroguanylin with
`
`a reasonable expectation of success. EX1002, ¶29.
`
`Claims 2-6 add only conventional limitations regarding various dosage
`
`preparations, which a skilled artisan also would have considered obvious at the
`
`time of filing. Accordingly, claims 1-6 involve the combination of familiar
`
`elements according to known methods to yield predictable results. Claims 1-6
`
`should be canceled. EX1002, ¶247.
`
`II. MANDATORY NOTICES
`A. Real Parties-In-Interest
`Petitioner Mylan Pharmaceuticals Inc. is a co-defendant with Mylan
`
`Laboratories Ltd., Agila Specialties Inc, Mylan API US LLC, Mylan Inc., and
`
`Viatris Inc. in parallel litigation.
`
`B. Related Matters
`Bausch asserted the involved patent in Bausch Health Ireland Ltd. v. Mylan
`
`Laboratories Ltd., 2:21-cv-573-WSH (W.D. Pa.); 2:21-cv-10403-SRC (D.N.J.)
`
`(now 1:22-cv-00020-TSK (N.D. W.Va.), post-venue transfer); and 1:21-cv-00611
`
`(D. Del.) (dismissed without service); and in Bausch Health Ireland Ltd. v. MSN
`-2-
`
`

`

`Labs., 2:21-cv-10057-SRC (D.N.J.).
`
`C. Identification of Counsel and Service Information
`Lead: Jad Mills, Reg. No. 63,344.
`
`First Backup: Richard Torczon, Reg. No. 34,448.
`
`Backup:
`
`Nicole Stafford, Reg. No. 43,929;
`
`Dennis Gregory, Reg. No. 52,967.
`
`Postal Address: 701 Fifth Avenue, Suite 5100, Seattle, WA 98104-7036.
`
`Telephone: 206-883-2554.
`
`Facsimile: 206-883-2699.
`
`Please direct all correspondence to the contact information above. Mylan consents
`
`to electronic-mail service at:
`
`jmills@wsgr.com,
`
`rtorczon@wsgr.com,
`
`nstafford@wsgr.com,
`
`dgregory@wsgr.com, and
`
`4863-5899-2145@mail.vault.netdocuments.com.
`
`III.
`
`STANDING CERTIFICATIONS
`Shailubhai is available for IPR. Mylan is not barred or estopped from
`
`requesting IPR on these grounds.
`
`IV. CHALLENGES AND PRECISE RELIEF REQUESTED
`Claims 1-6 are unpatentable under pre-AIA 35 U.S.C. §103 on these
`-3-
`
`

`

`grounds:
`
`Ground Claims Obvious from the Combined Teachings of
`
`1
`
`2
`
`3
`
`4
`
`1
`
`Currie1 (EX1005) & Li2 (EX1006)
`
`2, 4-5 Currie, Li & Narayani3 (EX1007)
`
`3-5
`
`Currie, Li, Narayani & Campieri4 (EX1008)
`
`6
`
`Currie, Li & Ekwuribe5 (EX1009)
`
`Exhibits, including a declaration from Professor Blake Peterson (EX1002), support
`
`these grounds. None of these references was applied in a rejection against these
`
`claims.
`
`1 Currie, M.G., et al., Human Uroguanylin, U.S. Pat. 5,489,670 (1996).
`2 Li, Z., et al., Purification, cDNA Sequence, and Tissue Distribution of Rat
`Uroguanylin, 68 REGUL. PEPT. 45-56 (1997).
`3 Narayani, R., et al., Polymer-Coated Gelatin Capsules as Oral Delivery Devices
`and their Gastrointestinal Tract Behaviour in Humans, 7 J. BIOMATER. SCI.
`POLYM. ED. 39-48 (1995).
`4 Campieri, M., et al., Oral Budesonide Is as Effective as Oral Prednisolone in
`Active Crohn’s Disease, 41 GUT 209-14 (1997).
`5 N.N. Ekwuribe, Conjugation-stabilized polypeptide compositions, therapeutic
`delivery and diagnostic formulations comprising same, and method of making and
`using the same, U.S. Pat. 5,359,030 (1994).
`-4-
`
`

`

`V.
`
`SHAILUBHAI PATENT
`A. Specification
`Shailubhai is entitled “Guanylate Cyclase Receptor Agonists for the
`
`Treatment of Tissue Inflammation and Carcinogenesis.” EX1001, cover [54];
`
`EX1002, ¶23. Bausch claims priority to a provisional application filed on January
`
`17, 2002, which is Shailubhai’s earliest possible effective filing date. EX1001,
`
`cover [60]; EX1054; EX1002, ¶¶38-39. Shailubhai “relates to the therapeutic use
`
`of guanylate cyclase receptor agonists as a means for enhancing the intracellular
`
`production of cGMP” (cyclic guanosine monophosphate). EX1001, 1:14-16.
`
`The Shailubhai specification, unlike the issued claims, focuses on treating
`
`cancer. See, e.g., EX1001, Abstract, 2:1-61; 3:61-4:42; see also EX1002, ¶¶23, 38-
`
`39. Yet uroguanylin was discovered as a naturally-occurring laxative. EX1005,
`
`2:20-24 (“The human uroguanylin may thus act as a laxative and be useful in
`
`patients suffering from constipation”). Indeed, Bausch markets [Glu3]-human
`
`uroguanylin as TRULANCE® (plecanatide) for treating chronic idiopathic
`
`constipation and irritable bowel syndrome with constipation, not for cancer. See
`
`EX1055, 1 (“TRULANCE is a guanylate cyclase-C agonist indicated in adults for
`
`treatment of chronic idiopathic constipation”). The Shailubhai specification
`
`mentions neither “constipation” nor a “laxative” for treating constipation with a
`
`peptide. EX1001, passim.
`
`-5-
`
`

`

`Instead, the Abstract identifies the invention as a “method of treatment of
`
`inflamed, pre-cancerous or cancerous tissue or polyps in a mammalian subject.”
`
`Id., cover [57]. While disclaiming any “particular mechanism of action,” id.,
`
`Shailubhai speculates “this treatment may restore a healthy balance between
`
`proliferation and apoptosis in the subject’s population of epithelial cells, and also
`
`suppress carcinogenesis.” Id. According to Shailubhai, the disclosed peptides
`
`“prevent or treat cancerous, pre-cancerous and metastatic growths, particularly in
`
`the gastrointestinal tract and lungs.” Id., 1:15-25. For treating cancer, “[a]ny
`
`known form of uroguanylin or guanylin can be used. . ., although the human
`
`peptides are preferred.” Id., 4:11-13. The challenged claims, however, are not
`
`directed to treating cancer. Id., 37:1-38:6.
`
`Shailubhai reports the prior art taught “Uroguanylin, guanylin and bacterial
`
`ST peptides are structurally related peptides that bind to a guanylate cyclase
`
`receptor [GC-C] and stimulate intracellular production of cyclic guanosine
`
`monophosphate (cGMP).” EX1001, 1:25-30. Consequently, Shailubhai obliquely
`
`notes uroguanylin was known to stimulate GC-C causing “transepithelial secretion
`
`of chloride [which] leads to stimulation of sodium and water secretion into the
`
`intestinal lumen.” Id., 1:30-40. However, to further its anti-cancer narrative,
`
`Shailubhai speculates that “uroguanylin also binds to a currently unknown
`
`receptor, which is distinct from GC-C.” Id., 2:20-25.
`
`-6-
`
`

`

`Shailubhai discloses a peptide sequence (SEQ ID NO:20, below) for [Glu3]-
`
`human uroguanylin, reproduced below:
`
`EX1001, 5:3-15 (single conservative substitution highlighted; asterisks indicate
`
`disulfide pairs); EX1002, ¶¶23, 117.
`
`[Glu3]-human uroguanylin has a glutamate at the third amino-acid position instead
`
`of the aspartate shown in human uroguanylin (SEQ ID NO:1, below, only
`
`difference highlighted):
`
`Compare id., 5:1-15, with id., Table 2.1; EX1002, ¶24.
`
`This single Glu3-substitution is the only difference between the peptide sequences
`
`of [Glu3]-human uroguanylin and naturally-occurring human uroguanylin.
`
`EX1002, ¶¶24-27, 118-19.
`
`Moreover, uroguanylin provides the same function as [Glu3]-human
`
`uroguanylin. Shailubhai measures cellular cGMP activation in cultured human T84
`
`colon carcinoma cells. EX1001, 15:25-40 (“T84 cell-based assay for determining
`
`the intracellular levels of cGMP.”); also 5:10-15, 16:1-20, Table 2.1. Shailubhai’s
`
`cGMP production data (Table 4, below) shows human uroguanylin activity (SEQ
`-7-
`
`

`

`ID No. 1) achieved 65.1% of the cGMP production achieved by [Glu3]-human
`
`uroguanylin (SEQ ID No. 20),6 a difference of degree rather than kind. Id., 16:1-
`
`20; EX1002, ¶253.
`
`Indeed, Shailubhai discloses the functional equivalence of guanylin family
`
`peptides generally. Id., 6:51-53 (“Any known form of uroguanylin or guanylin can
`
`be used for this purpose [i.e., treating cancer], although the human peptides are
`
`preferred.”).
`
`Shailubhai credits those skilled in the art as having a high degree of ability
`
`in formulating [Glu3]-human uroguanylin into a viable medicament because it
`
`6205315∗100%=65.1%
`
`-8-
`
`

`

`recites many options without any further enabling disclosures. For example, the
`
`disclosure expresses confidence in the artisan’s ability—without further
`
`guidance—to identify appropriate—
`
` excipients, id., 3:32-34:
`
`The peptides may be in a pharmaceutical composition in unit dose
`form, together with one or more pharmaceutically acceptable
`excipients.
`
` combinations and dosages, id., 3:45-51:
`
`The invention also encompasses combination therapy utilizing a
`guanylate cyclase receptor agonist administered either alone or
`together with an inhibitor of cGMP-dependent phosphodiesterase, an
`anti-inflammatory agent or an anticancer agent. These agents should
`be present in amounts known in the art to be therapeutically effective
`when administered to a patient.
`
`o See also id., 15:13-17:
`
`The amount of compound administered is dependent upon factors
`known to a person skilled in this art such as, for example, chemical
`properties of the compound, route of administration, location and type
`of cancer, and the like.
`
` administration modes, id., 5:24-43:
`
`The guanylate cyclase receptor agonists used in the methods described
`above may be administered either orally, systemically or locally.
`
`-9-
`
`

`

`Dosage forms include preparations for inhalation or injection,
`solutions, suspensions, emulsions, tablets, capsules, topical salves and
`lotions, transdermal compositions, other known peptide formulations
`and pegylated peptide analogs.… Adjustments in dosage will be made
`using methods that are routine in the art and will be based upon the
`particular composition being used and clinical considerations…. In all
`cases, additional drugs should be administered at a dosage that is
`therapeutically effective using the existing art as a guide. Drugs may
`be administered in a single composition or sequentially.
`
`o See also id., 13:19-30:
`
`Formulations and dosage forms may be made using methods well
`known in the art (see, e.g., Remington's Pharmaceutical Sciences, 16th
`ed., A. Oslo ed., Easton, Pa. (1980).)
`
` carriers and other ingredients, id., 13:40-52:
`
`The selection of carriers (e.g., phosphate-buffered saline or PBS) and
`other components suitable for use in compositions is well within the
`level of skill in this art.
`
`Shailubhai also discloses that its calculations show:
`
`γ-carboxyls of the Glu residues in position 3 are clearly stretched
`‘outwards’ of the bulk of the molecules farther than the corresponding
`β-carboxyls of the Asp residues. The above observation strongly
`suggests that the negatively charged carboxyl group of the side chain
`in position 3 specifically interacts with a positively charged binding
`site on the receptor; therefore, analogs containing Glu3 instead of
`
`-10-
`
`

`

`Asp3 should be more active.
`
`Id., 10:50-56; see also EX1002, ¶28. Shailubhai does not purport to have invented
`
`the conventional energy calculations that informed this expectation. EX1002, ¶30.
`
`Shailubhai’s specification references treatment of a mammal, not necessarily
`
`a human, but its only working example was performed on human cell culture. Id.,
`
`15:18-20, 15:25-55.
`
`B. Challenged Claims
`Shailubhai has six claims, each of which is unpatentable. EX1002, ¶¶31-36.
`
`Independent claim 1 defines the subject matter as:
`
` 1. A peptide consisting of the amino acid sequence of SEQ ID
`NO:20.
`
`Independent claim 2 defines a composition comprising the claim 1 peptide:
`
`A composition in unit dose comprising a guanylate cyclase
`2.
`receptor agonist peptide consisting of the amino acid sequence of
`SEQ ID NO:20.
`
`Independent claim 3 defines a composition in unit-dose form comprising the
`
`claim 1 peptide combined with another agent:
`
`A composition in unit dose form comprising: a) a guanylate
`3.
`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
`
`-11-
`
`

`

`phosphodiesterase inhibitor, an anti-inflammatory agent, an
`antiviral agent and an anticancer agent.
`
`Claim 4 is a multiply-dependent claim “of either claim 2 or claim 3,” further
`
`requiring that “the unit dose form is selected from the group consisting of a tablet,
`
`a capsule, a solution and an inhalation formulation.” EX1002, ¶37.
`
`Claim 5 is a multiply-dependent claim “of either claim 2 or claim 3, further
`
`comprising one or more excipients.” EX1002, ¶37.
`
`Independent claim 6 is a peptide conjugate “comprising polyethylene glycol
`
`(PEG) attached to” the claim 1 peptide.
`
`C. Prosecution History
`The prosecution focused on evaluating whether the full genus of the original
`
`claims had adequate written description support, whether cancer treatment was an
`
`unpredictable art, and ultimately whether SEQ ID NO:20 was anticipated.
`
`Shailubhai faced only one prior-art rejection—anticipation by a 1998 journal
`
`article by Hikada in view of its teaching of a truncated human uroguanylin.
`
`EX1004, 0172-73. Shailubhai traversed this rejection because “the residue at
`
`position 3 is an aspartic acid,” and not glutamic acid as in the claimed peptide. Id.,
`
`0192. The examiner also rejected the claims for failing to comply with 35 U.S.C.
`
`§112 for the full scope of the original claims. EX1004, 0160-72. Shailubhai
`
`addressed these rejections by narrowing the claims to only [Glu3]-human
`
`-12-
`
`

`

`uroguanylin. Id., 0188, 0190-91. The examiner deleted certain other limitations and
`
`subsequently allowed the amended claims. Id., 0271-77 (deleting
`
`“pharmaceutical,” “therapeutically effective amount,” etc.).
`
`VI. LEVEL OF ORDINARY SKILL
`The applied references reflect the knowledge and skill in the art by January
`
`17, 2002. A skilled artisan would have been familiar with signaling peptides and
`
`their biochemistry, as the accompanying exhibits prove. The specification admits
`
`an artisan would also have known how to choose and prepare various dosage forms
`
`when it notes the use of known alternatives without further guidance on when and
`
`how to use them. A Ph.D. in peptide chemistry, protein engineering, or a related
`
`field, or alternatively, a master’s degree in one of these fields plus two to five years
`
`of experience in drug development would represent typical education and
`
`experience for a skilled artisan. EX1002, ¶¶40-43. This individual would have
`
`worked in consultation with a team including, e.g., a pharmaceutical chemist
`
`and/or a pharmacist familiar with formulating peptides for administration.
`
`Professor Peterson, whose declaration accompanies this petition (see
`
`EX1002, ¶¶12-14), has over two decades of experience in the relevant field. Id.,
`
`¶¶1-11. Professor Peterson was a person of ordinary skill in the art by 2002. Id.,
`
`¶43.
`
`As noted above, Shailubhai invokes a high level of skill in the art,
`
`-13-
`
`

`

`encompassing all the formulation and dosing considerations relating to these
`
`claims. Shailubhai also reported routine analyses of guanylin-related peptides and
`
`the GC-C receptor, reflecting a reasonable expectation that substituting glutamate
`
`for aspartate at the third position would improve affinity with a positively-charged
`
`binding site. See §Shailubhai PatentV.A above; EX1002, ¶30.
`
`VII. CLAIM CONSTRUCTION
`SEQ ID NO:20, an element of each challenged claim, is reproduced below,
`
`with the glutamate substitution at issue highlighted.
`
`EX1001, 5:1-15.
`
`The plain meaning of excipient includes coating agents:
`
`Excipients are materials used in the formulation of pharmacologically
`active drugs; currently over 1000 such materials are used in marketed
`pharmaceuticals. They have a variety of roles including
`diluents/fillers/bulking agents, binders/adhesives, propellants,
`disintegrants, lubricants/glidants, colors, flavors, coating agents,
`polishing agents, fragrances, sweetening agents, polymers, and waxes;
`vaccine adjuvants also represent an excipient form.
`
`EX1043, 210 (emphasis added); EX1002, ¶¶95-96, 206-208.
`
`The claim terms do not require construction to apply the grounds. EX1002,
`
`¶¶44-45. The claims are not limited to a specific use, such as treatment of a
`
`-14-
`
`

`

`specific disease or animal.
`
`VIII. PRIOR ART
`All the applied and background references were publicly available by
`
`January 2002.
`
`A. Background
`Peptides are amino-acid polymers, many of which bind with receptors and
`
`act as chemical messengers. EX1002, ¶¶46-49, EX1011, 1088; EX1013, 133, 139.
`
`The table below shows the twenty proteogenic (i.e., protein-making) amino
`
`acids.
`
`-15-
`
`

`

`EX1012, 119, FIG. 5-5; EX1002, ¶¶53-54.
`
`Among these 20 different amino acids, only aspartate and glutamate, shown
`
`in the bottom right of the figure above, are negatively charged at neutral pH.
`
`EX1002, ¶¶54-57. They are also the only amino acids with a carboxylic acid
`
`functional group. Id. As the figure shows, glutamate has an additional methylene
`
`(-CH2-) link in its side chain (shaded in original). Aspartate and glutamate
`
`-16-
`
`

`

`otherwise differ only in their measure of dissociation (pKa): 3.65 and 4.25,
`
`respectively. EX1002, ¶¶55-57; EX1012, 118, Table 5-1. This difference means
`
`that, as pH approaches neutral, glutamic acid remains protonated longer than
`
`aspartic acid. Id.
`
`Naturally occurring peptides evolve and—as they diverge—fall into several
`
`categories. Generally, related but divergent peptides are called homologs.
`
`Orthologs are ancestrally from the same peptide but produced by divergent
`
`organisms. EX1002, ¶76. Human and rat uroguanylin, for example, are orthologs.
`
`Paralogs are divergent peptides ancestrally from the same peptide, but in the same
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`organism. Id. Human uroguanylin and human guanylin are paralogs. EX1002,
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`¶133; see also, e.g., EX1002, ¶¶76, 80; EX1052 (describing paralogous loci). As
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`discussed in further detail below, it was known in the art that uroguanylin
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`orthologs shared 80% identity and nearly all differences reflect conservative
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`substitutions. EX1006, 53.
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`Uroguanylin is a small peptide that stimulates intestinal guanylate cyclase, a
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`receptor displayed in the mucosa of the intestinal endothelium. EX1002, ¶58. By
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`2002, natural uroguanylin’s known laxative function suggested the peptide as a
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`treatment for constipation. Id., ¶¶59-60; EX1005, 2:20-25; EX1016, E957, E962.
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`Uroguanylin stimulates water transfer into the intestine. EX1002, ¶¶59-60; see also
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`EX1020, FIG. 2.
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`Uroguanylin evolved to have markedly enhanced potency in acidic mucosa
`
`in the intestines subject to efflux from the stomach. EX1002, ¶¶61-65. The graphs
`
`below demonstrate uroguanylin’s pH-dependent enhancement, with activity
`
`compared for pH 5 and 8, using uroguanylin in the upper graph showing the
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`enhancement, and truncated uroguanylin in the lower graph, which does not exhibit
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`the same enhancement. Id., ¶65.
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`EX1021, FIG. 5.
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`As seen in the upper graph, uroguanylin triggers a rapid increase in cGMP
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`activity at a lower concentration in a more acidic environment (pH 5, open circles)
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`than in a more basic environment (pH 8, solid circles). As Professor Peterson
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`-18-
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`

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`explains, skilled artisans believed that this pronounced pH effect on enhancing
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`signaling activity correlated with the presence of acidic amino acid residues at
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`positions 2 and 3 of the peptide. EX1002, ¶65.
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`The lower graph performs the same experiment as the upper graph, but after
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`truncating the uroguanylin to remove the first three amino acid residues from the
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`peptide. As shown in the bottom graph, the truncated (98-109) uroguanylin variant
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`lacks the activity enhancement at lower pH. Id. It was thus observed that “All
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`uroguanylin peptides have aspartate or glutamate residues at [the second and third]
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`positions” because these “N-terminal residues of uroguanylin are required for the
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`increased binding affinities, and therefore, the enhanced potency of uroguanylin of
`
`activation of receptors under acidic conditions.” EX1021, 2709.
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`Skilled artisans understood that “oral administration of uroguanylin
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`markedly stimulates intestinal fluid secretion.” EX1018, G641. Thus, uroguanylin
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`was identified as a good candidate for oral administration for delivery to the
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`intestines to treat constipation. EX1002, ¶¶59-61, 82-86, 89-93, 99, 107.
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`Formulating peptides, such as uroguanylin analogues, into tablets or
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`capsules in combination with any number of well-known excipients was well-
`
`within the routine skill in the art. EX1002, ¶¶95-96; see also, e.g., EX1010,
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`generally; EX1043, 210 (describing routine formulation); EX1044, 237
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`(formulating a vaccine with excipients). For example, Remington’s notes that
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`-19-
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`

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`“[d]rug substances are most frequently administered orally by means of solid
`
`dosage forms such as tablets and capsules.” EX1010, 1553. Thus, those of ordinary
`
`skill in the art routinely formulated unit-dose forms such as tablets and capsules for
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`oral delivery. As explained by Remington’s, “[l]arge-scale production methods” of
`
`these unit-dose forms routinely and conventionally “require[d] the presence of
`
`other materials in addition to the active ingredients,” such as additives to “enhance
`
`the physical appearance, improve stability, and aid in disintegration after
`
`administration.” Id.; EX1002, ¶¶95-99. These conventional formulation techniques
`
`were also well known to be useful in the preparation of peptide-based drugs with
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`intestinal targets. See, e.g., EX1046, 28-29; EX1047, 3708.
`
`A natural peptide is the obvious starting point for developing drugs to
`
`intervene in the natural peptide’s signaling pathway. EX1002, ¶71. By the critical
`
`date, skilled artisans had proven for decades their ability to make more potent or
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`predictable synthetic analogs (or optimize where the peptides are most potent to
`
`better target the desired tissue) as compared to the natural analogs. Id., ¶72; see
`
`EX1025, 44 (creating more than 2000 synthetic analogs of a naturally occurring
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`peptide hormone); EX1028, 279 (preparing synthetic analogs of insulin); EX1029,
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`19-20 (similar); EX1030, 7185 (modulating charges to control peptide binding);
`
`see also, e.g., EX1026, 171 (teaching conservative substitutions for making peptide
`
`analogs); EX1027, generally (describing biosynthetic studies of peptide
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`hormones).
`
`Skilled artisans thus routinely took three approaches to such development.
`
`First, skilled artisans began with conservative substitutions. That is, simply
`
`substituting one amino-acid residue for another similar amino-acid residue.
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`EX1002, ¶¶73-75; see also id., ¶138 (discussing conservative agonist design in
`
`EX1050, 68-70). Second, skilled artisans implemented design modifications
`
`suggested by orthologs or paralogs, the sequences of which were available due to
`
`mass sequencing. EX1002, ¶¶76-80. So-called shuffling strategies were known to
`
`be useful for designing drugs beginning from naturally occurring peptides that are
`
`both somewhat functional and already homologous. EX1002, ¶¶76-80, 136. Third,
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`skilled artisans optimized how the peptide binds to its receptor. Id., ¶81. As
`
`Professor Peterson explains, when following this mechanistic approach, skilled
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`artisans often targeted electrostatic interactions between peptide and receptor
`
`because electrostatic interactions are often important to the binding interaction. Id.;
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`see also EX1002, ¶¶50-52 (describing peptide hormone-receptor binding);
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`EX1014, 101, EX1015, 10308.
`
`The state of the art at the time was sufficiently well developed that making a
`
`desired peptide using the proteogenic amino acids was a matter of routine skill. For
`
`example, solid-phase peptide synthesis routinely enabled skilled artisans to
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`synthesize large numbers of different peptides with relative ease. EX1002, ¶¶66-
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`70. That is, the threshold for making a particular peptide was very low. Skilled
`
`artisans thus routinely created even hundreds of peptide analogs to known
`
`hormones and routinely characterized the properties of those peptides. But, as
`
`Professor Peterson explains, certain amino acids, such as aspartate (but not
`
`glutamate), were particularly prone to interfering side reactions during synthesis
`
`resulting in un