UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`MYLAN PHARMACEUTICALS INC., DR. REDDY’S
`LABORATORIES, INC., DR. REDDY’S LABORATORIES, LTD., and
`SUN PHARMACEUTICALS INDUSTRIES LTD.,
`Petitioners,
`
`v.
`
`MERCK SHARP & DOHME CORP.,
`Patent Owner.
`__________________
`
`IPR2020-000401
`Patent 7,326,708
`__________________
`
`
`
`PATENT OWNER’S SUR-REPLY
`
`
`
`1 Dr. Reddy’s Laboratories, Inc. and Dr. Reddy’s Laboratories, Ltd. were joined as
`parties to this proceeding via a Motion for Joinder in IPR2020-01060; and Sun
`Pharmaceuticals Industries Ltd. was joined as a party to this proceeding via Motion
`for Joinder in IPR2020-01072.
`
`

`

`
`
`
`I.
`
`IPR2020-00040 | Patent 7,326,708
`
`TABLE OF CONTENTS
`
`MYLAN’S ANTICIPATION CASE FAILS .................................................. 3
`
`
`
`
`
`
`
`The POSA Would Not “At Once Envisage” a Sitagliptin
`Phosphate Salt ....................................................................................... 3
`
`1:1 Sitagliptin DHP Is Not Inherent ...................................................... 5
`
`The Dependent Claims Are Not Anticipated ...................................... 12
`
`1.
`
`2.
`
`3.
`
`Claim 3 ...................................................................................... 12
`
`Claims 17 and 19....................................................................... 13
`
`Claims 21-23 ............................................................................. 13
`
`II.
`
`CLAIM 4 IS NOT OBVIOUS ....................................................................... 14
`
`III. THE OTHER CLAIMS ARE NOT OBVIOUS ............................................ 21
`
` WO498 Is Not Prior Art for Obviousness ........................................... 21
`
`
`
`
`
`Claims 1 and 2 Are Not Obvious ........................................................ 22
`
`Claims 3, 18-19, and 21-23 ................................................................. 23
`
` Mylan Fails to Rebut the Unexpectedly Superior Properties of
`1:1 Sitagliptin DHP and its Crystalline Monohydrate Form .............. 24
`
`CONCLUSION ........................................................................................................ 26
`
`
`
`
`
`
`
`
`
`i
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`IPR2020-00040 | Patent 7,326,708
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`
`
`TABLE OF AUTHORITIES
`
`
`Arthrex, Inc. v. Smith & Nephew, Inc.,
`941 F.3d 1320 (Fed. Cir. 2019) .......................................................................... 27
`
`Brand v. Miller,
`487 F.3d 862 (Fed. Cir. 2007) ............................................................................ 13
`
`Cohesive Tech. Inc. v. Waters Corp.,
`543 F.3d 1351 (Fed. Cir. 2008) .......................................................................... 22
`
`Eli Lilly & Co. v. Barr Labs., Inc.,
`251 F.3d 955 (Fed. Cir. 2001) .............................................................................. 7
`
`Eli Lilly & Co. v. Zenith Goldline Pharm., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) ............................................................................ 4
`
`Glaxo Inc. v. Novopharm Ltd.,
`52 F.3d 1043 (Fed. Cir. 1995) .............................................................................. 5
`
`Grunenthal GmbH v. Alkem Labs. Ltd.,
`919 F.3d 1333 (Fed. Cir. 2019) .................................................................... 19, 20
`
`Henny Penny Corp. v. Frymaster LLC,
`938 F.3d 1324 (Fed. Cir. 2019) ...................................................................... 6, 18
`
`Hospira, Inc. v. Genentech, Inc.,
`IPR2017-00805, Paper 83 (P.T.A.B. Oct. 3, 2018) .............................................. 6
`
`Impax Labs., Inc. v. Aventis Pharms. Inc.,
`468 F.3d 1366 (Fed. Cir. 2006) ............................................................................ 4
`
`In re Clarke,
`356 F.2d 987 (C.C.P.A. 1966) ............................................................................ 22
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 25
`
`In re Magnum Oil Tools Int’l, Ltd.,
`829 F.3d 1364 (Fed. Cir. 2016) .......................................................................... 13
`
`ii
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`

`

`IPR2020-00040 | Patent 7,326,708
`
`
`
`In re Power Integrations, Inc.,
`884 F.3d 1370 (Fed. Cir. 2018) .......................................................................... 14
`
`Janssen Prods. L.P. v. Lupin Ltd.,
`109 F. Supp. 3d 650 (D.N.J. 2014) ............................................................... 16, 17
`
`Millennium Pharms., Inc. v. Sandoz, Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 25
`
`Monsanto Tech. LLC v. E.I. DuPont de Nemours & Co.,
`878 F.3d 1336 (Fed. Cir. 2018) ............................................................................ 6
`
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 21
`
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) ........................................................................ 3, 8
`
`Pfizer Inc. v. Mylan Pharms. Inc.,
`71 F. Supp. 3d 458 (D. Del. 2014) ...................................................................... 24
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .............................................................. 23, 24, 25
`
`Sandoz Inc. v. Pharmacyclics LLC,
`IPR2019-00865, Paper 29 (P.T.A.B. Sept. 24, 2020) ......................................... 13
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) .......................................................................... 24
`
`Shire LLC v. Amneal Pharms, LLC,
`2014 WL 2861430 (D.N.J. June 23, 2014) ....................................................... 4, 5
`
`Spectrum Int’l, Inc. v. Sterilite Corp.,
`164 F.3d 1372 (Fed. Cir. 1998) .......................................................................... 14
`
`Trintec Indus., Inc. v. Top-U.S.A. Corp.,
`295 F.3d 1292 (Fed. Cir. 2002) ............................................................................ 7
`
`U.S. Water Services, Inc. v. Novozymes A/S,
`843 F.3d 1345 (Fed. Cir. 2016) ............................................................................ 7
`
`iii
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`IPR2020-00040 | Patent 7,326,708
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`
`
`Valeant Int’l v. Watson Pharms., Inc.,
`2011 WL 6792653 (S.D. Fla. Nov. 8, 2011) ...................................................... 24
`
`37 C.F.R. § 42.23(b) ............................................................................................ 6, 18
`
`
`
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`iv
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`IPR2020-00040 | Patent 7,326,708
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`
`
`Mylan’s Reply is remarkable for what it does not dispute. Though it bases
`
`its anticipation case on inherency, Mylan does not dispute that non-1:1 sitagliptin
`
`phosphate salts exist. As to obviousness, Mylan does not dispute that the POSA
`
`would not have known whether the crystalline monohydrate of claim 4 could exist,
`
`much less have had a motivation to make it. And it does not dispute that Merck
`
`made 1:1 sitagliptin dihydrogenphosphate (“DHP”) before the publication of
`
`WO498, a fact that eliminates Mylan’s obviousness case on the other
`
`claims. These three undisputed points, without more, are fatal to Mylan’s case.
`
`Instead of contesting these points, Mylan changes the subject. On
`
`anticipation, it advances a new theory that the POSA trying to make a phosphate
`
`salt would follow Example 7 of WO498, with numerous modifications, to the
`
`exclusion of other techniques. The Petition did not make this argument, which is
`
`not even really an anticipation argument. Example 7 does not mention phosphoric
`
`acid, much less show how to make the claimed salt. And Mylan’s assertion that
`
`Dr. Chyall made 1:1 sitagliptin DHP by “reproducing” Example 7 is false.
`
`Example 7 starts with a different material, combines it with a different acid, and
`
`makes a different salt—sitagliptin hydrochloride—using different reaction
`
`conditions. Example 7 does not anticipate any claim, inherently or otherwise.
`
`Regarding the claim 4 obviousness ground, Mylan simply ignores most of
`
`Merck’s arguments. It argues (incorrectly) that the POSA would have reason to
`
`
`
`
`
`1
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`

`

`
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`make crystalline salts, but as in its Petition, fails to advance any motivation to
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`IPR2020-00040 | Patent 7,326,708
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`focus on sitagliptin or to make the claimed 1:1 DHP crystalline monohydrate. And
`
`Mylan’s reasonable expectation case still centers erroneously on how common
`
`monohydrates are among hydrates—ignoring that most pharmaceutical compounds
`
`are not hydrates, and the POSA would have no idea whether the claimed
`
`crystalline monohydrate exists or how to make it. Mylan’s argument that the
`
`monohydrate results from “typical” techniques is wrong factually and does not
`
`prove obviousness because of the vast number of techniques available to the POSA
`
`and their undisputedly unpredictable results. The POSA would not reasonably
`
`have expected to be able to make the claimed crystalline monohydrate, much less
`
`its unexpectedly superior properties, which Merck explained and Mylan does not
`
`rebut.
`
`Mylan’s remaining obviousness arguments are deficient on the merits, but
`
`also are eliminated because Mylan does not even attempt to challenge Merck’s
`
`swear-behind. Mylan’s only response is that Merck had to show an earlier
`
`reduction to practice of the monohydrate too. But because one need only swear
`
`behind what the art teaches, the failure of Mylan’s case on claim 4 undermines its
`
`obviousness arguments on the other claims as well.
`
`
`
`
`
`2
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`

`

`
`
`I. MYLAN’S ANTICIPATION CASE FAILS
`
`IPR2020-00040 | Patent 7,326,708
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` The POSA Would Not “At Once Envisage” a Sitagliptin
`Phosphate Salt
`
`Undisputedly, WO498 does not expressly teach combining sitagliptin and
`
`phosphoric acid, much less any resulting salt. POR 7-14. Instead, the central
`
`anticipation theory in the Petition was that WO498 (and, near-identically, the ’871
`
`patent2) teach lists of basic compounds and acids that together allow the POSA to
`
`“at once envisage” a sitagliptin DHP salt. Pet. 12-13. The breadth of WO498 and
`
`the unpredictability of salt formation each undermine this theory.
`
`Mylan ignores that claim 15 discloses 33 different compounds, not just
`
`sitagliptin, and recites any pharmaceutically acceptable salt. Reply 4. And it
`
`provides no argument at all for why the POSA would envisage combining those
`
`compounds with eight “particularly preferred” counterions, but not envisage the
`
`millions of other combinations WO498 undisputedly encompasses.
`
`Unable to address these failings, Mylan focuses on Perricone to argue that
`
`two supposedly “well-defined lists” teach the required combination of sitagliptin
`
`and phosphoric acid. Reply 2-5. But Perricone involved a single list, and the
`
`claimed compound was an item on that list. 432 F.3d 1368, 1376-77 (Fed. Cir.
`
`2005). It is inapposite here, where phosphoric acid and sitagliptin must be
`
`
`2 As in the POR, Merck’s discussion of WO498 applies also to the ’871 patent.
`
`
`
`
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`3
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`

`

`
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`combined from disparate parts of WO498, and the combination plucked from
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`IPR2020-00040 | Patent 7,326,708
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`myriad potential combinations.
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`Worse for Mylan, the claims require a salt, not just a combination of
`
`ingredients. Whatever “lists” the POSA might look to, the POSA would not (and
`
`could not) “envisage each member” of a genus of salts, or the claimed salt, because
`
`the POSA undisputedly would not know what salts could form, or how to make
`
`them. Eli Lilly & Co. v. Zenith Goldline Pharm., Inc., 471 F.3d 1369, 1376 (Fed.
`
`Cir. 2006); POR 9-12; Matzger (EX2103) ¶¶31, 90. Whether sitagliptin DHP can
`
`be made “easily” or would be found in a “salt screen,” Reply 5, is irrelevant to
`
`whether WO498 anticipates that salt under the required “envisaging” standard. “If
`
`[a genus’s] members cannot be envisioned, the reference does not disclose the
`
`species[.]” Impax Labs., Inc. v. Aventis Pharms. Inc., 468 F.3d 1366, 1383 (Fed.
`
`Cir. 2006).
`
`Mylan’s cursory dismissal of Shire, Reply 5, misses the mark; Shire
`
`demonstrates why Mylan’s “envisaging” argument, and thus anticipation grounds,
`
`must fail. Under Shire, envisaging a simple combination of ingredients is different
`
`from envisaging a chemical reaction to form a new compound. 2014 WL 2861430,
`
`*15 (D.N.J. June 23, 2014). Mylan has no response to this holding. Instead, it
`
`raises an irrelevant point about an unrelated part of Shire—whether the acid used
`
`to make dimesylate was on any disclosed list. Like the reaction in Shire, the salt
`
`
`
`
`
`4
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`

`

`
`
`here is not “something that you get just by mixing a little” sitagliptin and
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`IPR2020-00040 | Patent 7,326,708
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`phosphoric acid. Id.
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`
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`1:1 Sitagliptin DHP Is Not Inherent
`
`1.
`
`Even if the POSA would have “envisaged” a combination of
`
`sitagliptin and phosphoric acid, that does not show anticipation of the specific
`
`claimed 1:1 DHP salt. To bridge the gap, Mylan’s Petition asserted that 1:1
`
`sitagliptin DHP forms “every time” sitagliptin and phosphoric acid are combined.
`
`Pet. 18-22 & n.8. The record now conclusively disproves that—so WO498 does
`
`not inherently anticipate. Glaxo Inc. v. Novopharm Ltd., 52 F.3d 1043, 1045-48
`
`(Fed. Cir. 1995).
`
`It is undisputed that non-1:1 phosphate salts of sitagliptin exist. WO420
`
`(EX2220) reports such salts. Dr. Matzger synthesized such salts. Matzger
`
`(EX2103) ¶¶119-76. And while Mylan’s Reply newly touts Dr. Chyall’s initial
`
`success in forming 1:1 sitagliptin DHP while performing a screen of phosphate
`
`salts (in a methanol-based solvent), it simultaneously ignores later experiments in
`
`which he made non-1:1 sitagliptin phosphate (in solvents other than methanol).
`
`Matzger (EX2103) ¶¶123-33 (discussing EX2224-EX2227). Even Mylan’s expert
`
`Dr. Chorghade concedes that altering crystallization conditions like this could yield
`
`different salts. Chorghade (EX1035) ¶¶33, 52, 57.
`
`
`
`
`
`5
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`

`

`
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`2.
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`Because these other salt forms end Mylan’s anticipation case, Mylan
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`IPR2020-00040 | Patent 7,326,708
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`pivots to a new theory of inherency and argues that the POSA would have adhered
`
`to WO498’s Example 7 to make a phosphate salt, and it would yield 1:1 sitagliptin
`
`DHP. The Board should disregard Mylan’s untimely new theory. Henny Penny
`
`Corp. v. Frymaster LLC, 938 F.3d 1324, 1330-31 (Fed. Cir. 2019); 37 C.F.R.
`
`§ 42.23(b).
`
`Mylan’s new theory is also wrong and results-driven. To begin with, no
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`“prior art process” combines sitagliptin with phosphoric acid. Reply 6. Example
`
`7 makes sitagliptin hydrochloride. It does not teach 1:1 sitagliptin
`
`dihydrogenphosphate, inherently or otherwise. Chorghade (EX1035) ¶¶9, 27;
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`Chorghade (EX2283) 15:2-12, 50:18-52:22. Thus, while Mylan embraces Dr.
`
`Chyall’s experiments, they are no more “prior art” than Dr. Matzger’s. And Dr.
`
`Matzger’s experiments disprove inherency; “[i]t is well established” that evidence
`
`regarding inherency “need not antedate the critical date of the patent[.]” Monsanto
`
`Tech. LLC v. E.I. DuPont de Nemours & Co., 878 F.3d 1336, 1345 (Fed. Cir.
`
`2018).3
`
`
`3 Mylan’s citation, Hospira, Inc. v. Genentech, Inc., IPR2017-00805, Paper 83
`
`(P.T.A.B. Oct. 3, 2018), has nothing to do with inherency or even anticipation.
`
`
`
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`6
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`

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`IPR2020-00040 | Patent 7,326,708
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`
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`To show inherent anticipation from Example 7, Mylan must show that 1:1
`
`sitagliptin DHP is the “inevitabl[e] result from the disclosed steps,” U.S. Water
`
`Services, Inc. v. Novozymes A/S, 843 F.3d 1345, 1350 (Fed. Cir. 2016) (emphasis
`
`added and citation omitted), or at least the “‘natural result’ flowing from the
`
`reference’s explicitly explicated limitations,” Eli Lilly & Co. v. Barr Labs., Inc.,
`
`251 F.3d 955, 970 (Fed. Cir. 2001) (citation omitted). No authority exists for the
`
`proposition that a reference like WO498, which does not “explicitly explicate[]”
`
`making 1:1 sitagliptin DHP, but would need to be modified in many ways to do so,
`
`can anticipate. Id. Even if Mylan could prove obviousness, “obviousness is not
`
`inherent anticipation.” Trintec Indus., Inc. v. Top-U.S.A. Corp., 295 F.3d 1292,
`
`1296 (Fed. Cir. 2002).
`
`Mylan’s characterization of Dr. Chyall’s work as a “reproduction of
`
`WO498,” e.g., Reply 5, is false. Mylan’s expert admits Example 7 differs from Dr.
`
`Chyall’s experiments in numerous respects. E.g., Chorghade (EX2283) 43:12-
`
`45:10. Example 7 starts with a different material: BOC-protected sitagliptin
`
`instead of sitagliptin base. Id. 53:6-14. It then uses the methanol solvent Mylan
`
`emphasizes, combined with large quantities of hydrochloric acid, to remove the
`
`protecting group. Id. 27:15-18, 53:15-20; EX1004 28:7-9. That in turn yields a
`
`different product—sitagliptin hydrochloride, not 1:1 sitagliptin DHP. Dr. Chyall’s
`
`methods also differ from Example 7 in:
`
`
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`
`
`7
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`

`

`IPR2020-00040 | Patent 7,326,708
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`
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`(1) use of phosphoric acid instead of hydrochloric acid;
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`(2) molar ratio of the acid to sitagliptin;
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`(3) dropwise instead of all-at-once addition of the acid;
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`(4) concentration of the reactants;
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`(5) use of an aqueous solvent system;
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`(6) use of slurry crystallization;
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`(7) reaction time; and
`
`(8) isolation of reaction products through “vacuum filtration” and washing
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`instead of evaporative concentration.
`
`Chorghade (EX1035) ¶¶26-42; Chorghade (EX2283) 33:18-34:10, 43:12-45:10,
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`48:15-49:7, 63:14-64:8, 78:21-79:4. These differences can lead to different,
`
`unclaimed salts, e.g., EX2220, 30-36; EX2221 ¶¶30-45, but more importantly, they
`
`preclude Mylan’s reliance on Dr. Chyall’s experiments as proof of inherency.
`
`WO498 does not disclose any of these modifications to Example 7, so it cannot
`
`support inherency as a matter of law. Perricone, 432 F.3d at 1379.
`
`In fact, Dr. Chyall did not even purport to follow or modify Example 7; his
`
`declaration and lab notebook nowhere mention WO498. Chorghade (EX2283)
`
`13:12-15, 22:9-23:11. Dr. Chyall performed a “screen” to investigate what form of
`
`sitagliptin phosphate results in different conditions. EX2225 ¶¶13, 23; Chorghade
`
`(EX2283) 23:12-17, 42:15-43:5. As Merck’s evidence shows, Dr. Chyall’s screen
`
`
`
`
`
`8
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`

`

`
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`did not include a variety of additional reasonable conditions (including different
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`IPR2020-00040 | Patent 7,326,708
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`solvents) that uncontestedly produce other salts. Matzger (EX2103) ¶¶123-76;
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`Vydra (EX2002) ¶11 (showing solvents used in screen including 2-propanol
`
`(isopropanol)). Dr. Chyall “did not try to establish that a 1:1 salt of sitagliptin and
`
`phosphoric acid is the only salt that could be formed.” EX2192 ¶72.4
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`3.
`
`In an effort to lump Example 7 and Dr. Chyall’s work, Mylan selects
`
`a single parameter in each—use of methanol—and on that basis distinguishes them
`
`from Dr. Matzger’s isopropanol-based crystallizations. Reply 10; Chorghade
`
`(EX1035) ¶43. Mylan’s focus on methanol misses the mark in multiple respects.
`
`First, its arguments are just wrong. Example 7 and Dr. Chyall did not
`
`actually use the same solvent—Dr. Chyall’s methods all contain water (from the
`
`phosphoric acid solution) as well as methanol, while Example 7 does not.
`
`
`4 This testimony puts the lie to Mylan’s characterization as “unrebutted” of Dr.
`
`Chyall’s statement that “there is only one possible molecular ratio, a 1:1 ratio” of
`
`sitagliptin phosphate, Reply 6-7—even putting aside Dr. Matzger’s undisputed
`
`creation of non-1:1 salts. Dr. Chyall is not Merck’s expert; his hearsay statements
`
`from another proceeding are neither admissible generally nor “unrebutted.” Merck
`
`offered Dr. Chyall’s declaration (EX2225) to show the motive for Dr. Matzger’s
`
`experiments. Mylan also ignores Dr. Atwood’s rebuttal. EX2221-EX2223.
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`9
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`
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`Chorghade (EX2283) 44:8-18; Chorghade (EX2051) 201:8-17. The record does
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`IPR2020-00040 | Patent 7,326,708
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`not even contain a method of making 1:1 sitagliptin DHP in methanol alone.
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`Mylan also ignores record evidence that non-1:1 phosphate salts do form in
`
`methanol; Example 2 of WO ’420 yields—“with methanol”—a 2:1 sitagliptin-to-
`
`phosphate salt. EX2220, 32; Chorghade (EX2283) 87:8-22 (expressing “no
`
`opinions” on WO420’s non-1:1 salts); see also EX2273; EX2274; Matzger
`
`(EX1025) 221:21-228:5 (discussing non-1:1 sitagliptin sulfate salts formed in
`
`methanol in EX2273-EX2274).
`
`Second, the POSA would recognize that Example 7 used methanol for a
`
`reason that is irrelevant to any method in the record (including Dr. Chyall’s) of
`
`making any phosphate salt: it used methanolic HCl to remove a BOC-protecting
`
`group. EX1004, 28:7-9; Chorghade (EX2283) 53:15-55:6. WO498 teaches that
`
`“methanolic hydrogen chloride” achieves this goal, and while it teaches
`
`“trifluoroacetic acid” as an alternative, Dr. Chorghade admitted that WO498 does
`
`not disclose the use of phosphoric acid for that de-protection step. Chorghade
`
`(EX2283) 55:10-20. The POSA would recognize that one could not simply
`
`substitute phosphoric acid for hydrochloric acid in Example 7. Chorghade
`
`(EX2283) 57:15-19, 58:11-59:19, 61:2-17, 70:19-71:7, 92:5-93:7. And if the
`
`POSA sought to make a phosphate salt, they would have no reason to focus
`
`exclusively on methanol, particularly while selectively changing other parameters
`
`
`
` 10
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`

`

`
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`of Example 7. Chorghade (EX2283) 30:12-31:5, 41:2-19, 67:4-11, 68:12-21;
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`IPR2020-00040 | Patent 7,326,708
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`Chorghade (EX2051) 162:13-19; Vydra (EX2002) ¶11; Matzger (EX1025) 219:1-
`
`17; cf. Reply 24 (emphasizing that an “isopropanol/water solution” is a “typical
`
`salt formation procedure[]” (citation omitted)).
`
`Finally, Mylan’s argument is illogical on its own terms: Example 7 does not
`
`turn into a teaching of 1:1 sitagliptin DHP just because Example 7 involves
`
`methanol and 1:1 sitagliptin DHP can be created using other methanol solutions.
`
`Nor does it imply that Dr. Matzger “avoided reproducing the prior art,” Reply 8, as
`
`Mylan asserts; Dr. Matzger and Dr. Chyall each used different conditions that one
`
`could use in a salt screen, and, consistent with the unpredictability of salt
`
`formation, obtained different salts. Matzger (EX2103) ¶¶149-76; Chorghade
`
`(EX2283) 33:4-10, 39:11-18.
`
`
`
`4. Mylan also makes a bizarre assertion that Merck’s “theoretical
`
`arguments cannot undo the actual experimental results,” Reply 7, ignoring that Dr.
`
`Matzger made non-1:1 sitagliptin phosphate salts, not just “theoretical arguments.”
`
`Matzger (EX2103) ¶¶123-76. Mylan says not one word to challenge his analysis
`
`of the physical products he made. Dr. Matzger explained, and then demonstrated
`
`experimentally, that a single polyprotic molecule of phosphoric acid can protonate
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`multiple sitagliptin molecules, forming a 2:1 or a 3:2 sitagliptin-to-phosphoric acid
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`salt. Id. All of Mylan’s theoretical discussions of the relative strength of
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`hydrochloric acid and phosphoric acid, Reply 3, and whether multiple sitagliptin
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`reaction sites can be protonated, id. 7, are thus irrelevant to inherent anticipation.
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`That is, the sitagliptin in Dr. Matzger’s salts is “mono-protonated at the primary
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`amine” as Mylan insists it must be, Pet. 19 n.8, yet still falls outside the claims,
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`because the salt contains more molecules of sitagliptin than acid (a non-1:1 ratio).
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`Matzger (EX2103) ¶¶123-76. Mylan has no response to this, so simply ignores it,
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`and disputes only whether 1:2 salts having one sitagliptin bonded to two acid
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`molecules also form. In fact, they do, id. ¶¶105-06, 122; EX2220, 16; EX1004,
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`37:1-43:29, but either independently suffices to avoid inherent anticipation.
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`*
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`*
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`*
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`In sum, WO498 does not teach 1:1 sitagliptin DHP. Example 7 does not
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`teach 1:1 sitagliptin DHP. And neither makes 1:1 sitagliptin DHP inherent. The
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`claims are not anticipated.
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` The Dependent Claims Are Not Anticipated
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`1.
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`Claim 3
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`Mylan’s Reply points only to WO498’s generic disclosure in that the
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`compounds disclosed therein “may contain one or more asymmetric centers,”
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`EX1004, 8:19-21; Reply 10. Mylan narrowly and improperly focuses on
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`sitagliptin, which is just one of the “millions of compounds” disclosed in WO498.
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`Matzger (EX2103) ¶73. Given this expansive genus, the POSA would not have
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`been able to envisage (S)-sitagliptin, much less the 1:1 DHP salt in claim 3.
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`2.
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`Claims 17 and 19
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`Mylan’s argument that WO498 discloses a therapeutically effective amount
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`of 1:1 sitagliptin DHP, Reply 11, ignores that its own expert would “not quite call”
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`the non-sitagliptin-specific dosage ranges in WO498 “a therapeutic dose level.”
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`Chorghade (EX2051) 185:21-22. Mylan’s expert declined to perform the requisite
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`analysis, even though Mylan bears the burden of proof. In re Magnum Oil Tools
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`Int’l, Ltd., 829 F.3d 1364, 1375 (Fed. Cir. 2016). Mylan invites the Board to err by
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`conducting its own expert analysis of whether the allegedly “overlapping doses” in
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`WO498 can fill this gap. EX1002 ¶90; Brand v. Miller, 487 F.3d 862, 868-69
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`(Fed. Cir. 2007).5
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`3.
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`Claims 21-23
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`Example 7 of WO498—the allegedly anticipatory process—does not involve
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`(1) a reaction with sitagliptin or (2) “contacting one equivalent of” sitagliptin with
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`5 Mylan’s citation to Sandoz Inc. v. Pharmacyclics LLC, IPR2019-00865, Paper
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`29, 9-10 (P.T.A.B. Sept. 24, 2020) is unavailing; unlike here, the prior art there
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`focused on a specific compound for which therapeutically effective doses were
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`disclosed.
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`“about[] one equivalent of phosphoric acid.” Example 7 uses a different
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`compound—a BOC-protected form of sitagliptin—and an excess of hydrochloric
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`acid. Matzger (EX2103) ¶¶185-95. Mylan’s characterization of these as
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`“irrelevant distinctions,” Reply 14, only underscores its failure to show that the
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`reference teaches the claimed process.
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`Mylan attempts to avoid these problems with a novel construction of
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`“contacting,” Reply 12, but there is no basis to interpret this term to turn on
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`molecular interactions rather than a process step. Mylan’s construction renders
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`irrelevant both the starting material, as long as sitagliptin is some downstream,
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`transitory intermediate, and the recited “one equivalent” of acid, so long as a salt
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`with 1:1 stoichiometry forms. This is fatal to Mylan’s argument. Black-letter
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`principles of claim construction do not permit constructions that “abrogate claim
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`limitations.” Spectrum Int’l, Inc. v. Sterilite Corp., 164 F.3d 1372, 1380 (Fed. Cir.
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`1998); see In re Power Integrations, Inc., 884 F.3d 1370, 1375-77 (Fed. Cir. 2018).
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`The BOC-deprotection reaction in WO498 bears no resemblance to the salt-
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`formation process described in the ’708 patent. EX1001, 12:61-13:15. Example 7
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`comes nowhere near anticipating claim 21.
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`II. CLAIM 4 IS NOT OBVIOUS
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`Mylan’s cursory treatment of its sole ground challenging claim 4 similarly
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`concedes dispositive factual issues and ignores relevant legal precedent. Claim 4 is
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`non-obvious, particularly in light of the unpredictability of whether and when a
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`particular polymorph might form.
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`1. Mylan never disputes the absence of a motivation to make the
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`crystalline monohydrate, reciting only that the “POSA would have been motivated
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`to make the crystalline form.” Reply 23 (citing EX1031, 70:1-72:21). Mylan cites
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`Merck’s expert, who discussed certain advantages of crystalline over amorphous
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`forms—disconnected from the particular polymorphic form in question. That
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`ignores the reasons the POSA would not have preferred a crystalline solid, POR
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`56, and also misses the point: there was no motivation to pursue the claimed
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`crystalline monohydrate.
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`Mylan has no response to Merck’s authority establishing that Mylan must
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`prove a particularized motivation to obtain a claimed crystal form—not just a
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`general motivation to search for such forms. POR 53-54. Yet Mylan’s expert
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`admitted that Mylan offered no evidence that the POSA would have been
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`motivated to make a crystalline 1:1 sitagliptin DHP hydrate, much less the claimed
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`monohydrate. Chorghade (EX2051) 282:18-283:19. None of the compounds in
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`WO498 were prepared as hydrates. Myerson (EX2101) ¶136. And the POSA
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`undisputedly would have had numerous reasons for avoiding hydrates of 1:1
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`sitagliptin DHP, including expected lower solubility and poorer stability. POR 56-
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`59. Mylan does not dispute these facts or otherwise challenge Dr. Myerson’s
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`conclusion that they would have taught away from the claimed monohydrate.
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`Myerson (EX2101) ¶¶56-57, 128-137; Chorghade (EX2283) 89:12-19. That alone
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`is sufficient to find claim 4 non-obvious.
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`2. Mylan also never disputes that the POSA would not have been
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`motivated to select sitagliptin as a lead compound. POR 30-31, 54-55. Mylan’s
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`argument—that a lead-compound analysis is unnecessary for salt claims, Reply 19-
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`21—is incorrect, POR 31-33, and irrelevant to claim 4. Courts have consistently
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`required the identification of a lead compound for crystalline polymorph claims.
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`POR 54-55. If the POSA “wouldn’t have had any motivation to work on
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`[sitagliptin], then they certainly wouldn’t have found any new crystal forms of it.”
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`Janssen Prods. L.P. v. Lupin Ltd., 109 F. Supp. 3d 650, 688-89 (D.N.J. 2014)
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`(citation omitted). This is independently dispositive on claim 4.
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`3. Mylan also ignores Merck’s arguments regarding reasonable
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`expectation of success. Mylan has no response to the overwhelming evidence of
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`unpredictability of polymorphic crystal forms, including hydrates. Undisputedly,
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`the POSA would not have known whether 1:1 sitagliptin DHP could crystallize at
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`all, form a hydrate, or form a monohydrate, POR 41-42, 45-46; Myerson (EX2101)
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`¶¶58-63, 146-49; Chorghade (EX2051) 200:1-6, 245:21-246:6, 257:18-258:11,
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`238:8-18, or under what conditions, POR 50-51. Mylan also ignores the
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`unanimous case law rejecting obviousness challenges to crystal-form claims
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`because of this unpredictability. POR 42-44. Mylan’s failure to engage with
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`Lupin is particularly glaring, as it dealt with essentially Mylan’s same arguments
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`and an even broader hydrate claim. Id.
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`Rather than respond on these issues, Mylan focuses on WO498’s statement
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`that “[s]alts in the solid form may exist in more than one crystal structure, and may
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`also be in the form of hydrates.” Reply 24. But as Merck previously explained
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`(without rebuttal), that sentence would not suggest to the POSA that any individual
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`compound—much less undisclosed compounds like 1:1 sitagliptin DHP—actually
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`do form hydrates. POR 47. They “may”—or may not. WO498 provides no data.
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`Chorghade (EX2051) 197:22-198:4; EX2186, 2:18-19. Undisputedly, none of the
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`compounds in WO498 were prepared as hydrates. Myerson (EX2101) ¶136;
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`Chorghade (EX2051) 198:5-9.
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`From this shaky foundation, Mylan reasons that the POSA would have
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`expected to obtain a crystalline monohydrate because, according to Brittain,
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`monohydrates are the most common hydrates. Reply 24. Mylan utterly ignores
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`Merck’s cases rejecting this kind of probabilistic argument for reasonable
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`expectation. POR 48-49. The POSA would not reasonably have expected to be
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`able to make a crystalline monohydrate of a salt where no hydrate—much less a
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`monohydrate—was known. POR 47-48. In fact, Mylan’s expert conceded that,
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`according to Brittain’s data, only about one-sixth of APIs are even capable of
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`forming monohydrates, and Mylan does not dispute that Brittain overstates the
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`actual likelihood of finding a crystalline hydrate. POR 48 & n.15; Chorghade
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`(EX2051) 204:18-205:1.
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`4.
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`There also is no reasonable expectation of success or enablement by
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`the prior art in making claim 4’s crystalline monohydrate because the POSA
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`undisputedly would not have known how to obtain that form, even