(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`1111111111111111 IIIIII IIIII IIIII IIIII IIII I II Ill lllll lllll lllll lllll lllll 11111111111111111111111
`Organization
`International Bureau
`(10) International Publication Number
`WO 2012/166420 Al
`
`~ ~
`
`(43) International Publication Date
`6 December 2012 (06.12.2012) WIPO I PCT
`
`(51) International Patent Classification:
`A61K 31/4985 (2006.01) A61P 3/10 (2006.01)
`
`(21) International Application Number:
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`PCT/US2012/0389l 7
`
`22 May2012 (22.05.2012)
`
`English
`
`English
`
`(84)
`
`(30) Priority Data:
`61/490,819
`
`27 May20ll (27.05.2011)
`
`us
`(71) Applicant (for all designated States except US): MERCK
`SHARP & DOHME CORP. [US/US]; 126 East Lincoln
`Avenue, Rahway, NJ 07065-0907 (US).
`
`(72)
`(75)
`
`Inventor; and
`Inventor/Applicant (for US only): ATWOOD, Jerry, L.
`[US/US]; 5704 Short Line Drive, Columbia, MO 65203
`(US).
`
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA,CH,CL,CN,CO,CR,CU,CZ,DE,DK,DM,DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ,
`OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`
`Declarations under Rule 4.17:
`
`as to applicant's entitlement to apply for and be granted a
`patent (Rule 4.17 (ii))
`
`;;;;;;;;;;;;;;
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`;;;;;;;;;;;;;; -
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`- --------------------------------------------
`- (54) Title: PHOSPHORIC ACID SALTS OF SITAGLIPTIN
`----
`--;;;;;;;;;;;;;; -
`----;;;;;;;;;;;;;; -
`
`(74) Common Representative: MERCK SHARP & DOHME
`CORP.; 126 East Lincoln Avenue, Rahway, NJ 07065-
`0907 (US).
`
`as to the applicant's entitlement to claim the priority of the
`earlier application (Rule 4.17 (iii))
`(81) Designated States (unless otherwise indicated, for every Published:
`kind of national protection available): AE, AG, AL, AM,
`
`with international search report (Art. 21(3))
`
`Counts
`
`10000
`
`5000
`
`10
`
`20
`Position [0 2Theta]
`
`30
`
`FIG.1
`
`(57) Abstract: The present invention relates to
`novel phosphoric acid salts of 4-oxo-4-[3-(tri(cid:173)
`fluoromethyl)-5,6-dihydro[ l ,2,4 ]triazolo[ 4,3-
`a. ]pyrazin-7(8H)-yl]-l-(2,4,5-
`trifluorophenyl)butan-2-amine, and polymorphs,
`hydrates and solvates thereof, which are potent
`inhibitors of dipeptidyl peptidase-IV useful for
`the prevention and/or treatment of non-insulin
`dependent diabetes mellitus, also referred to as
`type 2 diabetes. The present invention also
`relates to the process for preparing the novel
`phosphoric acid salts of 4-oxo-4-[3-(trifluoro(cid:173)
`methyl)-5,6-dihydro[ l ,2,4 ]triazolo [ 4,3-
`a. ]pyrazin-7(8H)-yl]-l-(2,4,5-
`trifluorophenyl)butan-2-amine, as well as phar(cid:173)
`maceutical compositions containing the novel
`phosphoric acid salts, and methods of use thereof
`for the treatment of diabetes, obesity, and high
`blood pressure.
`
`Merck Exhibit 2220, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
`
`PCT/0S2012/038917
`
`TITLE OF THE INVENTION
`PHOSPHORIC ACID SAL TS OF SITAGLIPTIN
`
`FIELD OF THE INVENTION
`The present invention relates to novel phosphoric acid salts of 4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l ,2,4 ]-triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, also known as sitagliptin, which is a potent inhibitor of dipeptidyl
`peptidase-N. More particularly, the invention relates to the bis(sitagliptin) phosphoric acid salt,
`the sitagliptin ammonia phosphoric acid salt, and the sitagliptin bis(phosphoric acid) salt, and
`polymorphs, hydrates and solvates thereof. These novel phosphoric .acid salts, and their
`polymorphs, hydrates and solvates, are useful for the treatment and prevention of diseases and
`conditions for which an inhibitor of dipeptidyl peptidase-N is indicated, in particular Type 2
`diabetes, obesity, and high blood pressure. The invention further concerns pharmaceutical
`compositions comprising the bis(sitagliptin) phosphoric acid salt, the sitagliptin ammonia
`phosphoric acid salt, and the sitagliptin bis(phosphoric acid) salt, and polymorphs, hydrates and
`solvates thereof, and methods of using these novel phosphoric acid salts, and their polymorphs,
`hydrates and solvates, to treat Type 2 diabetes, obesity, and high blood pressure. The invention
`further concerns processes for preparing the novel phosphoric acid salts of 4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l ,2,4 ]-triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, and polymorphs, hydrates and solvates thereof.
`
`BACKGROUND OF THE INVENTION
`Inhibition of dipeptidyl peptidase-N (DP-N), an enzyme that inactivates both glucose(cid:173)
`dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), represents a novel
`approach to the treatment and prevention of Type 2 diabetes, also known as non-insulin
`dependent diabetes mellitus (NIDDM). The therapeutic potential ofDP-N inhibitors for the
`treatment of Type 2 diabetes has been reviewed: C. F. Deacon and J.J. Holst, "Dipeptidyl
`peptidase N inhibition as an approach to the treatment and prevention of Type 2 diabetes: a
`historical perspective," Biochem. Biophys. Res. Commun., 294: 1-4 (2000); K. Augustyns, et al.,
`"Dipeptidyl peptidase N inhibitors as new therapeutic agents for the treatment of Type 2
`diabetes," Expert. Opin. Tuer. Patents, 13: 499-510 (2003); and D.J. Drucker, "Therapeutic
`potential of dipeptidyl peptidase N inhibitors for the treatment of Type 2 diabetes," Expert Opin.
`lnvestig. Drugs, 12: 87-100 (2003).
`WO 03/004498 (published 16 January 2003), assigned to Merck & Co., describes a class
`of beta-amino tetrahydrotriazolo[4,3-a]pyrazines, which are potent inhibitors ofDP-N and
`
`- 1 -
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`Merck Exhibit 2220, Page 2
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`therefore useful for the treatment of Type 2 diabetes. Specifically disclosed in WO 03/004498 is
`4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine. Pharmaceutically acceptable salts of this compound are
`generically encompassed within the scope of WO 03/004498. WO 05/003135, assigned to
`Merck & Co., describes other phosphoric acid salts of 4-oxo-4-(3-(trifluoromethyl)-5,6-
`dihydro(l ,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine.
`
`SUMMARY OF THE INVENTION
`The present invention is concerned with novel phosphoric acid salts of the dipeptidyl
`peptidase-IV (DP-IV) inhibitor 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro[l ,2,4 ]triazolo[ 4,3-
`a ]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine and polymorphs, hydrates and
`solvates thereof, in particular the bis(sitagliptin) phosphoric acid monohydrate salt, the
`bis(sitagliptin) monohydrogen phosphate trihydrate salt, the sitagliptin ammonia phosphoric acid
`2.5 hydrate salt, and the sitagliptin bis(phosphoric acid) salt. The novel phosphoric acid salts,
`polymorphs and hydrates of the present invention have advantages in the preparation of
`pharmaceutical compositions of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[ 1,2,4 ]-triazolo[ 4,3-
`a ]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine, such as physical stability and the
`resulting ease of processing, handling, and dosing. The invention also concerns pharmaceutical
`compositions containing the novel phosphoric acid salts, polymorphs, hydrates and solvates
`thereof, as well as methods for using them as DP-IV inhibitors, in particular for the prevention or
`treatment of Type 2 diabetes, obesity, and high blood pressure.
`
`BRIEF DESCRIPTION OF THE FIGURES
`FIG. 1 is a X-ray diffraction pattern of the crystalline trihydrate of the bis(sitagliptin)
`phosphoric acid salt of structural formula ill-a.
`FIG. 2 is a thermogravimetric analysis (TOA) curve of the crystalline trihydrate of the
`bis(sitagliptin) phosphoric acid salt of structural formula ill-a.
`FIG. 3 is a differential scanning calorimetry (DSC) curve of the crystalline trihydrate of
`the bis(sitagliptin) phosphoric acid salt of structural formula ill-a.
`FIG. 4 is a X-ray diffraction pattern of the crystalline monohydrate of the bis(sitagliptin)
`phosphoric acid salt of structural formula IV-a.
`FIG. 5 is a thermogravimetric analysis (TOA) curve of the crystalline monohydrate of the
`bis(sitagliptin) phosphoric acid salt of structural formula IV-a.
`FIG. 6 is a differential scanning calorimetry (DSC) curve of the crystalline monohydrate
`of the bis(sitagliptin) phosphoric acid salt of structural formula IV-a.
`
`-2-
`
`Merck Exhibit 2220, Page 3
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`IPR2020-00040
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`

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`PCT/0S2012/038917
`
`FIG. 7 is a X-ray diffraction pattern of the crystalline 2.5 hydrate of the sitagliptin
`ammonia phosphoric acid salt of structural formula VI-a.
`FIG. 8 is a thermogravimetric analysis (TOA) curve of the crystalline 2.5 hydrate of the
`sitagliptin ammonia phosphoric acid salt of structural formula VI-a.
`FIG. 9 is a differential scanning calorimetry (DSC) curve of the crystalline 2.5_hydrate of
`the sitagliptin ammonia phosphoric acid salt of structural formula VI-a.
`FIG. 10 is a X-ray diffraction pattern of the amorphous sitagliptin bis(phosphoric acid)
`salt of structural formula VII-a.
`FIG. 11 is a thermogravimetric analysis (TOA) curve of the amorphous sitagliptin
`bis(phosphoric acid) salt of structural formula VII-a.
`
`DETAILED DESCRIPTION OF THE INVENTION
`This invention provides novel phosphoric acid salts of 4-oxo-4-[3-(trifluoromethyl)-5,6-
`dihydro[ 1,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine
`(sitagliptin), which is the compound of structural formula I:
`
`F
`
`F
`
`and polymorphs, hydrates and solvates thereof. In a class of this embodiment, the present
`invention provides a bis-[ 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4 ]triazolo[ 4,3-a ]pyrazin-
`7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine] phosphoric acid trihydrate salt, a bis-[ 4-oxo-
`4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine] phosphoric acid monohydrate salt, a 4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)(cid:173)
`butan-2-amine ammonia phosphoric acid 2.5 hydrate salt, and a 4-oxo-4-[3-(trifluoromethyl)-5,6-
`dihydro[l,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)-butan-2-amine
`bis(phosphoric acid) salt, and polymorphs, and solvates thereof.
`The phosphoric acid salts of the present invention has a center of asymmetry at the
`stereogenic carbon atom indicated with an * and can thus occur as a racemate, racemic mixture,
`and single enantiomers, with all isomeric forms being included in the present invention. The
`
`-3 -
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`IPR2020-00040
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`
`separate enantiomers, substantially free of the other, are included within the scope of the
`invention, as well as mixtures of the two enantiomers.
`One embodiment of the present invention provides novel phosphoric acid salts of (2R)-4-
`oxo-4-[3-( trifluoromethyl)-5 ,6-dihydro[ 1,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, which is the compound of structural formula I-a (also known as
`sitagliptin free base):
`
`F
`
`F
`
`F
`
`(I-a)
`
`and polymorphs, hydrates and solvates thereof. In a class of this embodiment, the present
`invention provides a bis(sitagliptin) phosphoric acid trihydrate salt, a bis(sitagliptin) phosphoric
`acid monohydrate salt, a sitagliptin ammonia phosphoric acid 2.5 hydrate salt, and a sitagliptin
`bis(phosphoric acid) salt, and polymorphs, hydrates and solvates thereof.
`Another embodiment of the present invention provides novel phosphoric acid salts of
`(2S)-4-oxo-4-[3-( trifluoromethyl)-5 ,6-dihydro[ 1,2,4]triazolo[ 4,3-a ]pyrazin-7 (8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, which is the compound of structural formula 1-b:
`
`F
`
`F
`
`F
`
`N~N,
`~N'{N
`CF3
`
`(1-b)
`
`and polymorphs, hydrates and solvates thereof. In a class of this embodiment, the present
`invention provides a bis-[ (2S)-4-oxo-4-(3-( trifluoromethyl)-5 ,6-dihydro( 1,2,4 ]triazolo[ 4,3-
`a ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine] phosphoric acid trihydrate salt, a
`bis-[(2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-
`(2,4,5-trifluorophenyl)butan-2-amine] phosphoric acid monohydrate salt, a (2S)-4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine ammonia phosphoric acid 2.5 hydrate salt, and a (2S)-4-oxo-4-[3-
`
`-4-
`
`Merck Exhibit 2220, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
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`PCT/0S2012/038917
`
`(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-
`trifluorophenyl)butan-2-amine bis(phosphoric acid) salt, and polymorphs, and solvates thereof.
`Another embodiment of the present invention provides the bis-[4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine] phosphoric acid salt of structural formula II:
`
`F
`
`F
`
`2
`or a polymorph, hydrate and/or solvate thereof. In a class of this embodiment, the salt of
`structural formula II is a hydrate. In another class of this embodiment, the salt of structural
`formula II is crystalline. In another class of this embodiment, the salt of structural formula II is a
`crystalline hydrate. In another class of this embodiment, the salt of structural formula II is a
`trihydrate. In a subclass of this class, the trihydrate salt of structural formula II is crystalline. In
`another class of this embodiment, the salt of structural formula II is a monohydrate. In a subclass
`of this class, the monohydrate salt of structural formula II is crystalline.
`The salt of structural formula II is comprised of two molar equivalents of 4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, and one molar equivalent of phosphoric acid (H3P04).
`The trihydrate salt of structural formula II is comprised of two molar equivalents of 4-
`oxo-4-[3-( trifluoromethyl)-5 ,6-dihydro[l ,2,4 ]triazolo[ 4,3-a ]pyrazin-7 (8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of phosphoric acid (H3P04), and three
`molar equivalents of water.
`The monohydrate salt of structural formula II is comprised of two molar equivalents of 4-
`oxo-4-[3-(trifluoromethyl)-5 ,6-dihydro[l ,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of phosphoric acid (H3P04), and one molar
`equivalent of water.
`Another embodiment of the present invention provides the bis(sitagliptin) phosphoric
`acid salt, which corresponds to the bis-[(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-
`
`- 5 -
`
`Merck Exhibit 2220, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
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`PCT/0S2012/038917
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`dihydro[l,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-l-(2A,5-trifluorophenyl)butan-2-amine]
`phosphoric acid salt of structural formula II-a:
`
`F
`
`F
`
`F
`
`(II-a)
`
`2
`or a polymorph, hydrate and/or solvate thereof. In a class of this embodiment, the salt of formula
`II-a is a hydrate. In another class of this embodiment, the salt of formula II-a is crystalline. In
`another class of this embodiment, the salt of formula II-a is a crystalline hydrate. In another class
`of this embodiment, the salt of formula II-a is a trihydrate. In a subclass of this class, the
`trihydrate salt of formula II-a is crystalline. In another class of this embodiment, the salt of
`formula II-a is a monohydrate. In a subclass of this class, the monohydrate salt of formula II-a is
`crystalline.
`The bis(sitagliptin) phosphoric acid salt of the present invention is comprised of two
`molar equivalents of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo-[ 4,3-
`a ]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine, and one molar equivalent of
`phosphoric acid (H3P04).
`The bis(sitagliptin) phosphoric acid trihydrate salt of the present invention is comprised
`of two molar equivalents of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-
`a ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine, one molar equivalent of phosphoric
`acid (H3P04), and three molar equivalents of water.
`The bis(sitagliptin) phosphoric acid monohydrate salt of the present invention is
`comprised of two molar equivalents of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-
`dihydro[l,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine, one
`molar equivalent phosphoric acid (H3P04), and one molar equivalent of water.
`Another embodiment of the present invention provides the bis-[(2S)-4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-l-(2,4,5-
`trifluorophenyl)butan-2-amine] phosphoric acid salt of structural formula II-b:
`
`-6-
`
`Merck Exhibit 2220, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`F
`
`F
`
`F
`
`(11-b)
`
`2
`or a polymorph, hydrate and/or solvate thereof. In a class of this embodiment, the salt of
`structural formula 11-b is a hydrate. In another class of this embodiment, the salt of structural
`formula 11-b is crystalline. In another class of this embodiment, the salt of structural formula 11-b
`is a crystalline hydrate. In another class of this embodiment, the salt of structural formula 11-b is
`a trihydrate. In a subclass of this class, the trihydrate salt of structural formula 11-b is crystalline.
`In another class of this embodiment, the salt of structural formula 11-b is a monohydrate. In a
`subclass of this class, the monohydrate salt of structural formula 11-b is crystalline.
`The salt of structural formula 11-b is comprised of two molar equivalents of (2S)-4-oxo-4-
`[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, and one molar equivalent of phosphoric acid (H3P04).
`The trihydrate salt of structural formula 11-b is comprised of two molar equivalents of
`(2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of phosphoric acid (H3P04), and three
`molar equivalents of water.
`The monohydrate salt of structural formula 11-b is comprised of two molar equivalents of
`(2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of phosphoric acid (H3P04), and one molar
`equivalent of water.
`Another embodiment of the present invention provides the bis-[ 4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)(cid:173)
`butan-2-amine] phosphoric acid trihydrate salt of structural formula ill:
`
`-7-
`
`Merck Exhibit 2220, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
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`PCT/0S2012/038917
`
`F
`
`F
`
`(Ill)
`
`2
`
`or a polymorph and/or solvate thereof.
`The salt of structural formula ID is comprised of two molar equivalents of 4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of phosphoric acid (H3P04), and three
`molar equivalents of water.
`Another embodiment of the present invention provides the bis(sitagliptin) monohydrogen
`phosphate trihydrate salt, which corresponds to the bis-[(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-
`dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine]
`phosphoric acid trihydrate salt of structural formula ID-a:
`
`F
`
`F
`
`(Ill-a)
`
`2
`
`or a polymorph and/or solvate thereof.
`The bis(sitagliptin) phosphoric acid trihydrate salt of structural formula III-a is comprised
`of two molar equivalents of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-
`a ]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine, one molar equivalent of phosphoric
`acid (H3P04), and three molar equivalents of water.
`
`-8-
`
`Merck Exhibit 2220, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
`
`PCT/0S2012/038917
`
`Another embodiment of the present invention provides the bis-[(2S)-4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine] phosphoric acid trihydrate salt of structural formula ffi-b:
`
`F
`
`F
`
`(111-b)
`
`2
`
`or a polymorph and/or solvate thereof.
`The salt of structural formula ffi-b is comprised of two molar equivalents of (2S)-4-oxo-
`4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of phosphoric acid (H3P04), and three
`molar equivalents of water.
`Another class of this embodiment of the present invention provides the phosphoric acid
`salt drug substance of structural formulae m, III-a and ID-b. Another class of this embodiment of
`the present invention provides the phosphoric acid salt drug substance of structural formula ill,
`III-a and ffi-b that comprises the crystalline trihydrate present in a detectable amount. By "drug
`substance" is meant the active pharmaceutical ingredient ("API"). The amount of crystalline
`trihydrate in the drug substance can be quantified by the use of physical methods such as X-ray
`powder diffraction, solid-state fluorine-19 magic-angle spinning (MAS) nuclear magnetic
`resonance spectroscopy, solid-state carbon-13 cross-polarization magic-angle spinning (CPMAS)
`nuclear magnetic resonance spectroscopy, solid state Fourier-transform infrared spectroscopy,
`and Raman spectroscopy or any other technique. In a class of this embodiment, about 1 % to
`about 100% by weight of the crystalline trihydrate is present in the drug substance. In a second
`class of this embodiment, about 5% to about 100% by weight of the crystalline trihydrate is
`present in the drug substance. In a third class of this embodiment, about 10% to about 100% by
`weight of the crystalline trihydrate is present in the drug substance. In a fourth class of this
`embodiment, about 25% to about 100% by weight of the crystalline trihydrate is present in the
`drug substance. In a fifth class of this embodiment, about 50% to about 100% by weight of the
`
`- 9 -
`
`Merck Exhibit 2220, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
`
`PCT/0S2012/038917
`
`crystalline trihydrate is present in the drug substance. In a sixth class of this embodiment, about
`75% to about 100% by weight of the crystalline trihydrate is present in the drug substance. In a
`seventh class of this embodiment, substantially all of the salt of structural formulae III, III-a and
`IIl-b drug substance is the crystalline trihydrate of the present invention, i.e., the salt of structural
`formulae III, III-a and III-b drug substance is substantially phase pure trihydrate.
`Another embodiment of the present invention provides the bis-[4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-l-(2,4,5-
`trifluorophenyl)butan-2-amine] phosphoric acid monohydrate salt of structural formula IV:
`
`F
`
`F
`
`(IV)
`
`or a polymorph and/or solvate thereof.
`The salt of structural formula IV is comprised of two molar equivalents of 4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of phosphoric acid (H3PO4), and one molar
`equivalent of water.
`Another embodiment of the present invention provides the bis(sitagliptin) phosphoric
`acid monohydrate salt, which corresponds to the bis-[(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-
`dihydro[l,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine]
`phosphoric acid monohydrate salt of structural formula IV -a:
`
`- 10-
`
`Merck Exhibit 2220, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
`
`PCT/0S2012/038917
`
`F
`
`F
`
`(IV-a)
`
`2
`
`or a polymorph and/or solvate thereof.
`The bis(sitagliptin) phosphoric acid monohydrate salt of structural formula IV-a is
`comprised of two molar equivalents of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-
`dihydro[l,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine, one
`molar equivalent of phosphoric acid (H3P04), and one molar equivalent of water.
`Another embodiment of the present invention provides the bis-[(2S)-4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine] phosphoric acid monohydrate salt of structural formula IV-b:
`
`F
`
`F
`
`(IV-b)
`
`2
`
`or a polymorph and/or solvate thereof.
`The salt of structural formula IV-b is comprised of two molar equivalents of (2S)-4-oxo-
`4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of phosphoric acid (H3P04), and one molar
`equivalent of water.
`Another class of this embodiment of the present invention provides the phosphoric acid
`salt drug substance of structural formulae IV, IV-a and IV-b. Another class of this embodiment
`of the present invention provides the phosphoric acid salt drug substance of structural formulae
`IV, IV-a and IV-b that comprises the crystalline monohydrate present in a detectable amount. By
`
`- 11 -
`
`Merck Exhibit 2220, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
`
`PCT/0S2012/038917
`
`"drug substance" is meant the active pharmaceutical ingredient ("API"). The amount of
`crystalline monohydrate in the drug substance can be quantified by the use of physical methods
`such as X-ray powder diffraction, solid-state fluorine-19 magic-angle spinning (MAS) nuclear
`magnetic resonance spectroscopy, solid-state carbon-13 cross-polarization magic-angle spinning
`(CPMAS) nuclear magnetic resonance spectroscopy, solid state Fourier-transform infrared
`spectroscopy, and Raman spectroscopy or any other technique. In a class of this embodiment,
`about 1 % to about 100% by weight of the crystalline mono hydrate is present in the drug
`substance. In a second class of this embodiment, about 5% to about 100% by weight of the
`crystalline monohydrate is present in the drug substance. In a third class of this embodiment,
`about 10% to about 100% by weight of the crystalline monohydrate is present in the drug
`substance. In a fourth class of this embodiment, about 25% to about 100% by weight of the
`crystalline mono hydrate is present in the drug substance. In a fifth class of this embodiment,
`about 50% to about 100% by weight of the crystalline monohydrate is present in the drug
`substance. In a sixth class of this embodiment, about 75% to about 100% by weight of the
`crystalline mono hydrate is present in the drug substance. In a seventh class of this embodiment,
`substantially all of the salt of structural formulae IV, IV-a and IV-b drug substance is the
`crystalline monohydrate of the present invention, i.e., the formulae IV, IV-a and IV-b salt drug
`substance is substantially phase pure monohydrate.
`Another embodiment of the present invention provides the ammonia phosphoric acid salt
`of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine of structural formula V:
`
`F
`
`F
`
`(V)
`
`or a polymorph, hydrate and/or solvate thereof.
`The salt of structural formula V is comprised of one molar equivalent of 4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`
`- 12 -
`
`Merck Exhibit 2220, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
`
`PCT/0S2012/038917
`
`trifluorophenyl)butan-2-amine, one molar equivalent of ammonia (NH3), and one molar
`equivalent of phosphoric acid (H3P04).
`Another embodiment of the present invention provides the sitagliptin ammonia
`phosphoric acid salt, which corresponds to the ammonia phosphoric acid salt of (2R)-4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l ,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine of structural formula V-a:
`
`F
`
`F
`
`(V-a)
`
`or a polymorph, hydrate and/or solvate thereof.
`The sitagliptin ammonia phosphoric acid salt of structural formula V -a is comprised of
`one molar equivalent of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4 ]triazolo[ 4,3-
`a ]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine, one molar equivalent of ammonia
`(NH3), and one molar equivalent of phosphoric acid (H3P04).
`Another embodiment of the present invention provides the ammonia phosphoric acid salt
`of (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine of structural formula V-b:
`
`F
`
`F
`
`or a polymorph, hydrate and/or solvate thereof.
`
`(V-b)
`
`- 13 -
`
`Merck Exhibit 2220, Page 14
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
`
`PCT/0S2012/038917
`
`The salt of structural formula V-b is comprised of one molar equivalent of (2S)-4-oxo-4-
`[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8.H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of ammonia (NH3), and one molar
`equivalent of phosphoric acid (H3P04).
`Another embodiment of the present invention provides the ammonia phosphoric acid 2.5
`hydrate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[ 4,3-a]pyrazin-7(8.H)-yl]-
`1-(2,4,5-trifluorophenyl)butan-2-amine of structural formula VI:
`
`F
`
`F
`
`(VI)
`
`or a polymorph and/or solvate thereof.
`The salt of structural formula VI is comprised of one molar equivalent of 4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8.H)-yl]-l-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of ammonia (NH3), one molar equivalent of
`phosphoric acid (H3P04), and 2.5 molar equivalents of water.
`Another embodiment of the present invention provides the sitagliptin ammonia
`phosphoric acid 2.5 hydrate salt, which corresponds to the ammonia phosphoric acid 2.5 hydrate
`salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8.H)-yl]-1-
`(2,4,5-trifluorophenyl)butan-2-amine of structural formula VI-a:
`
`F
`
`F
`
`(VI-a)
`
`- 14 -
`
`Merck Exhibit 2220, Page 15
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2012/166420
`
`PCT/0S2012/038917
`
`or a polymorph and/or solvate thereof.
`The sitagliptin ammonia phosphoric acid 2.5 hydrate salt of structural formula VI-a is
`comprised of one molar equivalent of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-
`dihydro[l ,2,4 ]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine, one
`molar equivalent of ammonia (NH3), one molar equivalent of phosphoric acid (H3P04), and 2.5
`molar equivalents of water.
`Another embodiment of the present invention provides the ammonia phosphoric acid 2.5
`hydrate salt of (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)(cid:173)
`yl]-1-(2,4,5-trifluorophenyl)butan-2-amine of structural formula VI-b:
`
`F
`
`F
`
`(Vl-b)
`
`or a polymorph and/or solvate thereof.
`The salt of structural formula VI-b is comprised of one molar equivalent of (2S)-4-oxo-4-
`[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[ 4,3-a ]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine, one molar equivalent of ammonia (NH3), one molar equivalent of
`phosphoric acid (H3P04), and 2.5