CONFIDENTIAL–PROTECTIVE ORDER MATERIAL
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN INSTITUTIONAL LLC and PFIZER INC.,
`Petitioners,
`
`v.
`
`NOVO NORDISK A/S,
`
`Patent Owner.
`
`Case No. IPR2020-003241
`U.S. Patent No. 8,114,833
`
`PETITIONER’S REPLY IN SUPPORT OF PETITION FOR
`INTER PARTES REVIEW OF U.S. PATENT NO. 8,114,833
`
`REDACTED VERSION
`
`1
`
`IPR2020-01252 has been joined with this proceeding.
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`CONFIDENTIAL–PROTECTIVE ORDER MATERIAL
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`B.
`
`V.
`
`I.
`II.
`
`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 5
`THE PREAMBLES OF CLAIMS 25-31 ARE NOT
`LIMITATIONS ................................................................................................ 5
`III. CLAIMS 1-15 WERE ANTICIPATED .......................................................... 7
`Flink Anticipates Claims 1-15............................................................... 9
`A.
`Flink is Enabled ................................................................................... 13
`B.
`IV. CLAIMS 1-15 WERE OBVIOUS OVER FLINK ........................................ 14
`A.
`Flink Teaches the Use of PG as an Isotonic Agent in a GLP-1
`Formulation ......................................................................................... 14
`Petitioner Demonstrated Motivation and Reasonable
`Expectation of Success ........................................................................ 15
`ALL CLAIMS OF THE ’833 PATENT WERE OBVIOUS
`OVER FLINK IN VIEW OF BETZ .............................................................. 18
`A.
`Claims 1-15 are Obvious ..................................................................... 18
`Betz Teaches Formulations That Include PG Without
`1.
`Mannitol .................................................................................... 18
`Protein Drug Physical Instability Provides Motivation to
`Combine Flink and Betz with a Reasonable Expectation
`of Success .................................................................................. 19
`Claims 16-22 are Obvious ................................................................... 21
`B.
`Claims 23-29 are Obvious ................................................................... 21
`C.
`SECONDARY CONSIDERATIONS FAIL TO OVERCOME
`THE PRIMA FACIE CASE .......................................................................... 22
`Claim 14 of Flink is the Closest Prior Art........................................... 22
`A.
`B.
`PG’s Performance Was Expected ....................................................... 23
`Differences in Degree Do No Support Patentability ........................... 24
`C.
`Novo’s Evidence is Not Commensurate in Scope .............................. 25
`D.
`VII. BETZ IS PRIOR ART ................................................................................... 26
`
`2.
`
`VI.
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`CONFIDENTIAL–PROTECTIVE ORDER MATERIAL
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`TABLE OF AUTHORITIES
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`CASES
`Alcon Rsch. Ltd. v. Barr Labs., Inc.,
`745 F.3d 1180 (Fed. Cir. 2014) .......................................................................... 14
`Boehringer. Boehringer Ingelheim Vetmedica, Inc. v. Schering-
`Plough Corp.,
`320 F.3d 1339 (Fed. Cir. 2003) ............................................................................ 7
`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) ............................................................................ 8
`Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc.,
`769 F.3d 1339 (Fed. Cir. 2014) .......................................................................... 25
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) .......................................................................... 12
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) .......................................................................... 28
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 26
`Griffin v. Bertina,
`285 F.3d 1029 (Fed. Cir. 2002) ............................................................................ 7
`Hayward Indus., Inc. v. Pentair Water Pool & Spa Inc.,
`814 F.App’x 592 (Fed. Cir. 2020) ...................................................................... 13
`Impax Labs. Inc. v. Aventis Pharm. Inc.,
`468 F.3d 1366 (Fed. Cir. 2006) .......................................................................... 14
`In re Donohue,
`766 F.2d 531 (Fed. Cir. 1985) ............................................................................ 14
`In re Gleave,
`560 F.3d 1331 (Fed. Cir. 2009) .......................................................................... 15
`In re Grasselli,
`713 F.2d 731 (Fed. Cir. 1983) ............................................................................ 26
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`CONFIDENTIAL–PROTECTIVE ORDER MATERIAL
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`In re Heck,
`699 F.2d 1331 (Fed. Cir. 1983) .......................................................................... 13
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 26
`In re Steed,
`802 F.3d 1311 (Fed. Cir. 2015) .......................................................................... 28
`Merck & Co. v. Biocraft Labs., Inc.,
`874 F.2d 804 (Fed. Cir. 1989) ............................................................................ 16
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) .......................................................................... 11
`Powervip, Inc. v. Static Control Components, Inc.,
`2011 WL 2669059 (W.D. Mich. July 6, 2011) ..................................................... 7
`RF Delaware, Inc. v. Pacific Keystone Techs., Inc.,
`326 F.3d 1255 (Fed. Cir. 2003) ............................................................................ 6
`SmithKline Beecham Corp. v. Apotex Corp.,
`403 F.3d 1331 (Fed. Cir. 2005) ............................................................................ 9
`Titanium Metals Corp. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985) ............................................................................ 12
`TomTom, Inc. v. Adolph
`790 F.3d 1315 (Fed. Cir. 2015) ............................................................................ 8
`Upsher-Smith Labs., Inc. v. Pamlab, L.L.C.,
`412 F3d 1319 (Fed. Cir. 2005) ............................................................................. 9
`STATUTES
`35 U.S.C. §102(b) ...................................................................................................... 8
`35 U.S.C. §102(e) .............................................................................................. 27, 28
`Public Health Service Act, Section 351(i)(1) .......................................................... 21
`OTHER AUTHORITIES
`MPEP § 2136 ........................................................................................................... 28
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`CONFIDENTIAL–PROTECTIVE ORDER MATERIAL
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`TABLE OF ABBREVIATIONS
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`Disodium phosphate dihydrate ............................................................................ DPD
`
`International Publication WO 03/002136 (Ex.1004) .......................................... Flink
`
`International Publication WO 04/004781 (Ex.1005) ........................................... Betz
`
`Patent Owner Novo Nordisk A/S ........................................................................ Novo
`
`Person of ordinary skill in the art ...................................................................... POSA
`
`Petitioners Mylan Institutional LLC and Pfizer Inc. ................................... Petitioner
`
`Propylene glycol ..................................................................................................... PG
`
`U.S. Patent No. 8,114,833 ......................................................................... ’833 patent
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`CONFIDENTIAL–PROTECTIVE ORDER MATERIAL
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`I.
`
`INTRODUCTION
`Novo’s response takes the remarkable position that a patent application
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`drafted and amended specifically to cover a propylene glycol-containing liraglutide
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`formulation neither anticipates nor renders obvious the claimed propylene glycol-
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`containing liraglutide formulation. Nothing in Novo’s response changes the clear
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`disclosures of Flink, a patent application that claims the exact formulation the ’833
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`patent seeks to protect. Flink claims a GLP-1 agonist formulation with an
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`isotonicity agent and a buffer. Flink’s specification informs that POSA that the
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`isotonicity agent can be propylene glycol, specifically identifying that compound.
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`Flink’s specification likewise tells POSAs that the buffer can be disodium
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`phosphate dihydrate. Flink epitomizes an anticipatory disclosure of claims 1-15.
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`To the extent there are any gaps between the ’833 patent’s claims and Flink,
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`those gaps are miniscule and easily traversed by Flink’s explicit identification of
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`the isotonicity agent and buffer to be used whether considered alone or in view of
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`other prior art.
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`II.
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`THE PREAMBLES OF CLAIMS 25-31 ARE NOT LIMITATIONS
`The Board’s determination that “the preambles of claims 23, 26, and 29 are
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`not limiting” should stand. Paper 13 at 8. While the District Court found otherwise,
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`that is not dispositive here. See RF Delaware, Inc. v. Pacific Keystone Techs., Inc.,
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`326 F.3d 1255, 1261-62 (Fed. Cir. 2003) (no preclusive effect of claim
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`construction opinions before final judgment); Powervip, Inc. v. Static Control
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`Components, Inc., 2011 WL 2669059, at *6 (W.D. Mich. July 6, 2011) (no
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`preclusive effect of claim construction decision, noting that district courts are often
`
`overturned and in ongoing litigations “constructions may…still be changed”).
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`Indeed, the District Court, in its own words, was “not entirely comfortable” with
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`its decision. Ex.1116, 46:3-8.
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`While Novo presents attorney argument in support of its construction, it
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`offers nothing from POSAs. And those arguments fail. Novo’s argument that the
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`preambles are limitations because the purpose of the invention “is recited only in
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`the preambles” should be rejected. While it may be true that the inventors intended
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`to reduce deposits and clogging, that does not convert the preambles into claim
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`limitations. Boehringer and Griffin each demonstrate why. In both cases, the steps
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`in the body of the claim lacked utility or a result if the preambles were not
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`considered limiting, and so terms that followed would have consisted of “empty
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`language” as in Griffin and resulted in the “absence of fathomable utility” as in
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`Boehringer. Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp., 320
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`F.3d 1339, 1345 (Fed. Cir. 2003); Griffin v. Bertina, 285 F.3d 1029, 1033 (Fed.
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`Cir. 2002). Here, however, the method steps (i.e., replacing a previously-used
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`isotonicity agent) results in the intended reductions.
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`CONFIDENTIAL–PROTECTIVE ORDER MATERIAL
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`Moreover, Novo’s position as to the specification and prosecution history is
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`inapposite. While the intended purpose of the invention is reductions, that is the
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`not the same as the invention being so limited. The specification and claims
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`confirm the alleged invention is a formulation, with the reductions being an
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`intended result. Indeed, much of the specification is directed solely towards the
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`formulation. Ex.1001, 3:34-14:55. Novo’s reference to the prosecution history
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`likewise fails. The claims were allowed because of amendments to the formulation,
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`not reliance on the preambles. Ex.1003, 180, 188, 190-192.
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`Finally, Novo’s claim differentiation and “antecedent basis” arguments
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`should be rejected. Claim differentiation “is not a ‘hard and fast’ rule,” Bristol-
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`Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1376 (Fed. Cir. 2001),
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`and should not apply here as explained in the Petition. As to antecedent basis,
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`simply referring in the body of the claim to a term in the preamble does not convert
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`the preamble into a limitation. TomTom, Inc. v. Adolph 790 F.3d 1315, 1323 (Fed.
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`Cir. 2015). None of Novo’s arguments convert the preambles of claims 23, 26, and
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`28 into limitations.
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`III.
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`CLAIMS 1-15 WERE ANTICIPATED
`Each limitation of claims 1-15 is not only disclosed but is claimed by Flink.
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`Novo appears to, in other contexts, share this view. While Flink is unchallenged as
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`§102(b) prior art, by its own admission, “Flink describes Novo Nordisk’s earlier,
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`CONFIDENTIAL–PROTECTIVE ORDER MATERIAL
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`laboratory-scale formulation work with GLP-1.” Paper 25, 2. Thus, Novo listed its
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`U.S.
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`counterpart
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`to Flink
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`(U.S. Patent No. 8,846,618
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`“the
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`’618
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`patent”)(Ex.1107)—with a nearly identical specification as Flink—as covering its
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`own liraglutide product. Ex.1117. That patent has broad claims to isotonic agents
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`(e.g., compare claim 6 with claim 14 of Flink) and identically lists PG in the same
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`list in the specification. Ex.1117. By extension Novo has also alleged infringement
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`by Mylan of the same patent claims in District Court litigation related to Mylan’s
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`proposed liraglutide product. Ex.1118. Novo would thus have the Board find that
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`for the purposes of anticipation, Flink does not anticipate, while maintaining that
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`functionally the same patent covers its own liraglutide product2 and that Mylan’s
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`proposed liraglutide product infringes it. Such a proposition is difficult, if not
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`impossible, to square with a central tenet of the law of anticipation: that which
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`infringes if later, anticipates if earlier. See Upsher-Smith Labs., Inc. v. Pamlab,
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`L.L.C., 412 F3d 1319, 1322 (Fed. Cir. 2005) (“A century-old axiom of patent law
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`holds that...‘which would literally infringe if later in time anticipates if earlier.”
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`(citations omitted)); see also SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d
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`1331, 1341 (Fed. Cir. 2005) (“Because Apotex seeks to practice the prior art, and
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`Notably, Novo’s expert, Dr. Tessier testified he didn’t “know how [he]
`2
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`would get from Flink to Victoza,” making plain Dr. Tessier’s tortured reading of
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`Flink. Ex.1077, 95:12-13.
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`because that practice infringes, the next logical inquiry involves anticipation. That
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`is, if the prior art infringes now, logically the prior art should have anticipated the
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`claim before the filing of the...patent.”).
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`Flink Anticipates Claims 1-15
`A.
`Flink provides a clear roadmap for POSAs to arrive at the formulation
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`recited in claims 1-15.
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`First, Novo’s argument (at 20) that Flink is not anticipatory because POSAs
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`“would see six genuses of chemicals that can be used as isotonicity agents”
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`presents POSAs “with hundreds of choices” misses the mark. As Dr. Forrest
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`explains, Flink specifically identifies PG as an example of an isotonic agent to be
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`used in the claimed formulation. Ex.1106, ¶¶16-17. Moreover, PG is one of just
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`eighteen exemplary isotonicity agents listed. Id. Flink’s listing of PG as a specific
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`example raises it well above the alleged “hundreds of choices.” Id.; Ex.1004, 19.
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`Novo’s argument that POSAs would view the disclosure of PG as only a
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`polyhydric alcohol, and not an isotonicity agent at all, is dubious at best. As Dr.
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`Forrest testifies, POSAs would read Flink as disclosing the exemplary polyhydric
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`alcohols to be used as isotonicity agents. Ex.1106, ¶¶16-17. Novo’s reading is
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`belied by the words of Flink itself given the use of “e.g.”
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`Notably, during prosecution, Novo added PG as an “e.g.” example. In four
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`priority applications to Flink, PG was absent, but it was later added, indicating
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`CONFIDENTIAL–PROTECTIVE ORDER MATERIAL
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`Novo wanted to ensure PG was an isotonicity agent covered by the claims.
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`Exs.1108-1113. Given Flink’s disclosure of PG as a specified example, which
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`Novo deliberately added, Novo’s position should be rejected. Perricone v. Medicis
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`Pharm. Corp., 432 F.3d 1368, 1375-77 (Fed. Cir. 2005) (finding anticipation and
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`stating that where “the prior art does not merely disclose a genus...[but a] specific
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`disclosure, even in a list, makes [the] case different from cases involving
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`disclosure of a broad genus without reference to the potentially anticipating
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`species”).
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`Second, Dr. Tessier’s concerns about alleged instability, hemolysis, pain,
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`thrombophlebitis, and dermatitis do not remove Flink as an anticipatory reference.
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`Ex.1106, ¶18. Even if POSAs would be concerned about these issues–and they
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`would not be–Flink remains anticipatory. Id. The claims are to a formulation, and
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`thus do not require it to be free from side effects, for example. See, e.g., Ex.1077,
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`18:16-29:7 (claims are to “formulation”).
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`Third, Flink anticipates the disclosed PG ranges. Claim 14 of Flink requires
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`that the claimed isotonic agent (e.g., PG) be present at a concentration of 1mg/ml
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`to 50mg/ml. Ex.1004, 47-48. Novo’s statements (at 32) that finding the “right
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`concentration” is “critical to carry out [PG’s] function” are of no moment. The
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`claims do not require that the formulation be isotonic, nor do they require that PG
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`function as an isotonic agent. The range recited in claim 14 of Flink–1mg/ml to
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`CONFIDENTIAL–PROTECTIVE ORDER MATERIAL
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`50mg/ml–is a species with the range recited in claims 1-2 and is therefore
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`anticipatory. Titanium Metals Corp. v. Banner, 778 F.2d 775 (Fed. Cir. 1985).
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`Flink’s claimed range overlaps the broad ranges recited in claims 3-4, thereby
`
`disclosing them with sufficient specificity to anticipate. ClearValue, Inc. v. Pearl
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`River Polymers, Inc., 668 F.3d 1340 (Fed. Cir. 2012) (claims to alkalinity below
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`50ppm anticipated by prior art disclosure of alkalinity less than 150ppm); see also
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`Ex.1106, ¶¶19-23.
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`Fourth, as to DPD, Novo again proffers a tortured reading of Flink. Novo’s
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`argument that “disodium phosphate dihydrate” is “not even mentioned” ignores
`
`POSAs’ knowledge and understanding. As Dr. Forrest explained, a “disodium
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`hydrogen phosphate” buffer, which is explicitly listed, is of the same species as the
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`“disodium phosphate dihydrate” agent in solution. Ex.1106, ¶¶24-28. Indeed, as
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`Dr. Forrest notes, Flink’s use of DPD in Example 7 demonstrates that the dihydrate
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`form of disodium hydrogen phosphate was a specific example of a buffering agent
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`used to prepare the preferred disodium hydrogen phosphate buffer embodiment
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`listed on page 18. Id.
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`Fifth, Novo’s focus on Example 7 does not preclude a finding of
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`anticipation. Flink broadly claims formulations of GLP-1 with various isotonicity
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`agents and buffers, with Example 7 providing an embodiment of certain claimed
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`formulations. Ex.1106, ¶¶26-27. For Flink to anticipate, Example 7 alone does not
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`need to teach the use of PG. Instead, for anticipation one looks to the whole
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`reference. Hayward Indus., Inc. v. Pentair Water Pool & Spa Inc., 814 F.App’x
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`592, 596 (Fed. Cir. 2020) (“[P]rior art references should be considered for all that
`
`they teach, rather than being limited to a particular embodiment.”) (citing Belden
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`Inc. v. Berk-Tek LLC, 805 F.3d 1064, 1076 (Fed. Cir. 2015)). Thus, as the Board
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`properly stated upon Institution, Flink, viewed holistically, teaches looking to
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`Example 7, with an alternate isotonicity agent such as PG (denoted as an example
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`with an “e.g.”).
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`Moreover, the Board was correct that “Flink’s claim language indicating that
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`mannitol will not be selected…for some of its formulations, provides additional
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`support”. Paper 13, 15 (emphasis added). While Novo tries to sidestep the
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`disclosure of PG as an example, Flink teaches PG as an isotonicity agent and its
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`claims cover a formulation containing it. Flink thus anticipates claims 1-15 of the
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`’833 patent.3
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`3 While Novo makes much of the multiple dependences in Flink’s claims,
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`Novo does not dispute that one aspect of the claim includes the embodiment
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`identified by Petitioner. This aspect of Flink cannot be ignored. In re Heck, 699
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`F.2d 1331, 1332-33 (Fed. Cir. 1983) (prior art patents are “part of the literature of
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`the art, relevant for all they contain”).
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`Flink is Enabled
`B.
`A prior art reference provides an enabling disclosure and thus anticipates a
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`claimed invention if the reference describes the claimed invention in sufficient
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`detail to enable POSAs to carry out the claimed invention. “[P]roof of efficacy is
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`not required for a prior art reference to be enabling for purposes of anticipation.”
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`Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383 (Fed. Cir. 2006). A
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`reference contains an “enabling disclosure” if the public was in possession of the
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`prior claimed invention before the effective filing date of the later claimed
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`invention. “Such possession is effected if one of ordinary skill in the art could have
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`combined the publication’s description of the invention with his [or her] own
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`knowledge to make the claimed invention.” In re Donohue, 766 F.2d 531, 533
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`(Fed. Cir. 1985). Flink disclosed to the public a PG and DPD-containing GLP-1
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`formulation before the priority date of the ’833 patent, and so it is enabled.
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`Novo’s argument (at 33) that “Flink falls far short of enabling the claimed
`
`formulations” is appropriately rejected. For example, Novo points to the lack of an
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`example formulation containing PG. However, a patent need not list a working
`
`example to be enabled. Alcon Rsch. Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1189
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`(Fed. Cir. 2014) (“[A] patentee is not required to provide actual working
`
`examples.”).
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`Novo’s argument (at 33) that there is “no guidance on using [PG] in
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`pharmaceutical formulations” likewise falls flat. Consistent with the law, as Dr.
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`Forrest notes, and as Dr. Tessier conceded in deposition, the claims require only
`
`combining the ingredients. Ex.1106, ¶¶29-31; Ex.1077, 18:16-29:7; In re Gleave,
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`560 F.3d 1331, 1335-36 (Fed. Cir. 2009) (for composition claims, a reference is
`
`enabled when POSAs would know how to make it; whether a particular compound
`
`works for its intended purpose is not relevant). Any testing would only confirm
`
`what POSAs would have expected. As the ’833 patent acknowledges, the
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`preparation of the claimed formulations could be accomplished by simply using
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`“conventional techniques.” Ex.1001, 12:64-13:3. Thus, any work to combine the
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`ingredients is well within the skill of an ordinarily POSA. Id. Flink is therefore
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`enabled.
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`IV.
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`CLAIMS 1-15 WERE OBVIOUS OVER FLINK
`Novo’s argument that claims 1-15 were not obvious over Flink mirror its
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`anticipation arguments and thus also fail.
`
`A.
`
`Flink Teaches the Use of PG as an Isotonic Agent in a GLP-1
`Formulation
`Novo does not meaningfully dispute that Flink discloses PG as an isotonic
`
`agent. Instead, Novo argues (at 20) that PG is just one non-emphasized example
`
`from hundreds of possible isotonic agents encompassed by the listed genuses.
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`Novo further—and wrongly—claims (at 35) that Petitioner reads Flink as
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`“teaching that any of the numerous isotonicity agents falling within the listed
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`genuses [spanning pages 19-20] . . . are equally suitable for use with GLP-1.” That
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`is not Petitioner’s argument.
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`Petitioner instead points to the eighteen expressly disclosed exemplary
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`agents that are denoted as examples from the genuses. Paper 2, 42-43; Ex.1002,
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`¶157; Ex.1106, ¶33. The Board likewise stated that “Flink taught or suggested
`
`using any of its disclosed isotonicity agents in combinations with any of its
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`[disclosed] buffers.” Paper 13, 21 (emphasis added). Accordingly, nobody has
`
`suggested that any species within the listed genuses of Flink are taught as suitable
`
`agents, and Petitioner need not do so. Rather, the smaller group of eighteen
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`exemplary agents expressly disclosed as isotonic agents—including PG—
`
`demonstrate it would be obvious to POSAs to select an isotonic agent from the
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`smaller, specifically-disclosed group. That is the case regardless of whether those
`
`eighteen agents are identified as “preferred.” Merck & Co. v. Biocraft Labs., Inc.,
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`874 F.2d 804, 807 (Fed. Cir. 1989).
`
`B.
`
`Petitioner Demonstrated Motivation and Reasonable Expectation
`of Success
`Petitioner has shown that POSAs would have been motivated to select both
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`PG and DPD with a reasonable expectation of success.
`
`First, POSAs understood that PG could adjust tonicity. Dr. Tessier admits
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`that every solute in a formulation will contribute to its tonicity. Ex.2022, ¶57. That
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`principle applies to agents known also as cosolvents with a propensity to diffuse
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`across cell membranes like PG and glycerol. Ex.1106, ¶¶36, 52. And while in vitro
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`test results inform POSAs that PG or glycerol may cause hemolysis under in vitro
`
`equilibrium conditions, Dr. Forrest explains that POSAs would understand that
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`such in vitro testing is not reflective of what occurs upon in vivo administration,
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`alleviating concerns related to the use of PG. Ex.1106, ¶¶43-53.
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`Further, Flink specifies that “[t]he use of an isotonic agent in pharmaceutical
`
`compositions is well-known to the skilled person” in view of Remington: THE
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`SCIENCE AND PRACTICE OF PHARMACY, 19th edition, 1995. Ex.1004, 20:17-19;
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`Ex.1013; Ex.2081. Far from “teach[ing] virtually nothing” s as Novo suggests (at
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`35), Flink made clear that POSAs understood the use of the isotonic agents, and
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`that disclosure was enough.
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`Second, while isotonicity is not required by the claims, POSAs knew how to
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`calculate a suitable amount of PG within the claimed ranges. As Dr. Forrest
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`explains, POSAs were well versed in ways to calculate the amount, and that an
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`appropriate estimate was the practice of not only POSAs, but of the inventors.
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`Ex.1106, ¶¶54-57.
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`Third, there were no “red flags” that would dissuade POSAs from using PG,
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`especially at the claimed concentrations. Dr. Tessier’s contention that hemolysis
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`and other side effects would warrant its exclusion is exaggerated and contrary to
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`conventional drug development. As Dr. Forrest states, virtually all drugs and
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`excipients are associated with some potential side effects, including PG and
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`mannitol. Ex.1106, ¶51. PG has been used in drug formulations for years and is
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`considered safe—even at high concentrations. Id., ¶38.
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`Fourth, Novo’s claims of instability problems are unfounded. While GLP-1
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`had been known to be unstable in its native form, Flink and others had established
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`that modifications to GLP-1 and optimizing the pH of the formulation greatly
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`improved GLP-1’s stability. Ex.1106, ¶¶61, 72. Thus, while POSAs would have
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`carefully considered excipients compatible with GLP-1 agonists like liraglutide, it
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`would not be as unpredictable as Novo suggests. Paper 25, 39-40; Ex.1106, ¶¶60-
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`64.
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`Moreover, Novo offers only conclusory testimony of its expert without
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`evidence that PG would in fact destabilize GLP-1—or any other peptide or protein.
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`In contrast, Dr. Forrest explains that the evidence presented would have motivated
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`POSAs to use PG to improve stability. Ex.1106, ¶¶62-71.
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` That’s hardly the evidence Novo claims it is.
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`Finally, as the Board correctly finds, the teachings of Flink are not limited to
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`its examples, so Flink’s disclosure of both DPD as a buffer and PG as an isotonic
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`agent allows for their combination because Flink “does not limit the selection of
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`the isotonic agent based upon the selection of the buffer”. Paper 13, 20-21.
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`V.
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`ALL CLAIMS OF THE ’833 PATENT WERE OBVIOUS OVER
`FLINK IN VIEW OF BETZ
`A. Claims 1-15 are Obvious
`Novo attempts to undercut Petitioner’s arguments regarding Flink and Betz
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`also fail.
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`1.
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`Betz Teaches Formulations That Include PG Without
`Mannitol
`Betz teaches that it is preferred for formulations to contain PG without an
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`additional tonicity adjusting agent (i.e., without mannitol) to minimize the number
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`of excipients. Ex.1005, 7. Also, in view of PG’s ability to act as a stabilizer while
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`also contributing to the tonicity of the formulation, POSAs would have naturally
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`used PG instead of mannitol. Ex.1106, ¶101-103.
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`Moreover, according to Novo, “the worst” formulation containing lesser or
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`no mannitol (i.e., Formulations 5-8) showed crystals at 7 weeks and was thus more
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`stable than “the worst” formulation containing greater amounts of mannitol (i.e.,
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`Formulations 1-4) that showed crystals at 4 weeks. Paper 25, 55; see also Ex.2022,
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`¶125). However, even that interpretation teaches having more PG than mannitol
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`results in a more stable formulation, undercutting Novo’s argument. Ex.1002,
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`¶199; Ex.1106, ¶102.
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`Further, Novo misinterprets (at 54-55) the data related to the results of the
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`tests performed at 2°-8°C. Betz does not conclude that Formulation 2 was the most
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`stable at that temperature. Instead, Betz states (at 18) that “[t]he formulations
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`stored at 2°-8°C do not show crystallization during the test period,” indicating that
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`none of the formulations showed instability, not that the length of the test period
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`correlated with increased stability. Ex.1106, ¶102. Thus, Novo’s criticisms are
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`unavailing.
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`2.
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`Protein Drug Physical Instability Provides Motivation to
`Combine Flink and Betz with a Reasonable Expectation of
`Success
`Protein drug physical instability provided POSAs with ample reason to
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`combine Flink and Betz with a reasonable expectation of success. As Dr. Forrest
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`explains, POSAs looking to improve stability of a peptide would consider the
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`effects of excipients used to improve stability in other peptide or protein drugs of
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`similar or greater complexity. Ex.1106, ¶¶74-75, 78-82. This is because proteins
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`having greater complexity often have stability issues that are the same as or similar
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`to peptides with less complexity; informing POSAs about common excipients used
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`in both. Id., ¶¶78-96. While Betz applies the solution to a different protein, POSAs
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`would look to it, providing motivation and a reasonable expectation of success. Id.
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`Betz thus motivated POSAs to use PG to stabilize a protein while simultaneously
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`contributing to the tonicity of the formulation leading one to combine the teachings
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`of Flink and Betz.
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`Novo argues (at 57) that POSAs would have “viewed [hGH and GLP-1] as
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`falling into distinct categories of therapeutic agents, each with different
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`challenges.” Novo leans on a statutory definition of “biological product” in section
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`351(i)(1) of the Public Health Service Act (effective March 2020) for its argument,
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`but regulatory definitions offer no support for how POSAs approaches formulation
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`development, let alone at the invention date.
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`Novo’s argument (at 58) that Betz “contravenes Flink’s core teaching” is
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`also unavailing because Mylan does not rely on Betz for teaching the claimed pH.
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`Further, as Dr. Forrest explains, the function of PG is not dependent on pH and
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`thus has no bearing on Betz’s teaching to use PG in formulations without mannitol.
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`Ex.1106, ¶¶97-99.
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`Moreover, despite Novo’s statement (at 58) that Petitioner “failed to
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`explain” why POSAs “would have expected success,” Petitioner explained the
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`known mannitol crystallization problem and how use of PG solves it. Paper 2, 21-
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`23. Mannitol was known to crystallize and precipitate out of solution at
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`“supersaturated” concentrations. Id. While mannitol-containing GLP-1 agonist
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`formulations are not prepared with supersaturated concentrations, equipment and
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`needles that contact the formulations are subject to supersaturated formulations due
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`to evaporation, leaving behind precipitated residue. Ex.1106, ¶¶108-110. PG, a
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`liquid at room temperature, was known to not crystallize, and so POSAs would not
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`expect a residue. Id., ¶108. Thus, POSAs would have been motivated to combine
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`Flink and Betz with a reasonable expectation of success.