IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`MYLAN PHARMACEUTICALS INC., TEVA PHARMACEUTICALS USA,
`INC., WATSON LABORATORIES, INC., DR. REDDY’S LABORATORIES,
`INC., DR. REDDY’S LABORATORIES, LTD., and SUN
`PHARMACEUTICALS INDUSTRIES LTD.1
`Petitioner,
`v.
`MERCK SHARP & DOHME CORP.
`Patent Owner.
`_________________________
`Case IPR2020-00040
`U.S. Patent 7,326,708 B2
`___________________________
`
`PETITIONERS’ REPLY
`
`1 Teva Pharmaceuticals USA, Inc. and Watson Laboratories, Inc. were joined as a
`party to this proceeding via Motion for Joinder in IPR2020-01045; Dr. Reddy’s
`Laboratories, Inc. and Dr. Reddy’s Laboratories, Ltd. were joined as a party 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.
`
`1
`
`
`___________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`MYLAN PHARMACEUTICALS INC., TEVA PHARMACEUTICALS USA,
`INC., WATSON LABORATORIES, INC., DR. REDDY’S LABORATORIES,
`INC., DR. REDDY’S LABORATORIES, LTD., and SUN
`PHARMACEUTICALS INDUSTRIES LTD.1
`Petitioner,
`v.
`MERCK SHARP & DOHME CORP.
`Patent Owner.
`_________________________
`Case IPR2020-00040
`U.S. Patent 7,326,708 B2
`___________________________
`
`PETITIONERS’ REPLY
`
`1 Teva Pharmaceuticals USA, Inc. and Watson Laboratories, Inc. were joined as a
`party to this proceeding via Motion for Joinder in IPR2020-01045; Dr. Reddy’s
`Laboratories, Inc. and Dr. Reddy’s Laboratories, Ltd. were joined as a party 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.
`
`1
`
`
`
`TABLE OF CONTENTS
`
`d.
`
`Page
`Claims 1-3, 17, 19, and 21-23 Are Anticipated (Grounds 1 & 2) ................... 2
`a.
`Overview ............................................................................................... 2
`b.
`Two Well-Defined Lists ........................................................................ 4
`c.
`The Uncontested Reproduction of WO498 Produces 1:1
`Sitagliptin DHP Every Time ................................................................. 5
`Dr. Matzger Avoided Reproducing the Prior Art ................................. 8
`1.
`Claim 3 ......................................................................................10
`2.
`Claims 17 and 19.......................................................................11
`1.
`Claims 21-23 .............................................................................11
`Claims 1-4, 17, 19, and 21-23 Would Have Been Obvious
`(Grounds 3-5) .................................................................................................15
`a.
`Merck Has Failed to Antedate WO498 ...............................................15
`b.
`There Is No Lead Compound Requirement ........................................19
`c.
`Claims 1-3, 17, 19, and 21-23 (Grounds 3 and 4) ...............................21
`d.
`Claim 4 (Grounds 4 and 5) ..................................................................23
`e.
`No Unexpected Results .......................................................................25
`1.
`Claims 1-3, 17, 19, and 21-23 ...................................................25
`2.
`Claim 4 ......................................................................................27
`CONCLUSION ..............................................................................................28
`
`1.
`
`2.
`
`3.
`
`i
`
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Amgen Inc. v. Hoechst Marion Roussel, Inc.,
`314 F.3d 1313 (Fed. Cir. 2003) .......................................................................... 19
`Biosig Instruments Inc. v. Nautilus, Inc.,
`783 F.3d 1374, 1381 n.3 (Fed. Cir. 2015) ......................................................... 16
`
`Daicel Corp. v. Celanese International Corp.,
`IPR2015-00170, Paper 14 (PTAB, Apr. 1, 2015) .......................................... 8, 10
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 23
`Dynamic Drinkware, LLC v. National Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) .......................................................................... 15
`Ex Parte Hass,
`Appeal 2017-011069, 2019 WL 2601860 (PTAB, June 12, 2019) .................... 20
`Grunenthal GMBH v. Actecip Bioventures II LLC,
`PGR2019-00027, Paper 24 (PTAB, Jul. 28 2020) ............................................. 22
`Hospira, Inc. v. Genentech, Inc.,
`IPR2017-00805, Paper 83 (PTAB, Oct. 3, 2018) ................................................. 8
`In re Aller,
`220 F.2d 454 (CCPA 1955) ................................................................................ 25
`In re Antor Media Corp.
`689 F.3d 1282 (Fed. Cir. 2012) .......................................................................... 19
`In re Clarke,
`356 F.2d 987 (CCPA 1966) ................................................................................ 16
`In re Crish,
`393 F.3d 1253 (Fed. Cir. 2004) ............................................................................ 8
`
`ii
`
`
`
`In re De Fano,
`480 F.2d 895 (CCPA 1973) ................................................................................ 18
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 25
`In re Mantell,
`454 F.2d 1398 (CCPA 1972) .............................................................................. 17
`In re Rainer,
`390 F.3d 771 (CCPA 1968) ................................................................................ 19
`In re Rozmus,
`928 F.2d 412, 1991 WL 17232 (Fed. Cir. 1991) ................................................ 18
`Institut Pasteur v. Facarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 24
`Interactive Gift Express, Inc. v. Compuserve Inc.,
`256 F.3d 1323 (Fed. Cir. 2001) .......................................................................... 12
`Merck Sharp & Dohme Corp. v. Sandoz Inc.,
`2015 WL 5089543 (D.N.J. Aug. 27. 2015) ........................................................ 19
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.,
`851 F.3d 1270 (Fed. Cir. 2017) .......................................................................... 10
`Otsuka Pharmaceutical Co., Ltd. v. Sandoz, Inc.,
`678 F.3d 1259 ..................................................................................................... 20
`Pernix Ireland Pain DAC v. Alvogen Malta Operations Ltd.,
`No. CV 16-cv-00139, 2018 WL 2225113 (D. Del. May 15, 2018) ................... 16
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) ............................................................................ 4
`Pfizer, Inc. v. Apotex Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 22
`Realtime Data, LLC v. Iancu,
`912 F.3d 1368 (Fed. Cir. 2019) .......................................................................... 21
`
`iii
`
`
`
`Sandoz Inc. v. Pharmacyclics LLC,
`IPR2019-00865, Paper 29 (PTAB Sept. 24, 2020)............................................. 11
`Shire LLC v. Amneal Pharm., LLC,
`2014 WL 2861430 (D.N.J. June 23, 2014) ........................................................... 5
`Unified Patents Inc. v. Harry Heslop.,
`IPR2016-01464, Paper 29 (PTAB, Feb. 6, 2018) ............................................... 16
`
`iv
`
`
`
`Unable to credibly dispute invalidity, Merck ignores the express teachings of
`
`WO4982—which discloses a 1:1 salt—relying instead on non-prior art to mask what
`
`WO498 shows. Compare EX2051 (Chorghade), 55:3-8 with EX1025 (Matzger),
`
`101:21-103:16. That is not surprising because WO498 renders the challenged claims
`
`invalid. Merck’s own exhibit establishes that when the earlier known process is
`
`reproduced, “there is only one possible molecular ratio, a 1:1 ratio…of…sitagliptin
`
`dihydrogen phosphate” (DHP). EX2225, ¶52, ¶24 (4063-19-01 using 1:5.01
`
`(sitaglitptin:phosphoric acid)), ¶37; EX1035, ¶¶10, 16, 24, 63-67:
`
`EX2225, ¶¶24, 37.
`
`Merck’s EX2225 contains 12 methanol-based experiments adhering to the
`
`WO498’s Example 7; each experiment resulted in the 1:1 sitagliptin DHP salt.
`
`EX2225, ¶¶24, 48, 52; EX1035, ¶18, ¶¶22-25, 63-67. The anticipation inquiry ends
`
`there. EX2103, ¶101. Merck’s contorted reliance on non-prior art cannot change
`
`that a 1:1 sitagliptin DHP salt results each time the teachings of WO498 are
`
`followed.
`
`2 Where possible, Mylan’s Reply discusses WO498 and the ’871 patent together as
`
`WO498.
`
`1
`
`
`
`There is more. The challenged claims are not only anticipated, they are also
`
`obvious. There, Merck resorts to nothing more than an inaccurate application of
`
`antedation law. Neither Merck’s reliance on non-prior art; nor its misapprehension
`
`of antedation; nor its flawed reliance on purported secondary considerations can
`
`rescue the challenged claims.
`
`1.
`
`Claims 1-3, 17, 19, and 21-23 Are Anticipated (Grounds 1 & 2)
`a.
`Overview
`WO498 has “two separate lists of possible starting materials.” EX1019, ¶42;
`
`EX1022, 117:1-118:6; EX1002, ¶¶78-81. The lists are not exhaustive. Far from it:
`
`in one, sitagliptin is among a narrow list of 33 exemplified and claimed compounds.
`
`EX1025, 117:19-21, 134:16-135:18; EX1031, 82:10-15. The only sitagliptin salt
`
`exemplified is a 1:1 HCl salt (Example 7):
`
`EX1025, 96:22-97:4; EX1004, 46:1-5. WO498 contemplates other salts as well.
`
`EX1025, 125:3-20. In the second list, WO498 “includes a short list of eight
`
`2
`
`
`
`particularly preferred acids for forming such salts, including explicitly phosphoric
`
`acid, to use with basic drug substances like sitagliptin.” Institution, p.52; EX1025,
`
`133:18-134:9 (“so 1:1 salts fall under the claims of the ’498 patent”), 135:7-136:2;
`
`146:13-147:5 (“you can imagine that the [1:1 phosphoric acid salt] would exist”);
`
`150:7-13.
`
`Nonetheless, Merck devotes much to the stoichiometry of the sitagliptin
`
`phosphate salt to obfuscate the issues. But, as Dr. Chorghade opines, sitagliptin
`
`freebase and phosphoric acid will form a 1:1 sitagliptin DHP salt each time WO498
`
`is followed.
`
` EX2051, 167:14-168:10; EX1002, ¶¶76, 99, p.44, n.15.
`
`Dr. Chorghade’s reasoning is straightforward: if using a highly saturated HCl
`
`methanol solution only creates a 1:1 sitagliptin HCl salt, then phosphoric acid (which
`
`is a weaker acid when compared to HCl) will fare no different. EX2051, 145:22-
`
`147:2, 92:13-18, 93:20-94:12, 149:12-150:9; EX1025, 155:16-20, 150:7-13. Putting
`
`aside the legal significance of this opinion, Dr. Chorghade is expounding scientific
`
`fact.
`
`Yet, Merck turns to non-prior art evidence (WO420), using different
`
`conditions than WO498, to contend other possible stoichiometries may exist.
`
`Tellingly, however, Dr. Matzger concedes that the only way to create a non-1:1 salt
`
`is to implement “other reaction conditions” besides WO498’s methanol system.
`
`EX2103, ¶113 (“other solvents”), ¶102 (opining that non-1:1 salts form under
`
`3
`
`
`
`“reasonable conditions,” i.e., changed conditions, but not stating that such conditions
`
`are the same as WO498). But, anyone can change experimental parameters to derive
`
`a result-oriented opinion. Respectfully, this Panel is charged with determining
`
`whether the WO498 renders the challenged claims invalid—not whether a non-prior
`
`art process yields a different salt. When following WO498, the 1:1 sitagliptin DHP
`
`salt results every time. EX2225, ¶52; EX1035, ¶¶14-44, 63-67.
`
`Two Well-Defined Lists
`b.
`Merck’s allegation that WO498 “discloses and claims millions of compounds
`
`of Formula I” (Response, 12) is disingenuous. WO498 exemplifies and claims a
`
`short list of 33 compounds, one of which is sitagliptin. “That specific disclosure,
`
`even in a list, makes this case different from cases involving disclosure of a broad
`
`genus without reference to the potentially anticipating species.” Perricone v.
`
`Medicis Pharm. Corp., 432 F.3d 1368, 1376 (Fed. Cir. 2005).
`
`Claim 15 of WO498 claims sitagliptin and concludes with “pharmaceutically
`
`acceptable salts thereof.” EX1004, p.60; EX1001, 1:55-56 (the ’708 patent
`
`acknowledging that WO498 discloses “salts of this compound.”); EX1025, 123:12-
`
`125:20. In identifying such salts, WO498 provides eight “[p]articularly preferred”
`
`acids. EX1004, 10:14-15. “A reference can anticipate even if one of the claim
`
`limitations ‘appears without special emphasis in a longer list.’” Response, 8 (citing
`
`Perricone).
`
`4
`
`
`
`Merck’s reliance on Shire LLC v. Amneal Pharm., LLC, 2014 WL 2861430
`
`(D.N.J. June 23, 2014) is inapposite. Response, 10-11. Shire found that “the acid
`
`that is used to form the dimesylate salt does not appear on any list in AU’168.” Id.
`
`at *16. Here, phosphoric acid expressly appears in the “[p]articularly preferred” list
`
`of WO498. As for Merck’s attempt to distinguish the instant case from Wrigley—
`
`comparing “a simple combination of two ingredients like Wrigley’s two chewing
`
`gum components [to] a chemical reaction forming a new compound” (Response, 11),
`
`as Perricone explained, “the anticipation analysis asks solely whether the prior art
`
`reference discloses and enables the claimed invention, and not how the prior art
`
`characterizes that disclosure.” 432 F.3d at 1376.
`
`Merck’s reliance on unpredictability and hindsight strains credulity.
`
`Response, 9. The 1:1 sitagliptin DHP salt can be made easily and was, in fact, first
`
`allegedly made doing nothing more than a simple, automated salt screen by a person
`
`with a skill level below the POSA. EX1032, 27:20-31:22, 39:13-40:22, 42:18-44:15,
`
`47:46:2-58:12; Ex. 2002, ¶¶16–19, Institution, p.53 n.28. In any event, there is no
`
`requirement of a “reasonable expectation of success” in anticipation.
`
`c.
`
`The Uncontested Reproduction of WO498 Produces 1:1 Sitagliptin
`DHP Every Time
`As noted, Merck contends that something other than a 1:1 sitagliptin DHP salt
`
`might form. Example 7 of WO498 was done in methanol/ambient conditions.
`
`EX1025, 93:2-94:2; EX1004, 14:23 (cross-referencing Example 1); EX1035, ¶46.
`
`5
`
`
`
`Merck placed into evidence experimental data using these conditions from “the
`
`Israeli opposition against Patent Application No. 172563, the Israeli equivalent of
`
`the ’708 patent [(hereafter “the Israeli Opposition”)].” EX2103, ¶123. EX2225 is a
`
`declaration offered by Dr. Chyall in the Israeli Opposition (EX2041, 15:7-14) and
`
`shows that a 1:1 sitagliptin DHP salt forms each time. EX2225, ¶¶22-52, 72, 75;
`
`EX1035, ¶24-25, ¶26, ¶¶63-67; EX2051, 148:16-19.
`
`Dr. Matzger’s Declaration references the very paragraph that provides the
`
`experimental data. EX2103, ¶126 (citing EX2225, ¶23-25). Nevertheless, Dr.
`
`Matzger neither criticizes nor rebuts any conclusions reached in EX2225, ¶¶22-52.
`
`EX1025, 13:5-15:15, 29:3-30:5; 76:13-77:4 (Declaration is complete response to
`
`each exhibit). Frankly, how could he? The data is incontrovertible. EX1035, ¶22-
`
`25, ¶26, ¶¶63-67.
`
`Alerting the PTAB (and Mylan) to carefully scrutinize its anticipation
`
`arguments in light of Dr. Chyall’s uncontested data—e.g., EX2225—Merck
`
`explained that such evidence “bear[s] on an issue that is already in this proceeding,
`
`whether this 1:1 salt is inherently[] anticipated.” EX2041, 15:7-14. Despite
`
`knowledge of its own exhibit, Merck offered no further explanation or rebuttal in its
`
`Response. As such, the unrebutted evidence demonstrates that when the prior art
`
`process is performed “there is only one possible molecular ratio, a 1:1 ratio…
`
`6
`
`
`
`of…sitagliptin dihydrogen phosphate.” EX2225, ¶52; EX1035, ¶22-25, ¶26, ¶¶63-
`
`67.
`
`Merck’s theoretical arguments cannot undo the actual experimental results.
`
`Merck contends that sitagliptin has two potential sites of reaction “the primary amine
`
`and the triazole ring,” theorizing that “sitagliptin can potentially be protonated at
`
`both sites.” Response, 16. But Example 7 (experimental data), undermines this
`
`theory—in a saturated HCl solution (HCl is a stronger acid than phosphoric acid),
`
`sitagliptin only created a 1:1 salt. EX2051, 145:22-147:2. Merck’s experts offer no
`
`explanation as to why Example 7 shows a 1:1 salt in the presence of ~1,000-fold
`
`excess of a strong acid, despite Merck’s supposed “two potential sites” theory.
`
`EX1025, 97:5-22 (“I did not express an opinion on that”); EX1031, 46:5-49:3.
`
`Merck’s alternative argument that “phosphoric acid is triprotic” and therefore may
`
`donate multiple protons (Response, 16) does not change what the prior art shows.
`
`As Dr. Matzger conceded, “just because something is a polyprotic acid, it doesn't
`
`necessarily follow that it will donate all of its protons.” EX1025, 149:11-150:11.
`
`Example 7 shows only 1:1 salt forms despite being exposed to ~1,000-fold
`
`excess of HCl. Merck has never been able to address this. EX1025, 97:5-22. As
`
`Dr. Metzger explained, “when you have experimental evidence that resolves that
`
`issue…you can’t any longer hold views that contradict the experimental evidence.”
`
`7
`
`
`
`EX1025, 166:19-22. The experimental evidence is the basis of Dr. Chorghade’s
`
`opinion.
`
`Dr. Matzger Avoided Reproducing the Prior Art
`d.
`Merck has gone to pains to avoid WO498, relying upon irrelevant, post-
`
`priority experimental protocols. Response, 17-19; EX2103, p.95 (“420 Salt”);
`
`Hospira, Inc. v. Genentech, Inc., IPR2017-00805, Paper 83 at 34-35 (PTAB. Oct. 3,
`
`2018) (rejecting post-priority references). At the risk of repetition, the relevant
`
`inquiry is whether the “prior art process” yielded the 1:1 sitagliptin DHP salt. In re
`
`Crish, 393 F.3d 1253, 1259 (Fed. Cir. 2004); Response, 16 (citing Trintec Indus.,
`
`Inc. v. Top-U.S.A. Corp., 295 F.3d 1292, 1295 (Fed. Cir. 2002) (“prior art”));
`
`Response, 16 (citing U.S. Water Servs., Inc. v. Novozymes A/S, 843 F.3d 1345, 1350-
`
`51 (Fed. Cir. 2016) (“prior art reference”)). It did.
`
`The changes implemented by Dr. Matzger when replicating Example 1 of
`
`WO420 result in a materially different protocol from Example 7 of WO498.
`
`EX1035, ¶¶45-57; Daicel Corp. v. Celanese International Corp., IPR2015-00170,
`
`Paper 14 at 20 (PTAB, Apr. 1, 2015) (rejecting reproductions that were not
`
`approximations of the prior art):
`
`8
`
`
`
`WO498 & Chyall
`(4063-19-01)
`Methanol
`
`Ambient temperature
`
`No additional water
`
`Matzger
`
`Record Evidence
`
`70°C
`
`Isopropanol
`
`EX1035, ¶32, ¶¶49-
`53
`EX1025, 82:3-85:10,
`96:3-8
`EX2221, ¶60
`EX1035, ¶33, ¶¶54-
`55
`EX1025: 92:15-21;
`EX2221, ¶¶57-59;
`EX1024, 48:17-49:6
`EX2192, ¶¶66-65
`1.4mL of distilled water added EX1035, ¶¶56-57
`EX2221, ¶64
`
`Dr. Matzger even admitted he was “not trying to reproduce anything in the ’498.”
`
`EX1025, 87:21-88:17, 86:4-19; 232:7-14; EX1035, ¶45, ¶47. This cannot be
`
`understated.
`
`Example 7 is clear: the solvent is methanol and the temperature is ambient.
`
`EX1025, 93:15-94:2; EX1035, ¶46. Using methanol and ambient conditions “is not
`
`a difficult experiment,” and when asked why Dr. Matzger had not done an
`
`experiment in methanol, he was impeded by privilege assertions. EX1025, 93:12-
`
`13, 86:4-88:17. Since Example 7 uses HCl (gas) (EX1025, 99:22-100:3, EX2051,
`
`9
`
`
`
`138:16-18)), the POSA would have to make changes to use aqueous phosphoric acid.
`
`EX1035, ¶¶27-28; EX1025, 178:20-179:6, 220:6-21. When asked what changes,
`
`Dr. Matzger only pointed to a different amount of (excess) phosphoric acid because
`
`a 1,000-fold excess of phosphoric acid (like HCl in Example 7) would not be
`
`feasible. EX1025, 220:6-21; EX1035, ¶¶27-28. Dr. Matzger’s proposed change,
`
`i.e., a different amount of phosphoric acid, was what Dr. Chyall did. EX2225, ¶24
`
`(4063-19-01 (using 1:5.01)).
`
`As to his other changes, e.g., using isopropanol, Dr. Matzger conceded that
`
`methanol and isopropanol are not equivalent solvents. EX1025, 96:3-8, 80:1-82:7;
`
`EX1035, ¶¶49-53. Had he used methanol, changes to temperature, the API to
`
`phosphoric acid ratio, and additional water have no impact—the 1:1 sitagliptin DHP
`
`salt forms each time. EX2225, ¶48; EX1035, ¶¶16, 23-24, 43-44, 63-67.
`
`Merck provided additional “comments” for Claims 3, 17, 19 and 21-23
`
`(Response, 19-21), which are addressed below:
`
`1.
`
`Claim 3
`With only one chiral center, there are only two isomers of sitagliptin: (R) and
`
`(S). EX1025, 22:13-9; EX1031, 28:15-31:6; EX1022, 107:19-108:2. WO498
`
`teaches both. Pet., 25; EX1004, 8:21-28; 9:24-26; EX1002, ¶¶84-86. As to Merck’s
`
`reliance on Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. (Response,
`
`19), Nidec does not allow a POSA to envision something that has no express
`
`10
`
`
`
`disclosure in the prior art. 851 F.3d 1270, 1274-75 (Fed. Cir. 2017). Here, WO498
`
`expressly discloses the (S)-form.
`
`Claims 17 and 19
`2.
`Merck focuses on Claims 17 and 19’s generic recitation of “therapeutically
`
`effective amount.” Since the generic recitation of these claims matches the teachings
`
`of WO498 (a cursory review of WO498 shows overlapping doses), these claims are
`
`anticipated. Sandoz Inc. v. Pharmacyclics LLC, IPR2019-00865, Paper 29 at 14
`
`(PTAB Sept. 24, 2020); Pet., 25; EX1025, 117:22-120:1; EX1002, ¶90. Thus,
`
`“therapeutically effective amount” does not rescue Claims 17 and 19.3 EX1025,
`
`120:2-121:6 (Dr. Matzger failing to fully analyze recitation).
`
`Claims 21-23
`1.
`Merck’s analysis ignores the claim language of Claims 21-23. The relevant
`
`limitations of Claim 21 are: “[a] process for preparing the salt of claim 2 [i.e., the
`
`final product] comprising the step of contacting one equivalent of [sitagliptin
`
`3 As to Dr. Chorghade’s statements (Response, 19-20), Merck focused on the
`
`broadest range possible in WO498 (EX2051, 185:8-17) while refraining from
`
`discussing Dr. Chorghade’s opinion on the narrower dose ranges (EX1004, 23:20-
`
`26), or the specific statements in Dr. Chorghade’s Declaration. EX1002, ¶90;
`
`EX2051, 293:16-305:11.
`
`11
`
`
`
`freebase]...with about a one equivalent of phosphoric acid.” Interactive Gift
`
`Express, Inc. v. Compuserve Inc., 256 F.3d 1323, 1331 (Fed. Cir. 2001) (“[T]he
`
`analytical focus must begin and remain centered on the language of the claims
`
`themselves.”). “Contact” means an actual physical interaction between molecules.
`
`EX2103, ¶194 (“contacting a compound”), ¶258 (using “contacting...with” in
`
`terms of molecular interactions); EX1020, p.7 (“[t]he touching of two objects or
`
`surfaces”); EX1002, ¶116 (“contacting...with” referring to molecular interactions),
`
`p.44 n.15 (“contact[]...with” referring to molecules), ¶99; EX1024, 72:25-73:12
`
`(contacting molecules).
`
`The uncontested data—replicating the reaction conditions of the salt-forming
`
`step of Example 7 of WO498 with phosphoric acid—demonstrates that the
`
`sitagliptin base molecule is only able to interact once with a phosphoric acid
`
`molecule to make the 1:1 DHP salt. EX1002, ¶99, p44 n.15 (“can only interact”);
`
`EX2225, ¶48; EX2192, ¶60 (no driving force for other reactions); Institution, n.29.
`
`Once the 1:1 DHP salt is formed, under Example 7, the uncontested evidence shows
`
`that it is “not possible” for the 1:1 DHP salt to form any other salt stoichiometry.
`
`EX2225, ¶24 (Experiment 4063-19-01), ¶48; EX2192, ¶60. Since no further
`
`reaction is possible, 1:1 DHP salt is the final salt. As Dr. Chorghade explained, “the
`
`salt formation reaction necessarily involves contacting the sitagliptin base molecule
`
`12
`
`
`
`with the acid molecule, in order to form the salt.” EX1002, ¶¶116, 99, p.44 n.15;
`
`EX2051, 119:12-120:1.4
`
`Dr. Matzger opines, “[E]xample 7 of WO498 does not teach contacting one
`
`equivalent of sitagliptin with one equivalent of an acid. Rather, Example 7 teaches
`
`contacting one equivalent of a BOC-protected sitagliptin with excess acid.”
`
`EX2013, ¶258, see also ¶¶190-192. This is a red herring. Dr. Matzger is trying to
`
`avoid the claim language and pivot to the starting conditions of the reaction. The
`
`relevant portion of the claim is the “step”, i.e., singular,5 where a sitagliptin freebase
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`molecule makes “contact[] with” a phosphoric acid molecule to “prepar[e]” the final
`
`1:1 salt. EX2103, ¶62 (Dr. Matzger describing the Claim 21 similarly). Dr.
`
`Matzger’s result-oriented opinion is divorced from this claim language. Though,
`
`“Example 7 teaches contacting one equivalent of a BOC-protected sitagliptin with
`
`excess acid,” (EX2013, ¶258) this step is the second-to-last step and does not result
`
`in the “salt of claim 2.” Rather, this step results in cleavage of the BOC protecting
`
`group to generate the sitagliptin free amine. Only when the BOC-free sitagliptin
`
`4 With respect to Dr. Matzger’s “excess acid” argument, (EX2010, ¶194), Claim 21
`
`is a “comprising” claim; thus, the inclusion of excess acid in Example 7 of WO498
`
`does not save the claims from anticipation.
`
`5 Compare Claim 24 (“steps”).
`
`13
`
`
`
`(the freebase amine) contacts the acid does the “salt of claim 2” form—and with a
`
`1:1 stoichiometry. EX1002, ¶¶116, 99, p.44 n.15.
`
`Mylan agrees with Dr. Matzger that so long as a BOC protecting group
`
`remains on the sitagliptin amine, a salt forming reaction at the amine site is
`
`impossible. EX2103, ¶258; EX1035, p.5, n.3. This is a tangential issue, much like
`
`the irrelevant distinctions Dr. Matzger makes directed to the process of Example 7
`
`(EX2103, ¶¶188-195). Not once, despite having worked with the BOC protecting
`
`group (EX1025, 43:16-44:6), does Dr. Matzger state that phosphoric acid would not
`
`remove the BOC protecting group upon contact to generate the free amine. EX1025,
`
`14:20-15:15, 76:13-77:4 (not advancing any distinction not in his Declaration). Nor
`
`could he—WO498 teaches that acids easily remove the BOC protecting group to
`
`generate the free amine. EX1004, 25:8-10; EX1035, p.5, n.3; EX2051, 150:21-
`
`151:3.
`
`When asked what would happen if the HCl in Example 7—which uses the
`
`BOC-protected sitagliptin—was substituted with phosphoric acid, Dr. Matzger
`
`automatically removed the BOC protecting group and explained you would get a
`
`“phosphoric acid solution of sitagliptin.” EX1025, 219:18-220:5. Mylan agrees that
`
`the second-to-last step in Example 7 results in a solution of sitagliptin freebase and
`
`excess phosphoric acid, and then proceeds to the last step of forming the final 1:1
`
`DHP salt. EX1002, ¶116. Dr. Matzger’s only so-called distinction is that in his
`
`14
`
`
`
`view (wrongly), the POSA would not be able to predict the stoichiometry of the
`
`resulting salt (i.e., the claimed, final salt of Claim 21) when replacing HCl with
`
`phosphoric acid. But in doing so, he is conceding the BOC protecting group would
`
`be removed by the phosphoric acid to generate the sitagliptin freebase. EX2103,
`
`¶127, EX1025, 219:18-220:5.
`
`With the sitagliptin freebase now generated in Example 7—and as
`
`Dr. Chorghade explains—it is able to find a phosphoric acid to “contact[] with” and
`
`the “salt of claim 2” is “prepar[ed].” EX1002, ¶¶116, 99, p44 n.15. This is the
`
`final salt; there is no further reaction. EX2192, ¶60. Merck provides no additional
`
`comments directed to Claims 22-23 (Pet., 30-31). Claims 21-23 are anticipated.
`
`2.
`
`Claims 1-4, 17, 19, and 21-23 Would Have Been Obvious (Grounds 3-5)
`a. Merck Has Failed to Antedate WO498
`The challenged claims are obvious as well. Merck’s disagreement largely
`
`rests on its flawed antedation argument to Claims 1, 2, 17, 19 and 21-23 (collectively
`
`“the antedating claims”).6 Merck fails to meet its burden and misapprehends the
`
`crux of antedation law. Dynamic Drinkware, LLC v. National Graphics, Inc., 800
`
`F.3d 1375, 1380 (Fed. Cir. 2015). To remove WO498, Merck “has the burden of
`
`proving priority with respect to so much of the claimed invention as the [prior art]
`
`6 Merck does not attempt to antedate Claim 3 or 4. Response, 27.
`
`15
`
`
`
`reference happens to show.” In re Clarke, 356 F.2d 987, 991 (CCPA 1966); Biosig
`
`Instruments Inc. v. Nautilus, Inc., 783 F.3d 1374, 1381 n.3 (Fed. Cir. 2015); Unified
`
`Patents Inc. v. Harry Heslop., IPR2016-01464, Paper 29 at 33 (PTAB, Feb. 6, 2018);
`
`Pernix Ireland Pain DAC v. Alvogen Malta Operations Ltd., No. CV 16-cv-00139,
`
`2018 WL 2225113, *15 (D. Del. May 15, 2018). “[I]t is not the entire scope of the
`
`claims which is determinative of the issue here. Rather, it is how much the reference
`
`shows of the claimed invention that is crucial to the requirement.” Clarke, 365 F.2d
`
`at 991.
`
`WO498 teaches that “[s]alts in the solid form may exist in more than one
`
`crystal structure, and may also be in the form of hydrates.” EX1004, 9:32-34;
`
`EX1031, 77:4-8 (explaining hydrates are always crystalline). As Dr. Myerson
`
`explained, a POSA would read this “hydrates” sentence to be “a general comment
`
`about the relationship between salts and hydrates—that is, that salts can exhibit
`
`polymorphism and can exist as hydrates.” EX2101, ¶¶102, 136, 150. Even though
`
`this “hydrates” sentence may be located within a discussion about basic counter-ions
`
`(EX1004, 9:33-35), no expert has suggested it is only limited to the basic counter-
`
`ions.
`
`To the contrary, as Dr. Myerson explained, this “hydrates” sentence is a
`
`“general comment”—without reference to the counter-ion. EX2101, ¶102, ¶151 (“to
`
`mean that for any given salt [without reference to any counter-ion], a hydrate may
`
`16
`
`
`
`exist.”); EX1031, 67:13-20 (“referring to some kind of hydrated form of the salt—
`
`of the salt form disclosed therein.”). Similarly, Dr. Matzger explained, the “general
`
`disclosure” and the claims of WO498 cover 1:1 sitagliptin DHP7 salt “and hydrates
`
`thereof.” EX1025, 131:6-21, 133:19-134:1; EX1002, ¶169. Likewise, Dr.
`
`Chorghade explained WO498’s “hydrates” teaching is a “general statement” that
`
`would apply to sitagliptin. EX2051, 306:14-307:1, 315:9-318:13; EX1002, ¶169.
`
`Merck argues that because “prior to monohydrate’s synthesis, three anhydrous
`
`forms had been identified and characterized,” it has met its antedation burden.
`
`EX2124, ¶9; EX2166, ¶28. Not so. Prior to WO498’s § 102(a) priority date, Merck
`
`admits that “no hydrates of the 1:1 DHP salt...had been identified.” EX2124, ¶9,
`
`¶14 (March 26, 2003, monohydrate isolation); EX2140, ¶40. The three anhydrous
`
`species without “hydrates” are insufficient because the “evidence shows actual
`
`reduction to practice of much less than the reference shows.” In re Mantell, 454
`
`F.2d 1398, 1401 (CCPA 1972).8
`
`In Claim Construction before the District Court, Merck maintained that the
`
`antedating claims do “not exclude hydrates” because the term “the salt of [X]”
`
`includes hydrates. EX1001, Claim 1 “or a hydrate thereof”; Paper 16, Chart 1;
`
`7 The acid counter-ion.
`
`8 Merck has not argued constructive reduction. Response, 23.
`
`17
`
`
`
`EX1034 at 9 (“the dependent claims of the ’708 patent consistently use ‘[t]he salt
`
`of claim X’ to encompass salts and their hydrate forms.”); EX1027, Markman Order,
`
`pp.7-12 (“Does not exclude hydrates”); EX2051, 315:18-316:10 (“A hydrate is a
`
`type of salt.”). This is critical to the antedation analysis. WO498 teaches: “[s]alts
`
`in the solid form may exist in more than one crystal structure, and may also be in the
`
`form of hydrates.” EX1004, 9:32-34; EX1031, 74:19-76:7. Accordingly, absent
`
`Merck showing actual reduction of the hydrates taught in WO498, its antedation
`
`argument fails.
`
`Merck could have attempted to provide evidence that is “sufficient to show
`
`possession of ‘variations and adaptions which would, at the same time, be obvious
`
`to one skilled in the art.’” In re Rozmus, 928 F.2d 412, 1991 WL 17232 at *2 (Fed.
`
`Cir. 1991). Dr. Matzger, however, did not review the Declaration that stated “no
`
`hydrates of the 1:1 DHP salt...had been identified.” EX2124, ¶9; EX1025, 74:4-
`
`75:21; EX2103, ¶45. As such, Dr. Matzger is in no position to offer such an opinion,
`
`nor did he (or any other inventor). EX1025, 78:4-79:1; In re De Fano, 480 F.2d 895
`
`(CCPA 1973). As for Dr. Myerson, he offered no opinions directed to inventorship.
`
`EX1031, 24:6-26:8.9 These omissions are telling.
`
`9 To the extent Merck attempts to expand Dr. Myerson’s terse opinion that WO498’s
`
`teaching to “hydrates” does not enable the crystalline monohydrate of Claim 4 to all
`
`18
`
`
`
`There Is No Lead Compound Requirement
`b.
`This “is not a structural obviousness case; this is a salt selection case.” Pet.,
`
`49. In another effort of distraction, Merck argues for a lead compound analysis. To
`
`support its position, Merck makes a passing reference to Merck Sharp & Dohme
`
`hydrates of the other claims, Merck would be incorrect. EX2101, ¶¶183-185; infra
`
`Section (2)(d) (rebutting Dr. Myerson’s non-enablement opinion). Indulging this
`
`opinion, which was presented without a Wands factor analysis, the antedating claims
`
`and the teachings of WO498 are not limited to crystalline monohydrates but cover
`
`all types of 1:1 DHP hydrates. EX1027; EX1026, ¶¶33-34; EX2101, ¶141; EX1031,
`
`49:17-55:3, 67:13-20, 73:4-76:2; EX1025, 106:20-108:14, 206:5-209:13; EX1005,
`
`pp.141-154; EX10
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