`
`Andrew O Larsen, Ph.D., Esq.
`Reg. No. 59,315
`MERCHANT & GOULD P.C.
`500 Fifth Avenue, Suite 4100
`New York, NY 10110
`Main Telephone: (212) 223-6658
`Main Facsimile: (212) 223-6521
`alarsen@merchantgould.com
`
`
`Christopher J. Sorenson, Esq.
`Pro Hac Vice
`MERCHANT & GOULD P.C.
`150 South Fifth Street, Suite 2200
`Minneapolis, MN 55402
`Main Telephone: (612) 336-4645
`Main Facsimile: (612) 332-9081
`csorenson@merchantgould.com
`
`Melissa Hayworth, Esq.
`Registration No. 45,774
`MERCHANT & GOULD P.C.
`1900 Duke Street, Suite 600
`Alexandria, VA 22314
`Main Telephone: (703) 684-2522
`Main Facsimile: (612) 332-9081
`mhayworth@merchantgould.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
` MSN LABORATORIES PRIVATE LTD. AND MSN PHARMACEUTICALS INC.
`Petitioners
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner
`_____________________
`
`IPR2023-00016
`Patent No. 7,041,786
`
`
`PETITION FOR INTER PARTES REVIEW
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. § 42.100 ET SEQ.
`
`
`
`By:
`
`
`
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`I. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ....................................... 1
`A. Real Parties-In-Interest under 37 C.F.R. § 42.8(b)(1) ...................................... 1
`B. Related Matters under 37 C.F.R. § 42.8(b)(2).................................................. 2
`C. Lead and Backup Counsel under 37 C.F.R. § 42.8(b)(3) ................................. 2
`D. Service Information under 37 C.F.R. § 42.8(b)(4) ........................................... 3
`E. Power of Attorney under 37 C.F.R. §42.10(b) ................................................. 3
`II. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104 ................................ 3
`A. Grounds For Standing Under 37 C.F.R. § 42.104(a) ....................................... 3
`B. Identification of Challenge and Precise Relief Requested, 37 C.F.R. §
`42.104(b) ................................................................................................................. 4
`III. SUMMARY OF THE SHAILUBHAI PATENT ................................................ 6
`A. Specification ..................................................................................................... 6
`B. Challenged Claims 1–6 ................................................................................... 13
`C. Prosecution History ........................................................................................ 14
`IV. LEVEL OF SKILL AND KNOWLEDGE IN THE ART ................................. 15
`V. CLAIM CONSTRUCTION .............................................................................. 16
`VI. PRIOR ART ....................................................................................................... 17
`A. Background ..................................................................................................... 17
`B. Currie (EX1005) ............................................................................................. 24
`C. Li (EX1006) .................................................................................................... 26
`D. Narayani (EX1007)......................................................................................... 28
`E. Campieri (EX1008) ........................................................................................ 29
`F. Ekwuribe (EX1009) ........................................................................................ 30
`VII. GROUNDS FOR UNPATENTABILITY ........................................................ 33
`A. Legal Standards .............................................................................................. 33
`B. Ground 1: Claim 1 Is Obvious Over Currie and Li ........................................ 34
`1. Claim 1 ........................................................................................................ 34
`2. Reason to Modify ........................................................................................ 36
`
`
`
`ii
`
`

`

`
`
`C. Ground 2: Claims 2, 4, and 5 Are Obvious Over Currie, Li,
`
`and Narayani ................................................................................................... 42
`1. Claim 2 ........................................................................................................ 42
`2. Claims 4 and 5 ............................................................................................. 44
`D. Ground 3: Claims 3-5 Are Obvious Over Currie, Li, Narayani,
`
`and Campieri ................................................................................................... 46
`E. Ground 4: Claim 6 Is Obvious Over Currie, Li, and Ekwuribe (1994) ......... 52
`VIII. THERE ARE NO SECONDARY CONSIDERATIONS
`
` OF NON-OBVIOUSNESS ............................................................................. 55
`IX. THE BOARD SHOULD NOT DECLINE TO INSTITUTE BASED ON
`
`ITS DISCRETIONARY AUTHORITY UNDER 35 U.S.C. §§ 314(a)
`
`or 315(d) ............................................................................................................ 56
`A. Co-pending Litigation .................................................................................... 56
`B. Prior Office Consideration ............................................................................. 58
`X. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 .............. 60
`
`
`
`
`
`
`
`iii
`
`

`

`
`
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Amneal Pharms. v. Supernus Pharms.,
`IPR2013-00368 (PTAB Dec. 17, 2013) ............................................................. 55
`Apple v. Fintiv,
`IPR2020-00019 ............................................................................................. 57, 58
`Bausch Health Ireland Limited et al v. Mylan Laboratories Ltd. et al.,
`1-21-cv-00611 (DDE) ..................................................................................... 2, 64
`Bausch Health Ireland Ltd. et al v. Mylan Laboratories Limited et al.,
`2-21-cv-00573 (WDPA) ....................................................................................... 2
`Bayer Pharma AG v. Watson Labs., Inc.,
`874 F.3d 1316 (Fed. Cir. 2017) .......................................................................... 40
`CRFD Research, Inc. v. Matal,
`876 F.3d 1330 (Fed. Cir. 2017) .......................................................................... 41
`In re Diamond,
`360 F.2d 214 (CCPA 1966) ................................................................................ 51
`In re Dillon,
`919 F.2d 688 (Fed. Cir. 1990) (en banc) ................................................ 33, 34, 55
`In re Fout,
`675 F.2d 297 (Fed. Cir. 1982) ............................................................................ 41
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) .......................................................................... 41
`Google LLC v. Koninklijke Philips N.V.,
`795 Fed. Appx. 840 (Fed. Cir. 2020) .................................................................. 41
`In re Harris,
`409 F.3d 1339 (Fed. Cir. 2005) .................................................................... 34, 55
`
`
`
`iv
`
`

`

`
`
`Intel Corp. v. VLSI Tech. LLC,
`IPR2022-00366, Paper No. 14 (PTAB Jun. 8, 2022) ......................................... 60
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 33, 40
`Merck & Co. v. Biocraft Labs.,
`874 F.2d 804 (Fed. Cir. 1989) ............................................................................ 41
`In re Mouttet,
`686 F.3d 1322 (Fed. Cir. 2012) .......................................................................... 41
`Par Pharm. v. TWI Pharm.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 41
`PTAB—Mylan Pharmaceuticals Inc. v. Bausch Health Ireland Ltd.
`IPR2022-00722 ............................................................................................... 2, 63
`Spectrum Pharm. v. Sandoz Inc.,
`802 F.3d 1326 (Fed. Cir. 2015) .......................................................................... 41
`Tyco Healthcare Group v. Ethicon Endo-Surgery,
`774 F.3d 968 (Fed. Cir. 2014) ............................................................................ 41
`Uber Tech., Inc. v. X One, Inc.,
`957 F.3d 1334 (Fed. Cir. 2020) .......................................................................... 46
`
`Valeant Pharmaceuticals Ireland Ltd. et al v. MSN Laboratories
`Private Limited et al.,
`2-21-cv-10057 (DNJ) ...................................................................................... 2, 56
`
`Valeant Pharmaceuticals Ireland Ltd. et al v. Mylan Laboratories
`Limited et al.,
`2-21-cv-10403 (DNJ) ............................................................................................ 2
`Statutes
`35 U.S.C. § 102(b) ............................................................................................passim
`35 U.S.C. § 103 ................................................................................................ 4, 5, 40
`35 U.S.C. § 112 .................................................................................................passim
`35 U.S.C. §§ 311-319 .............................................................................................. 63
`
`
`
`v
`
`

`

`
`
`35 U.S.C. §§ 314(a) and 315(c) ............................................................................... 56
`35 U.S.C. § 315(b) ..................................................................................................... 4
`35 U.S.C. § 315(c) ..................................................................................................... 4
`35 U.S.C. § 315(e)(1) ................................................................................................. 4
`35 U.S.C. § 325(d) ............................................................................................. 58, 60
`Other Authorities
`37 C.F.R. § 42.8 ................................................................................................... 1, 62
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 1
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 2
`37 C.F.R. § 42.8(b)(3) ................................................................................................ 2
`37 C.F.R. § 42.8(b)(4) ................................................................................................ 3
`37 C.F.R. § 42.10 ....................................................................................................... 2
`37 C.F.R. §42.10(b) ................................................................................................... 3
`37 C.F.R. § 42.15(a)(1-4) ......................................................................................... 60
`37 C.F.R. § 42.103 ................................................................................................... 60
`37 C.F.R. § 42.24(d) ................................................................................................ 62
`37 C.F.R. § 42.100 ET SEQ. .................................................................................... 63
`37 C.F.R. § 42.102(a)(2) ............................................................................................ 4
`37 C.F.R. § 42.104 ..................................................................................................... 3
`37 C.F.R. § 42.104(a) ................................................................................................. 3
`37 C.F.R. § 42.104(b) ................................................................................................ 4
`
`
`
`
`
`
`vi
`
`

`

`
`
`Petitioners MSN Laboratories Private Limited and MSN Pharmaceuticals
`
`Inc. (collectively “Petitioners” or “MSN”) request that the Board institute inter
`
`partes review (“IPR”) of claims 1-6 of U.S. Patent No. 7,041,786 (“the ’786
`
`patent”) (Ex. 1001), and determine that these claims be canceled as unpatentable.
`
`IPR of claims 1-6 of the ’786 patent was previously instituted in IPR2022-00722
`
`on March 21, 2022 ("the Mylan IPR"), based on a petition filed by Mylan
`
`Pharmaceuticals Inc. (“the Mylan Petition”). (IPR2022-00722, Paper 1 (Mylan
`
`Petition), Paper 16 (Institution Decision).) The present Petition is substantially
`
`identical to the Mylan Petition. A Motion for Joinder with IPR2022-00722 is filed
`
`concurrently with this Petition.
`
`I. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`A. Real Parties-In-Interest under 37 C.F.R. § 42.8(b)(1)
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioners certify that Petitioners MSN
`
`
`
`Laboratories Private Limited and MSN Pharmaceuticals, Inc. are the real parties-
`
`in-interest. Petitioners MSN Pharmaceuticals, Inc. and MSN Laboratories Private
`
`Limited have the sole authority to direct all activities relating to this Petition or any
`
`future proceedings related to this Petition. All of the costs associated with this
`
`Petition will be borne by Petitioners.
`
`
`
`1
`
`

`

`
`
`B. Related Matters under 37 C.F.R. § 42.8(b)(2)
`
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioners are aware of the following
`
`related matter at the PTAB—Mylan Pharmaceuticals Inc. v. Bausch Health
`
`Ireland Ltd. IPR2022-00722—and the Federal District Court proceedings listed in
`
`the table below.
`
`Disposition
`Pending
`
`Closed
`
`Closed
`
`Case Caption
`Bausch Health Ireland Ltd. f/k/a Valeant Pharmaceuticals Ireland
`Ltd. et al v. MSN Laboratories Private Limited et al., 2-21-cv-10057
`(DNJ)
`Bausch Health Ireland Ltd. f/k/a Valeant Pharmaceuticals Ireland
`Ltd. et al v. Mylan Laboratories Limited et al., 2-21-cv-10403 (DNJ)
`Bausch Health Ireland Limited et al v. Mylan Laboratories Ltd. et
`al., 1-21-cv-00611 (DDE)
`Bausch Health Ireland Ltd. et al v. Mylan Laboratories Limited et
`al., 2-21-cv-00573 (WDPA)
`Bausch Health Ireland Ltd. et al v. Mylan Laboratories Limited et
`al., 1-22-cv-00020 (NDWV)
`
`C. Lead and Backup Counsel under 37 C.F.R. § 42.8(b)(3)
`Petitioners provide the following designation of counsel:
`
`Closed
`
`Pending
`
`Lead Counsel:
`Andrew O. Larsen, Ph.D., Esq.
`Registration No. 59,315
`MERCHANT & GOULD P.C.
`500 Fifth Avenue, Suite 4100
`New York, NY 10110
`Main Telephone: (212) 223-6658
`Main Facsimile: (212) 223-6521
`alarsen@merchantgould.com
`
`Backup Counsel:
`Christopher J. Sorenson, Esq.
`(Pro Hac Vice ~ Pending) 1
`MERCHANT & GOULD P.C.
`150 South Fifth Street, Suite 2200
`Minneapolis, MN 55402
`Main Telephone: (612) 336-4645
`Main Facsimile: (612) 332-9081
`csorenson@merchantgould.com
`
`
`1 A motion to appear pro hac vice will be filed pursuant to 37 C.F.R. § 42.10.
`
`
`
`2
`
`

`

`
`
`
`Melissa Hayworth, Esq.
`Registration No. 45,774
`MERCHANT & GOULD P.C.
`1900 Duke Street, Suite 600
`Alexandria, VA 22314
`Main Telephone: (703) 684-2522
`Main Facsimile: (612) 332-9081
`mhayworth@merchantgould.com
`
`
`D.
`Service Information under 37 C.F.R. § 42.8(b)(4)
`Please direct all correspondence to counsel at the contact information below.
`
`MSN consents to electronic-mail service at:
`
`
`
`alarsen@merchantgould.com,
`csorenson@merchantgould.com,
`mhayworth@merchantgould.com,
`plecanatidemerchant@merchantgould.com
`E.
`Power of Attorney under 37 C.F.R. §42.10(b)
`A Power of Attorney is being filed concurrently herewith with designation
`
`of the counsel above.
`
`II. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104
`A. Grounds For Standing Under 37 C.F.R. § 42.104(a)
`Petitioners hereby certify that the ’786 patent is available for inter partes
`
`review, and that the Petitioners are not barred or estopped from requesting this IPR
`
`on the grounds identified in this Petition because: (1) Petitioners are patent owners
`
`of record; (2) Petitioners have not filed a civil action challenging the validity of
`
`
`
`3
`
`

`

`
`
`any claim in the patent; (3) the estoppel provisions of 35 U.S.C. § 315(e)(1) do not
`
`prohibit this IPR; and (4) the patent is not described in §3(n)(1) of the America
`
`Invents Act and so is available for IPR under 37 C.F.R. § 42.102(a)(2). Though
`
`Petitioners have been served with a complaint alleging infringement of the ’786
`
`patent, they are also not barred under 35 U.S.C. § 315(b) because that time
`
`limitation does not apply to a request for joinder under 35 U.S.C. § 315(c).
`
`B.
`
`Identification of Challenge and Precise Relief Requested,
`37 C.F.R. § 42.104(b)
` Petitioners request cancellation of claims 1-6 of the ’786 patent on Grounds
`
`1–4 below, which are the same grounds of unpatentability asserted in the Mylan
`
`Petition. (See IPR2022-00722, Paper 1, 3-4.) Claims 1-6 are unpatentable under pre-
`
`AIA 35 U.S.C. § 103 based on the combined teachings of:
`
`Ground Claims Basis Obvious from the Combined Teachings of
`1
`1
`§ 103 Currie2 (EX1005) and Li3 (EX1006)
`2
`2, 4-5 § 103 Currie, Li & Narayani4 (EX1007)
`
`2 Currie, M.G., et al., Human Uroguanylin, U.S. Pat. 5,489,670 (1996).
`
`3 Li, Z., et al., Purification, cDNA Sequence, and Tissue Distribution of Rat
`
`Uroguanylin, 68 REGUL. PEPT. 45-56 (1997).
`
`4 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
`
`

`

`
`
`Ground Claims Basis Obvious from the Combined Teachings of
`3
`3-5
`§ 103 Currie, Li, Narayani & Campieri5 (EX1008)
`4
`6
`§ 103 Currie, Li & Ekwuribe6 (EX1009)
`
`
`Petitioners’ Grounds 1-4, which are substantially identical to the grounds
`
`instituted by the Board in the Mylan IPR, challenge the same claims over the same
`
`prior art, and rely on the same exhibits, arguments, and expert testimony presented
`
`with the Mylan Petition. Each of Grounds 1-4 identifies a different prior art
`
`combination from which a person of ordinary skill in the art (“POSA” or "skilled
`
`artisan") would have easily arrived at the subject matter of the challenged claims,
`
`which are directed to a synthetic uroguanylin analog, i.e., [Glu3]-human
`
`uroguanylin (claim 1), compositions containing [Glu3]-human uroguanylin (claims
`
`2-5), and a peptide conjugate comprising polyethylene glycol (PEG) attach to
`
`[Glu3]-human uroguanylin (claim 6).
`
`Petitioners support their grounds with a Declaration of Dr. Blake R. Peterson
`
`(EX1002; “Peterson Declaration”), which is an exact copy the Declaration of Dr.
`
`
`5 Campieri, M., et al., Oral Budesonide Is as Effective as Oral Prednisolone in
`
`Active Crohn’s Disease, 41 GUT 209-14 (1997).
`
`6 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).
`
`
`
`5
`
`

`

`
`
`Blake R. Peterson relied upon in the Mylan Petition (see IPR2022-00722,
`
`EX1002). As mentioned above, this Petition is being filed concurrently with a
`
`motion to join IPR2022-00722. The same Peterson Declaration from IPR2022-
`
`00722 is cited in this Petition to avoid unnecessary cost and delay to these
`
`proceedings, and to advance judicial economy.
`
`III. SUMMARY OF THE SHAILUBHAI PATENT
`A. Specification
`Shailubhai is titled “Guanylate Cyclase Receptor Agonists for the Treatment
`
`of Tissue Inflammation and Carcinogenesis.” (EX1001, cover [54]; EX1002,7
`
`¶ 23.) The ’786 patent lists Kunwar Shailubhai, Gregory Nikiforovich, Gary S.
`
`Jacob as its inventors. (EX1001, cover [75].) The Patent Owner identifies Bausch
`
`Health Ireland Ltd as the assignee. Shailubhai claims priority to the provisional
`
`application of U.S. Patent Application No. 60/348,646 (“the ’646 application”)
`
`filed on January 17, 2002 (the earliest possible effective 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.)
`
`
`7 All refences of EX1002 refer to the corrected version of this exhibit, Mylan
`
`Exhibit 1002 (Corrected).
`
`
`
`6
`
`

`

`
`
`The Shailubhai specification, unlike the issued claims, focuses on treating
`
`cancer. (See e.g., EX1001, cover [57], 2:1-61; 3:61-4:42.) Yet uroguanylin was
`
`discovered as a naturally-occurring laxative. (See e.g., EX1005, 2:20-24 (“The
`
`human uroguanylin may thus act as a laxative and be useful in patients suffering
`
`from constipation . . .”); see also EX1002, ¶¶ 23, 38-39, 59.) 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.)
`
`Instead of discussing the use of the claimed peptides to treat constipation,
`
`the Abstract identifies the invention as a “method of treatment of inflamed, pre-
`
`cancerous or cancerous tissue or polyps in a mammalian subject.” (EX1001, cover
`
`[57].) While disclaiming any “particular mechanism of action,” 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., 1:14-22.) For treating cancer, “[a]ny known
`
`
`
`7
`
`

`

`
`
`form of uroguanylin or guanylin can be used. . ., although the human peptides are
`
`preferred.” (See id., 4:7-13.) The challenged claims, however, are not directed to
`
`treating cancer. (Id., 37:1-38:9.)
`
`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, 1:26-30 (citing references 1–6).)
`
`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., 2:20-22.)
`
`Shailubhai discloses a peptide sequence (SEQ ID NO:20, below) for [Glu3]-
`
`human uroguanylin, reproduced below:
`
`
`
`8
`
`

`

`
`
`SEQ ID NO: 20, [Glu3]-human uroguanylin8
`
`
`
`
`
`[Glu3]-human uroguanylin has a glutamate at the third amino-acid position
`
`instead of the aspartate shown in human uroguanylin (SEQ ID NO:1,9 below, only
`
`difference highlighted):
`
`This single Glu3-substitution is the only difference between the peptide
`
`sequences of [Glu3]-human uroguanylin and naturally-occurring human
`
`uroguanylin. (EX1002, ¶¶ 23-27, 118-19.)
`
`Moreover, uroguanylin provides the same function as [Glu3]-human
`
`uroguanylin. (EX1002, ¶ 253). 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 id., 5:10-15, 16:1-
`
`20, Table 2.1.) Shailubhai’s cGMP production data (Table 4, below) shows human
`
`uroguanylin activity (SEQ ID No. 1) achieved 65.1% of the cGMP production
`
`
`8 (EX1001, 5:3-15 (single conservative substitution highlighted in blue; asterisks
`
`indicate disulfide pairs); see also id., Table 2.1; EX1002, ¶¶ 23, 117.)
`
`9 (Compare EX1001, 5:3-15, with id. Table 2.1; EX1002, ¶ 24.)
`
`
`
`9
`
`

`

`
`
`achieved by [Glu3]-human uroguanylin (SEQ ID No. 20),10 a difference of degree
`
`rather than kind. (Id., 16:1-20; EX1002, ¶ 253.)
`
`
`(EX1001, Table 4; see also id., 5:10-15, 15:25-40, 16:1-20, Table 2.1; see also,
`
`
`
`EX1002, ¶ 253.)
`
`Indeed, Shailubhai discloses the functional equivalence of guanylin family
`
`peptides generally. (EX1001, 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
`
`
`10 (cid:2870)(cid:2868)(cid:2873)(cid:2871)(cid:2869)(cid:2873)∗100%(cid:3404)65.1%
`
`
`
`10
`
`

`

`
`
`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.
`Dosage forms include preparations for inhalation or injection,
`
`11
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`

`

`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.
`
` See also id., 13:19-30
`
` o
`
`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, but does not claim, conventional energy
`
`
`
`
`
`calculations:
`
`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
`
`
`
`12
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`
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`site on the receptor; therefore, analogs containing Glu3 instead of
`Asp3 should be more active.
`
`(Id., 10:48-56; see also EX1002, ¶ 28, 30.) 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 1–6
`Shailubhai has six claims, each of which is unpatentable. (EX1002, ¶¶ 31-
`
`37.) Claims 1, 2, 3, and 6 are independent claims. 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:
`
`2. A composition in unit dose comprising a guanylate cyclase
`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:
`
`
`
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`

`
`
`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.
`
`Independent claim 6 is a peptide conjugate “comprising polyethylene glycol
`
`(PEG) attached to” the claim 1 peptide:
`
`6. A peptide conjugate comprising polyethylene glycol (PEG)
`attached to a peptide consisting of the amino acid sequence SEQ
`ID NO:20.
`
`Claims 4 and 5 are multiple dependent claims “of either claim 2 or claim 3”
`
`(EX1002, ¶ 37):
`
`4. The composition of either claim 2 or 3, wherein the unit dose
`
`form is selected from the group consisting of a tablet, a capsule, a
`
`solution and an inhalation formulation.
`
`5. The composition of either claim 2 or 3, further comprising one
`or more excipients.
`
`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. (See
`
`
`
`14
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`

`
`
`EX1004 (Part 1).) Shailubhai faced only one prior-art rejection—anticipation by a
`
`1998 Biochemistry journal article by Hikada in view of its teaching of a truncated
`
`human uroguanylin. (Id., 172-73.) Shailubhai traversed this rejection because “the
`
`residue at position 3 is an aspartic acid,” and not glutamic acid as in the claimed
`
`peptide. (Id., 192.) The examiner also rejected the claims for failing to comply with
`
`35 U.S.C. § 112 for the full scope of the original claims. (Id., 160-72.) Shailubhai
`
`addressed these rejections by narrowing the claims to only [Glu3]-human
`
`uroguanylin. (Id., 188, 190-91.) The examiner deleted certain other limitations and
`
`subsequently allowed the amended claims. (See id., 271-77 (striking
`
`“pharmaceutical,” “therapeutically effective amount,” etc.).)
`
`IV. LEVEL OF SKILL AND KNOWLEDGE IN THE ART
`
`The applied references reflect the knowledge and skill in the art by January
`
`17, 2002. A POSA 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. In this petition, 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 POSA. (See EX1002, ¶¶ 40-43.) This individual would have
`
`
`
`15
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`

`
`
`worked in consultation with a team including, e.g., a pharmaceutical chemist
`
`and/or a pharmacist familiar with formulating peptides for administration. (See id.)
`
`Dr. Peterson earned his Ph.D. in Chemistry 1994 and now has over two
`
`decades of experience in the relevant field. Dr. Peterson met Petitioners’ definition
`
`of a POSA by 2002. (EX1002, ¶¶ 1-11, 40-43.) Dr. Peterson’s analysis of the state
`
`of the art assumed the ability and knowledge of a skilled artisan as of January 17,
`
`2002. (See id. at ¶ 41.)
`
`As Dr. Peterson discusses, and as noted above, Shailubhai invokes a high
`
`level of skill in the art, 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 id. at ¶ 30; see supra Section III.A; see
`
`also EX1001.)
`
`V. CLAIM CONSTRUCTION
`
`SEQ ID NO:20, an element of each challenged claim, is reproduced below,
`
`with the glutamate substitution at issue highligh