`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`MERCK SHARP & DOHME CORP.,
`Patent Owner.
`__________________
`
`Case IPR2020-00040
`U.S. Patent 7,326,708
`__________________
`
`PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
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`
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`Case IPR2020-00040 | U.S. Patent 7,326,708
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`TABLE OF CONTENTS
`
`
`BACKGROUND .................................................................................................... 4
`
`ARGUMENT.......................................................................................................... 6
`
`I. WO ’498 and the ’871 Patent Do Not Anticipate the Challenged
`Claims (Grounds 1 and 2). ............................................................................ 6
`
`
`
`
`
`
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`
`
`The POSA Would Not Immediately Envisage a Phosphate Salt
`of Sitagliptin (Claims 1-3, 17, 19, 21-23). ........................................... 7
`
`1. WO ’498 Does Not Teach a Well-Defined Genus of Salts
`that the POSA Would “At Once Envisage.” .............................. 9
`
`2. Mylan Improperly Narrows the Genus of Combinations. ........ 12
`
`Petitioners Do Not Establish that the Claimed Stoichiometry
`(1:1 Sitagliptin to Phosphoric Acid) is Inherently Anticipated
`(Claims 1-3, 17, 19, 21-23). .............................................................. 14
`
`The (S)-Configuration is Not Anticipated (Claim 3). ........................ 19
`
`The “Therapeutically Effective Amount” Claims Are Not
`Anticipated (Claims 17, 19). ............................................................. 19
`
`The Process Claims Are Not Anticipated (Claims 21-23). ................ 20
`
`II.
`
`The 1:1 Sitagliptin DHP Salt Would Not Have Been Obvious. ................... 22
`
` WO ’498 is Disqualified as Prior Art to the Salt Claims For the
`Obviousness Inquiry. ........................................................................ 22
`
`1. Merck Reduced Claims 1-2, 17, 19, and 21-23 to Practice
`Prior to January 16, 2003. ....................................................... 23
`
`2. WO ’498 is Disqualified as Obviousness Prior Art
`Because its Subject Matter was Subject to a Common
`Obligation of Assignment to Merck. ....................................... 27
`
` WO ’498 Does Not Render Claims 3, 17, 19, and 21-23
`Obvious (Ground 3). ......................................................................... 28
`
` WO ’498 and Bastin Do Not Render Claims 1-3, 17, 19, and
`21-23 Obvious (Ground 4). ............................................................... 29
`
`1.
`
`The POSA Would Not Have Been Motivated to Pursue a
`Sitagliptin-Phosphoric Acid Salt, Much Less 1:1
`Sitagliptin DHP. ...................................................................... 30
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`Case IPR2020-00040 | U.S. Patent 7,326,708
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`2.
`
`3.
`
`4.
`
`The POSA Would Not Have Had a Reasonable
`Expectation of Success of Obtaining 1:1 Sitagliptin DHP. ...... 37
`
`Claim 3. .................................................................................. 38
`
`Claims 21-23........................................................................... 38
`
`III. The Crystalline Monohydrate Claim Would Not Have Been Obvious. ....... 39
`
`
`
`
`
`
`
`There Are Substantial Differences Between the Scope and
`Content of the Prior Art and the Claimed Invention. ......................... 40
`
`The POSA Would Not Have Had a Reasonable Expectation of
`Success of Obtaining a Crystalline Monohydrate. ............................. 44
`
`1.
`
`2.
`
`The POSA Would Not Have Reasonably Expected a
`Crystalline Monohydrate of 1:1 Sitagliptin DHP to Exist........ 45
`
`The POSA Would Not Have Had a Reasonable
`Expectation of Obtaining a Crystalline Monohydrate. ............. 49
`
`The POSA Would Not Have Been Motivated to Pursue a
`Crystalline Monohydrate. .................................................................. 53
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Selecting Sitagliptin or Sitagliptin HCl as a Lead
`Compound. ............................................................................. 54
`
`Selecting 1:1 Sitagliptin Dihydrogenphosphate. ..................... 55
`
`Selecting Crystalline 1:1 Sitagliptin DHP. .............................. 55
`
`Selecting a Crystalline Hydrate of 1:1 Sitagliptin DHP. .......... 56
`
`Selecting a Crystalline Monohydrate of 1:1 Sitagliptin
`DHP. ....................................................................................... 59
`
`IV. The Claimed Salt and Crystalline Hydrate Exhibit Unexpected
`Properties. ................................................................................................... 60
`
`CONCLUSION .................................................................................................... 64
`
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`TABLE OF AUTHORITIES
`
`
`Amgen, Inc. v. Chugai Pharm. Co.,
`927 F.2d 1200 (Fed. Cir. 1991) ........................................................................ 49
`
`Bayer Pharma AG v. Watson Laboratories, Inc.,
`874 F.3d 1316 (Fed. Cir. 2017) ........................................................................ 31
`
`Cooper v. Goldfarb,
`154 F.3d 1321 (Fed. Cir. 1998) ........................................................................ 23
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ........................................................................ 42
`
`Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) ........................................................................ 42
`
`Eli Lilly & Co. v. Zenith Goldline Pharm., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) .................................................................. 13, 14
`
`Grunenthal GmbH v. Alkem Labs. Ltd.,
`919 F.3d 1333 (Fed. Cir. 2019) ................................................................. passim
`
`Impax Labs., Inc. v. Aventis Pharm. Inc.,
`468 F.3d 1366 (Fed. Cir. 2006) ........................................................................ 14
`
`In re Armodafinil Patent Litig. Inc.,
`939 F. Supp. 2d 456 (D. Del. 2013) .......................................................... passim
`
`In re Depomed Patent Litig.,
`2016 WL 7163647 (D.N.J. Sept. 30, 2016) ...................................................... 55
`
`In re Gleave,
`560 F.3d 1331 (Fed. Cir. 2009) ........................................................................ 12
`
`In re Kumar,
`418 F.3d 1361 (Fed. Cir. 2005) .................................................................. 51, 52
`
`In re Robertson,
`169 F.3d 743 (Fed. Cir. 1999) .......................................................................... 18
`
`In re Steed,
`802 F.3d 1311 (Fed. Cir. 2015) ........................................................................ 23
`
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`
`
`Janssen Prods. L.P. v. Lupin Ltd.,
`109 F. Supp. 3d 650 (D.N.J. 2014) ................................................. 41, 42, 46, 55
`
`Kowa Co., Ltd. v. Amneal Pharm.,
`2017 WL 10667089 (S.D.N.Y. Sept. 19, 2017 ..................................... 41, 43, 54
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ......................................................................................... 40
`
`Merck & Cie v. Watson Labs., Inc.,
`125 F. Supp. 3d 503 (D. Del. 2015), rev’d on other grounds, 822
`F.3d 1347 (Fed. Cir. 2016) ............................................................................... 43
`
`Merck Sharp & Dohme Corp. v. Hospira Inc.,
`2016 WL 5872620 (D. Del. July 10, 2016) ..................................................... 18
`
`Merck Sharp & Dohme Corp. v. Sandoz Inc.,
`2015 WL 5089543 (D.N.J. Aug. 27. 2015) ...................................................... 32
`
`Millennium Pharms., Inc. v. Sandoz, Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) ........................................................................ 53
`
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .............................................................. 7, 20, 21
`
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.,
`851 F.3d 1270 (Fed. Cir. 2017) .................................................................. 18, 19
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ........................................................................ 54
`
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) .......................................................................... 8
`
`Pfizer Inc. v. Mylan Pharm. Inc.,
`71 F. Supp. 3d 458 (D. Del. 2014) ....................................................... 10, 32, 34
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2017) .................................................................. 32, 60
`
`Sanofi-Synethelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) ............................................................ 10, 36, 37
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`Sanofi-Synthelabo v. Apotex Inc.,
`492 F. Supp. 2d 353 (S.D.N.Y. 2007) .................................................. 38, 60, 64
`
`Shire LLC v. Amneal Pharm., LLC,
`2014 WL 2861430 (D.N.J. June 23, 2014) ..................................... 10, 11, 32, 33
`
`Takeda Pharm. Co. v. Handa Pharm., LLC,
`2013 WL 9853725 (N.D. Cal. Oct. 17, 2013)................................. 42, 44, 45, 53
`
`Trintec Indus., Inc. v. Top-U.S.A. Corp.,
`295 F.3d 1292 (Fed. Cir. 2002) ........................................................................ 16
`
`U.S. Water Servs., Inc. v. Novozymes A/S,
`843 F.3d 1345 (Fed. Cir. 2016) ........................................................................ 17
`
`Valeant Int’l (Barbados) SRL v. Watson Pharm., Inc.,
`2011 WL 6792653 (S.D. Fla. Nov. 8, 2011) .................................................... 10
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA, LLC,
`683 F.3d 1356 (Fed. Cir. 2012) .................................................................... 8, 11
`
`Amneal Pharm. LLC v. Purdue Pharma L.P.,
`IPR2016-01412, Paper 9 (P.T.A.B. Feb. 14, 2017) .......................................... 32
`
`Argentum Pharm. LLC v. Cipla Ltd.,
`IPR2017-00807, Paper 19 (P.T.A.B. Oct. 30, 2017)................................... 14, 43
`
`Argentum Pharmaceuticals LLC v. Merck Patentgesellschaft,
`IPR2018-00423, Paper 7 (P.T.A.B. July 23, 2018)..................................... 43, 54
`
`Celanese Int’l Corp. v. Daicel Corp.,
`IPR2017-00163, Paper 46 (P.T.A.B. May 3, 2018) .......................................... 32
`
`Corning Inc. v. DSM IP Assets B.V.,
`IPR2013-00053, Paper 66, 21 (P.T.A.B. May 1, 2014) .................................... 28
`
`Ex parte Humber,
`217 U.S.P.Q. 265 (Bd. App. 1961) ................................................................... 63
`
`Gnosis S.p.A v. South Alabama Medical Science Foundation,
`IPR2013-00116, Paper 68 (P.T.A.B. June 20, 2014) ........................................ 32
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`
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`Limelight Networks, Inc., v. Akamai Techs., Inc.,
`IPR2017-00349, Paper 7, 27-28 (P.T.A.B. May 30, 2017) ............................... 28
`
`Lupin Ltd. v. Janssen Sciences Ireland UC,
`IPR2015-01030, Paper 17 (P.T.A.B. Oct. 16, 2015).................................. passim
`
`Mylan Pharms., Inc. v. Gilead Sciences, Inc.,
`IPR2014-00886, Paper 22 (P.T.A.B. Nov. 19, 2015) ....................................... 33
`
`Unified Patents Inc. v. Dynamic Data Techs., LLC,
`IPR2019-01085, Paper 12 (P.T.A.B. Dec. 3, 2019) .......................................... 23
`
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`PATENT OWNER’S EXHIBIT LIST
`
`
`Description
`Exhibit
`EX2001 Declaration of Bruce R. Genderson in Support of Pro Hac Vice
`Admission
`EX2002 Declaration of Vicky K. Vydra
`EX2003 Declaration of Robert M. Wenslow, Ph.D.
`EX2004 Declaration of Russell R. Ferlita
`EX2005 Declaration of Joanne Diddle
`Scheduling Order, In re Sitagliptin Phosphate (’708 & ’921)
`EX2006
`Patent Litigation, No. 1:19-md-02902-RGA (D. Del. Aug. 23,
`2019)
`EX2007 Order, Merck Sharp & Dohme Corp. v. Mylan Pharmaceuticals,
`Inc., No. 1:19-cv-00101-IMK (N.D. W. Va. Aug. 2, 2019)
`EX2008 Defendants’ Initial Invalidity Contentions, In re Sitagliptin
`Phosphate (’708 & ’921) Patent Litigation, No. 1:19-md-02902-
`RGA (D. Del. Oct. 25, 2019) (Excerpt)
`EX2009 Certified Assignment Record – US 7,326,708
`EX2010 Certified Assignment Record – WO 03/004498
`EX2011 U.S. Patent No. 9,718,880 (cited in Amgen Inc. v. Alexion Pharms.
`Inc., IPR2019-00740, Paper 15 (P.T.A.B. Aug. 20, 2019))
`EX2012 U.S. Patent No. 7,919,499 (cited in Amneal Pharmaceuticals LLC
`v. Alkermes Pharma Ireland Limited, IPR2018-00943, Paper 8
`(P.T.A.B. Nov. 7, 2018))
`EX2013 U.S. Patent No. 9,182,027 (cited in Fox Factory, Inc. v. SRAM,
`LLC, IPR2016-01876, Paper 8 (P.T.A.B. Apr. 3, 2017))
`EX2014 Declaration of Anthony H. Sheh
`EX2015 U.S. District Court for the District of Delaware, Civil Docket for
`Case # 1:19-md-2902-RGA (as of April 13, 2020)
`Stipulation and [Proposed] Order to Amend Scheduling Order, In
`re Sitagliptin Phosphate (’708 & ’921) Patent Litigation, No. 19-
`2902-RGA (D. Del. Mar. 16, 2020), ECF No. 83
`EX2017 U.S. District Court for the Northern District of West Virginia,
`Civil Docket for Case # 1:19-cv-00101-IMK (as of April 13, 2020)
`EX2018 Defendant’s Answer to Plaintiff’s Complaint and Counterclaims,
`Merck Sharp & Dohme Corp. v. Mylan Pharmaceuticals Inc., No.
`19-cv-101-IMK (N.D. W. Va. May 31, 2019), ECF No. 32
`
`EX2016
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`Case IPR2020-00040 | U.S. Patent 7,326,708
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`Exhibit
`EX2019
`
`Description
`Joint Quarterly Status Report, Merck Sharp & Dohme Corp. v.
`Mylan Pharmaceuticals Inc., No. 19-cv-101-IMK (N.D. W. Va.
`Jan. 3, 2020), ECF No. 50
`EX2020 REDACTED VERSION, Brief in Support of Mylan
`Pharmaceuticals Inc. and Mylan Inc.’s Motion to Dismiss for
`Improper Venue and Failure to State a Claim, Merck Sharp &
`Dohme Corp. v. Mylan Pharmaceuticals, Inc., No. 19-cv-315-
`RGA (D. Del. Mar. 28, 2019), ECF No. 15
`EX2021 U.S. Judicial Panel on Multidistrict Litigation, Civil Docket for
`Case # MDL No. 2902
`EX2022 Memorandum in Support of Motion to Transfer, In re Sitagliptin
`Phosphate (’708 & ’921) Patent Litigation, MDL No. 2902
`(J.P.M.L. May 15, 2019), ECF No. 1-1
`In re Sitagliptin Phosphate (’708 & ’921) Patent Litigation, 402 F.
`Supp. 3d 1366 (J.P.M.L. 2019)
`EX2024 Oral Order, Plastic Omnium Advanced Innovation and Research v.
`Donghee America Inc., No. 16-187-LPS (D. Del. Oct. 27, 2017),
`ECF No. 196
`EX2025 Declaration of Alexander S. Zolan in Support of Pro Hac Vice
`Admission
`EX2026 Declaration of Elise M. Baumgarten in Support of Pro Hac Vice
`Admission
`
`EX2023
`
`EX2027 TO EX2031 Reserved
`
`EX2032 U.S. Patent No. 8,309,724
`EX2033 WO 2013/001457
`EX2033 to EX2040 Reserved
`
`Transcript of July 15, 2020 Telephonic Hearing
`EX2041
`EX2042 A.T.M. Serajuddin & Pudipeddi, Salt-Selection Strategies, in
`HANDBOOK OF PHARMACEUTICAL SALTS (P.H. Stahl & C.G.
`Wermuth, eds., 2002)
`EX2043 U.S. Patent No. 8,329,696
`EX2044 WO 2012/166420
`Pandey et al., Importance of Polymorphs and Salts in the
`EX2045
`Pharmaceutical Industry, in DRUG DISCOVERY AND
`DEVELOPMENT, VOLUME 2: DRUG DEVELOPMENT (Mukund S.
`Chorghade ed., 2007)
`EX2046 Vippagunta et al., Crystalline Solids, 48 ADVANCED DRUG
`DELIVERY REVIEWS 3 (2001)
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`Case IPR2020-00040 | U.S. Patent 7,326,708
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`EX2051
`
`EX2107
`
`Description
`Exhibit
`EX2047 Reutzel-Edens et al., Anhydrates and Hydrates of Olanzapine:
`Crystallization, Solid-State Characterization, and Structural
`Relationships, 3 CRYSTAL GROWTH & DESIGN 897 (2003)
`EX2048 U.S. Patent No. 7,056,942
`EX2049 Bernstein, Crystal Growth, Polymorphism and Structure-Property
`Relationships in Organic Crystals, 26 J. PHYS. D. APPL. PHYS. B66
`(1993)
`EX2050 Bernstein, POLYMORPHISM IN MOLECULAR CRYSTALS (2002)
`(Chapter 3)
`Transcript of Aug. 6, 2020 Deposition of Mukund Chorghade,
`Ph.D.
`EX2101 Declaration of Allan S. Myerson, Ph.D.
`EX2102 Curriculum Vitae of Allan S. Myerson, Ph.D.
`EX2103 Declaration of Adam J. Matzger, Ph.D.
`EX2104 Curriculum Vitae of Adam J. Matzger, Ph.D.
`EX2105 Declaration of Lou Ann Eader
`EX2106
`Synopsis and Comprehensive Study Summary from the Clinical
`Study Report for Protocol 005, dated November 15, 2005 (excerpt)
`Synopsis and Comprehensive Study Summary from the Clinical
`Study Report for Protocol 006, dated April 1, 2005 (excerpt)
`EX2108 Module 3.2.P.5.4 Batch Analyses from Januvia® NDA, dated
`November 14, 2005 (excerpt)
`EX2109 Declaration of Gary Herman, M.D.
`EX2110
`Email Summary of December 9, 2002, Meeting Re: Clinical
`Development of MK-0431
`January 3, 2003 Email Re: DRAFT Preliminary Interim Analysis
`Memo/RMC Background Slides - L-224715
`EX2112 Demuth et al., Single Dose Treatment of Diabetic Patients by the
`DP IV Inhibitor P32/98, 49 DIABETES A102 (2000)
`Pospisilik et al., Long-Term Treatment with the Dipeptidyl
`Peptidase IV Inhibitor P32/98 Causes Sustained Improvements in
`Glucose Tolerance, Insulin Sensitivity, Hyperinsulinemia, and β-
`Cell Glucose Responsiveness in VDF (fa/fa) Zucker Rats, 51
`DIABETES 943 (2002)
`Thornberry & Weber, Discovery of JANUVIA (Sitagliptin), a
`Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of
`Type 2 Diabetes, 7 CURRENT TOPICS IN MEDICINAL CHEMISTRY
`557 (2007)
`
`EX2111
`
`EX2113
`
`EX2114
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`Case IPR2020-00040 | U.S. Patent 7,326,708
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`EX2120
`
`EX2121
`EX2122
`
`Description
`Exhibit
`EX2115 Rothenberg et al., Treatment with a DPP-IV Inhibitor, NVP-
`DPP728, Increases Prandial Intact GLP-1 Levels and Reduces
`Glucose Exposure in Humans, 49 DIABETES 160-OR (2000)
`Second Declaration of Robert M. Wenslow, Ph.D.
`EX2116
`EX2117 WO 2005/020920
`EX2118 WO 2005/072530
`EX2119 Compilation of L-224715 Phosphate Salt Anhydrous Polymorph
`Data
`Physical Characterization of L-224715-66839-113 (115) and -125
`(from ISAA)
`L-000224715 Monohydrate Evaluation
`Parallel Development of Multiple Crystal Forms for a New Drug
`Candidate: Selection of the Final Form via Integrated Chemical
`and Pharmaceutical Process Evaluation
`L-000224715 (MK-0431) Preliminary Market Formulation
`Development Report
`EX2124 Declaration of Stephen Howard Cypes
`EX2125 Merck Lab Notebook 66839 (Excerpt)
`EX2126
`S. Cypes Weekly Reports
`EX2127 Declaration of Karl B. Hansen, Ph.D.
`EX2128 Merck Lab Notebook 70130 (Excerpt)
`EX2129 Merck Lab Notebook 70316 (Excerpt)
`EX2130 Merck Lab Notebook 72471 (Excerpt)
`EX2131 K. Hansen Weekly Reports
`EX2132
`Email from M. Palucki to K. Hansen re Acid Salt Screen of L-
`224715 Free Base (and Attachment)
`Email from L. Shultz to K. Hansen re L-224715 salt selection
`EX2133
`Email from K. Hansen re L-224715 meeting follow-up
`EX2134
`EX2135 Delivery Sheet Lot 006F007
`EX2136 Delivery Sheet Lot 006F017
`EX2137
`L-000224715 Phosphate Salt Polymorph Screen
`EX2138
`Symyx Presentation L224715 H3PO4 Salt
`EX2139
`Email from C. Starbuck to K. Hansen re L-224,715 drying
`EX2140 Declaration of Rebecca Leigh Shultz, Ph.D.
`EX2141 Merck Lab Notebook 60659 (Excerpt)
`EX2142 Merck Lab Notebook 60659 Supplemental Data (Excerpt)
`EX2143 Merck Lab Notebook 26180 (Excerpt)
`EX2144 Merck Lab Notebook 26180 Supplemental Data (Excerpt)
`
`EX2123
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`Case IPR2020-00040 | U.S. Patent 7,326,708
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`EX2150
`
`EX2151
`
`EX2152
`
`Description
`Exhibit
`EX2145 Merck Lab Notebook 72917 (Excerpt)
`EX2146
`Preliminary Pharmaceutical Assessment of L-224715
`EX2147
`Pharmaceutical Evaluation of L-224715
`EX2148
`L-000224715 Preformulation Report
`EX2149
`Physico-chemical characteristics of L-000224715 phosphate salt,
`monohydrate form
`L. Shultz Merck Research Laboratories Progress Report December
`2001
`L. Shultz Merck Research Laboratories Progress Report January
`2002
`L. Shultz Merck Research Laboratories Progress Report February
`2002
`L. Shultz Merck Research Laboratories Progress Report March
`2002
`L. Shultz Merck Research Laboratories Progress Report September
`2002
`Email from C. Lindemann re: L-224715 Quick Update (and
`Attachment)
`Salt Selection for L-224715 and L-221869
`EX2156
`Email from I. Santos re: Salt selection for L-224715
`EX2157
`EX2158 December 7, 2002 Email re: Background Slides for Monday’s
`Meeting
`EX2159 Email from D. Zhang re: Physical Characterization of L-224715
`Phosphate
`EX2160 Rocco et al., Solid-State Characterization of Zanoterone, 122 INT’L
`J. PHARMACEUTICS 17 (1995)
`Poole et al., Dissolution Behavior and Solubility of Anhydrous and
`Trihydrate Forms of Ampicillin, 57 J. PHARM. SCIS. 1945 (1968)
`EX2162 Kobayashi, Physiochemical Properties and Bioavailability of
`Carbamazepine Polymorphs and Dihydrate, 193 INT’L J.
`PHARMACEUTICS 137 (2000)
`EX2163 Morris et al., Advances in Pharmaceutical Materials and
`Processing, 1 PSTT 235 (1998)
`EX2164 Gavezzotti, Are Crystal Structures Predictable?, 27 ACC. CHEM.
`RES. 309 (1994)
`EX2165 Day, Investigating the Latent Polymorphism of Maleic Acid,
`CHEM. COMMUN. 54 (2006)
`
`EX2153
`
`EX2154
`
`EX2155
`
`EX2161
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`Case IPR2020-00040 | U.S. Patent 7,326,708
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`EX2167
`
`Description
`Exhibit
`EX2166 Vishweshwar et al., The Predictably Elusive Form II of Aspirin,
`127 J. AM. CHEM. SOC. 16802 (2005)
`Fagan et al., An Ab Initio Approach to Crystal Structure
`Determination Using High-Resolution Powder Diffraction and
`Computational Chemistry Techniques: Application to 6,13-
`Dichlorotriphendioxazine, 7 CHEM. MATER. 2322 (1995)
`EX2168 Dunitz & Bernstein, Disappearing Polymorphs, 28 ACC. CHEM.
`RES. 193 (1995)
`EX2169 Bavin, Polymorphism in Process Development, CHEMISTRY &
`INDUSTRY 527 (Aug. 21, 1989)
`EX2170 Maddox, Crystals from First Principles, 335 NATURE 201 (1988)
`EX2171 U.S. Patent No. 6,861,426
`EX2172 Guillory, Generation of Polymorphs, Hydrates, Solvates, and
`Amorphous Solids, in POLYMORPHISM IN PHARMACEUTICAL SOLIDS
`(H.G. Brittain ed., 1st ed. 1999)
`EX2173 Kirwan & Orella, Crystallization in the Pharmaceutical and
`Bioprocessing Industries, in HANDBOOK OF INDUSTRIAL
`CRYSTALLIZATION (Allan S. Myerson ed., 2001)
`Taleb et al., Equilibrium Kinetics of Lysozome Crystallization
`Under an External Electrical Field, 232 J. CRYSTAL GROWTH 250
`(2001)
`EX2175 Garetz et al., Nonphotochemical, Polarization-Dependent, Laser-
`Induced Nucleation in Supersaturated Aqueous Urea Solutions, 77
`PHYS. REV. LETTERS 3475 (1996)
`EX2176 Ratsimba et al., Sonocrystallization: The End of Empiricism?, 17
`KONA POWDER & PARTICLE J. 38 (1999)
`International Conference on Harmonisation; Guidance on
`Impurities: Residual Solvents, 62 FR 67377 (Dec. 24, 1997)
`EX2178 Byrn et al., Solid-State Pharmaceutical Chemistry, 6 CHEM.
`MATER. 1148 (1994)
`EX2179 Myerson & Ginde, Crystals, Crystal Growth, and Nucleation, in
`HANDBOOK OF INDUSTRIAL CRYSTALLIZATION (Allan S. Myerson
`ed., 2001)
`EX2180 Rodriguez-Hornedo & Murphy, Significance of Controlling
`Crystallization Mechanisms and Kinetics in Pharmaceutical
`Systems, 88 J. PHARM. SCIS. 651 (1999)
`EX2181 Chopra, Surprises in Crystal Chemistry of Sugars, 17 ORG.
`PROCESS RES. DEV. 455 (2012)
`
`EX2174
`
`EX2177
`
`vi
`
`
`
`
`
`Case IPR2020-00040 | U.S. Patent 7,326,708
`
`Description
`
`Exhibit
`EX2182 U.S. Patent No. 7,157,429
`EX2183 U.S. Patent No. 5,939,560
`EX2184 Yu, Amorphous Pharmaceutical Solids: Preparation,
`Characterization and Stabilization, 48 ADVANCED DRUG
`DELIVERY REVIEWS 27 (2001)
`Smith & March, MARCH’S ADVANCED ORGANIC CHEMISTRY:
`REACTIONS, MECHANISMS, AND STRUCTURE (2001) (excerpt)
`EX2186 WO 2010/131035
`EX2187 U.S. Patent No. 8,334,319
`EX2188 Muhtadi & Hassan, Codeine Phosphate, 10 ANALYTICAL PROFILES
`OF DRUG SUBSTANCES 93 (1981)
`Langes et al., Codeine Dihydrogen Phosphate Hemihydrate, C65
`ACTA CRYST. O419 (2009)
`EX2190 Caira, Crystalline Polymorphism of Organic Compounds, 198
`TOPICS IN CURRENT CHEMISTRY, 163 (1998)
`EX2191 U.S. Patent No. 6,124,305
`EX2192 Chyall Second Declaration, March 7, 2012
`EX2193 A.T.M. Serajuddin, Salt Formation to Improve Drug Solubility, 59
`ADVANCED DRUG DELIVERY REVIEWS, 603 (2007)
`S.M. Berge, L.D. Bighley, & D.C. Monkhouse, Pharmaceutical
`Salts, 66 J. PHARM. SCIS 1 (1977)
`EX2195 G. Davies, Changing the Salt, Changing the Drug, 266 PHARM. J.
`322 (2001)
`EX2196 R.K. Verbeeck, I. Kanfer, & R.B. Walker, Generic substitution:
`The use of medicinal products containing different salts and
`implications for safety and efficacy, 28 EURO J. PHARM. SCIS 1
`(2006)
`P.L. Gould, Salt selection for basic drugs, 33 INT’L J.
`PHARMACEUTICS 201 (1986)
`EX2198 Ammonium phosphate monobasic, Sigma Aldrich Catalog
`EX2199 Ammonium phosphate dibasic, Sigma Aldrich Catalog
`EX2200
`Triammonium phosphate trihydrate, Combi-Blocks
`EX2201 Handbook of Pharmaceutical Excipients (4th ed.)
`J.A. Tamada & C.J. King, Extraction of Carboxylic Acids by
`EX2202
`Amine Extractants, Lawrence Berkeley Laboratory University of
`California Ph.D. Thesis, Received March 27, 1999
`
`EX2185
`
`EX2189
`
`EX2194
`
`EX2197
`
`vii
`
`
`
`
`
`Case IPR2020-00040 | U.S. Patent 7,326,708
`
`EX2205
`
`EX2206
`
`Description
`Exhibit
`EX2203 B. Grimball et al., Cyclohexylamine inexplicably induces antennae
`loss in Formosan subterranean termites (Coptotermes formosanus
`Shiraki): cyclohexylamine hydrogen phosphate salts are novel
`termiticides, 73 SOC. CHEM. INDUS. 2039 (2017)
`EX2204 A.B. Bjåen et al., Polymorphism of chloroquine diphosphate, 92
`INT’L J. PHARMACEUTICS 183 (1993)
`F. Takusagawa & T. F. Koetzle, A Study of the Charge Density in
`Putrescine Diphosphate at 85 K, 35 ACTA CRYST. 867 (1979)
`J.R. Rubin, Structure of the Anti-Malarial Drug Primaquine
`Diphosphate, 48 ACTA CRYST. 379 (1992)
`EX2207 Khan et al., The Crystal Structure of Diammonium Hydrogen
`Phosphate, (NH4)2HPO4, 28 ACTA CRYST. 2065 (1972)
`EX2208 Cotton et al., Structure of Bis(methylguanidinium) Monohydrogen
`Orthophosphate. A Model for the Arginine-Phosphate Interactions
`at the Active Site of Staphyloccocal Nuclease and Other
`Phosphohydrolytic Enzymes, 96 J. AM. CHEM. SOC. 4471 (1974)
`Low et al., Structure of Bis(guaninium) Hydrogenphosphate 2.5-
`Hydrate, 42 ACTA CRYST. 1045 (1986)
`EX2210 Adams & Small, The Crystal Structure of Bisguanidinium
`Hydrogen Phosphate Monohydrate, B32 ACTA CRYST. 832 (1976)
`EX2211 Averbuch-Pouchot & Durif, Structures of Ethylenediammonium
`Monohydrogentetraoxophosphate(V) and Ethylenediammonium
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`EX2212 Baouab & Jouini, Crystal Structures and Thermal Behavior of Two
`New Organic Monophosphates, 141 J. SOLID STATE CHEM., 343
`(1998)
`EX2213 Demir et al., N-(2-Hydroxyethyl)ethylene-diammonium
`hydrogenphosphate monohydrate, C58 ACTA CRYSTA. o407 (2002)
`EX2214 Kamoun et al., Chemical Preparations, Main Crystallographic and
`Structural Features of Two New Monophosphates:
`[NH3(CH2)3NH3].HPO4.H2O and
`[NH3(CH2)2NH(CH2)2NH3].HPO4.2H2O, 310 C.R. ACAD. SCI.
`PARIS 733 (1990)
`EX2215 M. L. Mrad et al., Tris(5-amino-1H-1,2,4-triazol-4-ium)
`dihydrogenphosphate hydrogenphosphate trihydrate, 68 ACTA
`CRYSTA. o3257 (2012)
`
`EX2209
`
`viii
`
`
`
`
`
`Case IPR2020-00040 | U.S. Patent 7,326,708
`
`Exhibit
`EX2216
`
`Description
`J. Fábry R. Krupková, P. Vanek, & M. Dusek,
`Tris(methylammonium) hydrogenphosphate dihydrogenphosphate,
`62 ACTA CRYSTA. o73 (2006)
`EX2217 A.E. Cohen et al., Structure and Thermal Vibrations of Spermine
`Phosphate Hexahydrate from Neutron Diffraction Data at 125 K,
`B53 ACTA CRYST. 787 (1997)
`EX2218 Newman & Stahly, Form Selection of Pharmaceutical
`Compounds, in HANDBOOK OF PHARMACEUTICAL ANALYSIS
`(Ohannesian ed., 2002)
`EX2219 Cruz-Cabeza, Acid-Base Crystalline Complexes and the pKa rule,
`14 CRYSTENGCOMM. 6362 (2012)
`EX2220 WO 2012/166420
`EX2221 Atwood First Affidavit, June 6, 2011
`EX2222 Atwood Second Affidavit, August 20, 2012
`EX2223 Atwood Third Affidavit, September 13, 2013
`EX2224 Chyall Third Declaration, February 19, 2013
`EX2225 Chyall First Declaration, August 3, 2010
`EX2226 Chyall Lab Notebook 4031
`EX2227
`Transcript of Jan. 29, 2015 Chyall Testimony
`EX2228 Matzger Lab Notebook 3
`EX2229 Matzger Lab Notebook 4
`EX2230 Wong-Foy Notebook
`EX2231 Collection of underlying data related to the Declaration of Adam J.
`Matzger
`EX2232 Galbraith Lab Notebook
`EX2233 D.E. Newberry & N.W.M. Ritchie, Performing elemental
`microanalysis with high accuracy and high precision by scanning
`electron microscopy/silicon drift detector energy-dispersive X-ray
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`P.K. Kipkemboi & A.J. Easteal, Vibrational spectroscopic studies
`of aqueous solutions of tert-butyl alcohol and terti-butylamine, 80
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`T. Visser & J.H. van der Maas, Systematic Interpretation of Raman
`Spectra of Organic Compounds, 7 J. RAMAN SPECTROSCOPY 279
`(1978)
`
`EX2234
`
`EX2235
`
`ix
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`
`
`Case IPR2020-00040 | U.S. Patent 7,326,708
`
`EX2239
`
`Description
`Exhibit
`EX2236 M. Xie, Y. Qi & Y. Hu, Conformational Equilibrium and
`Hydrogen Bonding in Liquid 2-Phenylethylamine Explored by
`Raman Spectroscopy and Theoretical Calculations, 115 J. PHYS.
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`Raman Spectrometry, 6 J. RAMAN SPECTROSCOPY 74 (1977)
`EX2238 A.M. Amado, M.M. Nolasco & P.J.A. Ribeiro-Claro, Proving
`Pseudopolymorphic transitions in Pharmaceutical Solids using
`Raman Spectroscopy: Hydration and Dehydration of Theophylline,
`96 J. PHARM. SCIS. 1366 (2007)
`J.M. Rollinger & A. Burger, Physico-Chemical Characterization
`of Hydrated and Anhydrous Crystal Forms of Amlodipine Besylate,
`68 J. THERMAL ANALYSIS & CALORIMETRY 361 (2002)
`EX2240 C. Lester et al., Dehydration of Risedronate Hemi-Pentahydrate:
`Analytical and Physical Characterization, 95 J. PHARM. SCIS. 2631
`(2006)
`EX2241 A.M. Amado, M.M. Nolasco & P.J.A. Ribeiro-Claro, Insights into
`phase stability of anhydrous/hydrate systems: a Raman-based
`methodology, 41 J. RAMAN SPECTROSCOPY, 340 (2010)
`EX2242 N.C.F. Stofella et al., Solid-State Characterization of Different
`Crystalline Forms of Sitagliptin, 12 MATERIALS 1 (2019)
`EX2243 B. Rees, L. Jenner & m. Yusupov, Bulk-solvent correction in large
`macromolecular structures, 61 ACTA CRYSTA. 1299 (2005)
`EX2244 NIST Solubility Table (excerpt)
`EX2245 Balkan et al., Inhibition of Dipeptidyl Peptidase IV with NVP-
`DPP728 Increases Plasma GLP-1 (7-36 Amide) concentrations
`and Improves Oral Glucose Tolerance in Obese Zucker Rats, 42
`DIABETOLOGIA 1324 (1999)
`EX2246 R.I. Ellin and J. H. Wills, Oximes Antagonistic to Inhibitors of
`Cholinesterase, 53 J. PHARM. SCI. 1143 (1964)
`EX2247 H.M. Koehler & J.J. Hefferren, Mineral Acid Salts of Lidocaine,
`53 J. PHARM. SCIS 1126 (1964)
`EX2248 V.C. Walton, M.R. Howlett, & G.B. Selzer, Anhydrotetracycline
`and 4-Epianhydrotetracycline in Market Tetracyclines and Aged
`Tetracycline Products, 59 J. PHARM. SCIS, 1160 (1970)
`EX2249 B. Hoener, T.D. Sokoloski, L.A. Mitscher & L. Malspeis, Kinetics
`of Dehydration of Epitetracycline in Solution, 63 J. PHARM. SCIS.
`1901 (1974)
`
`x
`
`
`
`Case IPR2020-00040 | U.S. Patent 7,326,708
`
`Description
`Exhibit
`EX2250 U. V. Shah et al., Effect of crystal habits on the surface energy and
`cohesion of crystalline powders, 472 INT’L J. PHARMACEUTICS 140
`(2014)
`EX2251 N. Rasenack and B.W. Muller, Crystal habit and tableting
`behavior, 244 INT’L J. PHARMACEUTICS 45 (2002)
`F. Podczeck and Y. Miah, The influence of particle size and shape
`on the angle of internal friction and the flow factor of unlubricated
`and lubricated powders, 144 INT’L J. PHARMACEUTICS 187 (1996)
`EX2253 U.S. Patent No. 8,518,987
`Janczak & Perpetuo, Hexakis(melaminium)
`EX2254
`Tetrakis(dihydrogenphosphate) Monohydrogenphosphate
`Tetrahydrate, C58 ACTA CRYST. o455 (2002)
`
`EX2252
`
`
`
`
`
`xi
`
`
`
`Case IPR2020-00040 | U.S. Patent 7,326,708
`
`
`
`Merck’s U.S. Patent No. 7,326,708 (“the ’708 patent”) is directed to novel
`
`forms of the compound sitagliptin. Unbeknownst to anyone in the prior art, the
`
`properties of sitagliptin’s freebase and hydrochloride salt forms caused problems
`
`for development of an oral drug formulation. Merck solved these problems with a
`
`brand-new sitagliptin salt—a dihydrogenphosphate salt with a 1:1 stoichiometric
`
`ratio (“1:1 sitagliptin DHP”)—and then a crystalline monohydrate form of that salt.
`
`Neither was taught anywhere in the art, and their very existence was unpredictable.
`
`They were new and anything but obvious. Their unexpectedly superior properties,
`
`moreover, paved the way to multiple highly successful diabetes medications,
`
`including Januvia®.
`
`1. Mylan’s Peti